Madeleine D. Kraus, MD, and Mark R. Wick, MD
In the years following the second edition of this book, multiple updates to the diagnostic criteria for hematologic proliferations have been published. These include new phenotypic and genotypic entities and also new insights into the predictive and prognostic markers required for risk stratification and treatment planning. Many are summarized in 2016 updates1-3 and will be formalized and further detailed when the full World Health Organization (WHO) document a touchstone for Neoplastic Hematopathology is published. New insights into the diagnosis and subclassification of thymic neoplasms,4 follicular lymphomas,5 the family of human herpesvirus (HHV)-8-related lymphomas,6 and the previously somewhat neglected category of T cell lymphomas7-9 are well established. Immunoglobulin (Ig)G4 disease has become firmly established as an entity, and lung involvement is now well characterized in the literature. At the same time, molecular profiling has expanded beyond large B cell lymphoma to develop predictive and prognostic perspective on multiple types of hematologic disease.10-15
A constant in this area is that morphologic, immunophenotypic, and immunoarchitectural features still drive the essential diagnosis of reactive and neoplastic proliferations, with genotypic data providing further resolving power when overlapping results cloud the distinction between specific entities. What has changed, though, is that the clinical team is increasingly taking an initial minimally invasive approach that yields quantitatively limited biopsy samples. To not squander material on useless tests, the pathologist managing the case must develop an accurate and tight differential diagnosis and be able to effectively use a broad array ofimmunohistochemistry (IHC), cytogenetic, and molecular genetic assays. Additionally, as regulatory control tightens, payers no longer reimburse if There is the perception of duplicate testing (e.g., both flow cytometry and IHC based cellular immunophenotyping).
This chapter describes the tests and techniques of hematopathology and the diagnoses that these tests enable.
Special Studies
Immunohistochemistry
Indications
Testing is performed to define the architecture of lymphoid neoplasms and their relationship to the tissue’s infrastructure (e.g., alveoli, bron- chiolar epithelium, vessels), to correlate the phenotype of specific cell populations with morphologic findings, and to identify clinically significant phenotypic variants of certain lymphomas.13-16
Specimen Requirements
Well-fixed and thinly sectioned (i.e., 0.2- to 0.3-cm thick slices of excisional specimens) tissue that has been in formalin for at least 6 hours is required. Rush processing of core biopsies should be undertaken only if the protocol has been tested and is known to yield satisfactory cytomorphology and immunohistochemical results. Some hematologic markers yield weak or nonreactive results in B5-, Bouin-, and Hollande- fixed tissue, even though the stain works well on formalin-fixed tissue from the same patient. Acidified zinc-formalin (AZF) preparations perform exceptionally well with most hematologic markers, and they may be the best choice for laboratories wishing to work without mercury and picrate.
Immunophenotypic analysis of tissue sections is an essential part of the evaluation of hematolymphoid proliferations in both nodal and extranodal sites. The number antibodies available for paraffin-embedded material continues to expand, but most differential challenges can be resolved with a handful of markers. Table 16.1 lists markers that cover all of the entities described in this chapter. Boxes 16.1 and 16.2 describe panels and the manner in which they might be used.
The judicious and cost-effective use of immunostains is maximized if the pathologist puts each marker ordered to specific purpose.15,17-19 In the work-up of hematolymphoid lesions of the lung, there are five principal goals:
1. Define the lineage. Is the lesional cell population of T lineage? B lineage? Histiocytic? Myeloid?19-21
2. Identify immunoarchitectural landmarks. Is the follicular dendritic meshwork in its normal compacted state, or are the edges frayed and the cell bodies more widely dispersed than usual? Is the mantle zone present or overrun? In the lymph nodes, are sinuses present but compressed, or are they entirely effaced?18,15,22
3. Document the aberrant phenotype that is indicative of neoplasia. Is the CD20+ cell population also positive for CD5 or CD43? Is There a restricted pattern of immunoglobulin light-chain expression? Is There a double-positive or double-negative CD4/CD8 profile on the T cells?18
4. Distinguish clinically different but morphologically similar entities.23 Is this a B lineage or a T lineage anaplastic lymphoma? Is this Burkitt lymphoma or a high-grade large cell lymphoma?23 Is this a cyclin D1+ large cell lymphoma or a mantle cell lymphoma?14,15,24 Does this T cell lymphoma express anaplastic lymphoma kinase (ALK) protein?25
5. Identify the presence of pathogenic viral or other infectious agents. Is this immunoblast-rich process Epstein-Barr virus (EBV) driven? Is HHV-6 or HHV-8 involved? Could the necrotizing lymphadenitis be due to herpes simplex virus (HSV)?
In working up hematologic tumors in the lung, the pathologist needs to be aware of certain pitfalls.17 It has long been recognized that CD138 (syndecan 1) marks both plasma cells and a range of epithelial tumors. More recently, PAX-5 has been shown in a broad range of neuroendocrine tumors,26 including small cell carcinoma and Merkel cell carcinoma.27 These studies show that, especially in the evaluation of lung tumors, no one marker should be the sole basis on which the B cell nature of a lung process is defined.28 Other pitfalls were reviewed recently by Yaziji and Barry.17
Requesting that immunohistochemical stains be performed in a specific sequence on sequentially obtained serial sections can be of immeasurable help. Performing semiquantitative assessment of cytoplasmic light-chain expression is easier if the kappa and lambda stains are performed on two sequential sections with essentially the same population of plasma cells. Similarly, if an assessment for follicular colonization is the goal, requesting that the CD20, CD3, bcl2, bcl6, and CD21 stains be performed on sequential serial sections usually allows evaluation of these markers in the same follicle/germinal center to be made.
Flow Cytometry
Indications
Flow cytometry is performed to define the lineage and cellular subsets within the lineage, (e.g., B cells that are monotypic/restricted or polytypic/ nonrestricted expression), to assess for aberrant and disease-defining coexpression or loss of expression of certain markers (e.g., CD5 expression on mantle cell lymphoma and loss of CD5 expression on a peripheral T cell lymphoma), or to identify and characterize maturational markers on myeloid and monocytic lineage cell populations.
Specimen Requirements
Fresh (nonfixed) tissue is held in tissue culture media (e.g., RPMI) if not processed immediately. The quantity varies according to how tightly the lesional cells are held in a fibrotic or reticulin meshwork. In a cellular, nonfibrotic lymph node, as little as a 0.5-cm cube may suffice, but in sclerotic mediastinal tissue, a larger piece of tissue may be needed for full analysis. As a guide in individual cases, in general, if a touch preparation makes a richly cellular slide, then the lower limit may suffice, but if only few cells adhere to the slide, attempting flow cytometry may be a fruitless expenditure of tissue for flow cytometry when IHC would be more likely to yield the diagnosis.
An advantage of flow cytometry over tissue section immunophenotyp- ing is that three or four markers can be evaluated simultaneously on specific small- and large-cell populations. trough this detailed multiparameter profile, many lymphoproliferative disorders can be classified more accurately.20,29-31 However, flow cytometric phenotyping does not allow for visualization of the immunoarchitecture of the proliferation, which can be an important element of accurate classification of lymphomas, particularly in the lung, where marginal zone lymphoma (MaZL) is so common. In tissue section-based immunophenotyping, the pathologist can readily identify situations in which the lesional foci have disappeared from the sections used for the stains. In flow cytometric immunophenotyping, however, the pathologist must ensure that the lesional cells are present on a cytospin made from the disaggregated cells.
With the rise of reference laboratories and the ease in sending out fresh tissue for flow cytometry, some pathologists without specialty training in hematopathology may be asked to interpret the histograms and data from such analyses. Attempting to simply “call it by the numbers” extracted from the histograms by the technician risks misrepresenting the data. The pathologist should first check to see that the cytospin contains the cells of interest and then determine from the histograms whether they have been appropriately selected (“gated”) for analysis. For instance, blasts, which are almost always very dimly CD45+, will not be present in the CD45-bright lymphocyte gate and will be missed if only the CD45-bright region data are analyzed. If the lesional cells are large, the low forward scatter CD45-bright small lymphocyte gate contains a polytypic population of B cells, and the only clue to clonality is present in a separately analyzed high forward scatter, CD45-bright large cell gate.
Table 16.1 Antibodies Useful in the Paraffin Section Evaluation of Hematolymphoid Proliferations
|
Marker |
Description |
|
B Cell Lineage Markers |
|
|
CD10 |
Positive in follicle center cell non-Hodgkin lymphoma (not lineage-specific; also present on some epithelial and stromal tumors) |
|
CD19 |
Early B cell marker (also present on B-LBL; not present on plasma cells) |
|
CD20 |
Mature B cell marker (not present on B-LBL; most plasma cells negative) |
|
CD23 |
Activated B cells |
|
CD79a |
lmmature and mature B cells (present on B-LBL as well as plasma cells) |
|
PAX5 |
lmmature B cells, including lymphoblasts, mature B cells; negative in plasma cells; also positive in some neuroendocrine tumors, including small cell carcinoma |
|
CD138 |
Plasma cells, some cases of classic Hodgkin lymphoma |
|
MUM1 |
ln the proper context, postfollicular B cells and plasma cells |
|
IgD |
lmmunoglobulin heavy-chain delta, present in benign mantle cells, some lymphomas |
|
к, X |
Immunoglobulin light chains (cell surface expression assessed by flow; cytoplasmic expression by IHC) |
|
T Cell Lineage Markers |
|
|
CD1a |
Some immature T cells (thymocytes), Langerhans cells |
|
CD2 |
Pan T cell marker; may also be present on natural killer cells by flow cytometry |
|
CD3 |
T cells |
|
CD4 |
Helper/suppressor T cells |
|
CD5 |
Preferential T cell marker (also positive in some B cell neoplasms) |
|
CD7 |
T cells, some natural killer cells |
|
CD8 |
Cytotoxic T cells |
|
CD43 |
Preferential T cell marker (also positive in some B cell neoplasms and granulocytic proliferations) |
|
CD56 |
Natural killer cells and some T cells; also positive in some neuroendocrine tumors |
|
CD57 |
Natural killer cells and some T cells; also expressed on some neuroendocrine tumors |
|
Monocyte/Macrophage/Accessory Cell Markers |
|
|
CD1a |
Langerhans cells, some T cells (thymocytes) |
|
CD14 |
Monocytes (paraffin markers available, not widely used) |
|
CD15 |
Granulocytes, also positive in Hodgkin lymphoma and adenocarcinoma |
|
CD21 |
Follicular dendritic cells, some B cells |
|
CD31 |
PECAM-1; marks vascular endothelium and monocytes, macrophages, and histiocytes |
|
CD33 |
Granulocytes (paraffin marker available, not yet widely used) |
|
CD68 |
Macrophages, monocytes (two clones; KP1 and PGM1 have slightly different specificities) |
|
CD163 |
Hemoglobin scavenger receptor; expressed on macrophages and histiocytes, including histiocytic malignancies |
|
Langerin |
Langerhans cells, both in Langerhans cell histiocytosis and Langerhans cell sarcoma |
|
Miscellaneous Markers |
|
|
ALK1 |
Positive in some peripheral T cell lymphomas, also in some inflammatory myofibroblastic tumors |
|
bcl6 |
Transcriptional regulator positive in germinal center B cells as well as some lymphoblasts; may be positive in the lesional cells of some T cell neoplasms |
|
bcl2 |
Anti-apoptosis protein positive in virtually all lymphoid proliferations except benign germinal center B cells and Burkitt lymphoma |
|
Cyclin D1 |
Cell cycle regulator positive in mantle cell lymphoma, myeloma, and rare cases of large B cell lymphoma |
|
CD45 |
Leukocyte common antigen present on lymphocytes, blasts, monocytes, and L&H type Reed-Sternberg cells |
|
Oct2 |
Transcription factor in some B and T cells; also present in L&H type Reed-Sternberg cells |
|
TdT |
Terminal deoxynucleotidyl transferase, a marker of the blastic stage |
|
EMA |
Epithelial membrane antigen (positive in some large cell lymphomas and some plasmacytomas) |
|
Ki67 |
Proliferation marker that helps to identify proliferation centers in chronic lymphocytic lymphoma/small lymphocytic leukemia and is also useful in the multiparameter distinction of high-grade large B cell lymphoma and Burkitt lymphoma |
B-LBL, B cell lymphoblastic lymphoma; lg, immunoglobulin; IHC, immunohistochemistry; L&H, lymphocytic and histiocytic; PECAM, platelet-endothelial cell adhesion molecule.
Flow cytometry yields continuous data that may be reported relative to the gated population (“32% of the gated CD45-dim+ cells are CD34+ blasts”) or relative to the total cellularity of the specimen (32% of the gated cells are CD34+ blasts, and the gate contains 2.4% of the total cellularity, so CD34+ blasts account for 0.6% of the total cellularity). If the pathologist is not personally extracting the numbers from the histograms, care should be taken to understand and clearly state which type of result is being presented. The difference between 32% blasts and 0.6% blasts in the example would, for instance, lead to different diagnoses.
Most reference laboratories performing flow cytometry have established panels for specific clinical scenarios (lymphoma panel, adult leukemia panel, pediatric leukemia panel, expanded T cell panel) that are tailored to efficiently identify the classic immunophenotypic profiles characteristic of common disease entities.32-35 the appropriate panel should be used to address the diagnostic question. Perhaps 10% to 15% of the time, however, a particular lymphoma or leukemia will have a variant phenotype.35,36 Examples include a lack of CD10 in a lymphoma of follicular origin, acquisition of CD10 in hairy cell leukemia, CD5 expression in large cell lymphoma, CD19 expression in acute myeloid leukemia, apparent dim CD23 expression in mantle cell lymphoma, and a lack of CD23 expression in chronic lymphocytic leukemia. For this reason and because the immunoarchitecture is an important part of the disease definition for some lymphomas, both flow cytometry and IHC may need to be performed in some cases; if the report provides sufficient detail regarding the rationale, this may minimize the billing implications of such an approach.
Cytogenetics
Indications
Karyotype testing is indicated whenever preliminary assessment suggests a high-grade lymphoma (tumoral necrosis with a brisk mitotic rate), a blastic process, or a myeloid disorder, and for all pediatric biopsy specimens in which lymphoma or leukemic involvement is possible or likely.
Specimen Requirements
Classic cytogenetic testing requires fresh (nonfixed) tissue taken sterilely (preferably in the operating room with a sterile scalpel and forceps) and transported in sterile tissue culture media to the laboratory performing the testing. Fluorescence in situ hybridization (FISH) can be performed on disaggregated cells left over from flow cytometry (if kept refrigerated) or on formalin-fixed, paraffin-embedded tissues.
Many leukemias and lymphomas have recurring chromosomal translocations that can be identified with FISH and classic cytogenetic testing.37-46 These tests are widely available at many referral laboratories, and the competition and automation have done well in bringing the price down on what used to be very expensive methodologies. Nonetheless, in an era in which patients have taken on greater responsibility for the cost of care through deductibles and coinsurance, it is important for the clinician and pathologist to work together to avoid a “shotgun” approach to test ordering while the sample is fresh. In circumstances in which There is sufficient tissue, keeping the material for cytogenetics on hold until the permanent hematoxylin and eosin (H&E) sections are reviewed will allow the pathologist to make an informed decision about whether karyotype or FISH is necessary, and if FISH is required, the most appropriate algorithm or panel must be determined.
One of the most important applications of cytogenetics is in distinguishing between morphologically similar tumors with widely different aggressiveness or treatment protocols. The distinction between small lymphocytic lymphoma and mantle cell lymphoma is an example of the first type, and the distinction between Burkitt lymphoma and high- grade large B cell lymphoma is an example of the second type. Although some translocations are characteristic of certain diseases, not all are as specific for a particular entity as once believed. For instance, c-myc-related translocations were once believed to be specific for Burkitt lymphoma, but they are now known to be present in some large B cell lymphomas and in some lymphomas that populate the new WHO category of B cell lymphoma unclassifiable with features intermediate between high-grade large B cell lymphoma and Burkitt lymphoma42,47 (discussed later). The most common and clinically relevant karyotypic changes related to leukemias and lymphomas are enumerated in Table 16.2.
Molecular Genetics
Indications
Molecular genetic testing is performed to document clonality in B or T lineage proliferations, to identify specific disease-defining rearrangement events (translocations), and to assess for genetic abnormalities that distinguish among chronic myeloproliferative disorders.
Specimen Requirements
The use of formalin-fixed, paraffin-embedded material for polymerase chain reaction (PCR) is standard, although if peripheral blood or bone marrow is extensively involved, these tissues may be suitable alternatives. Some referral laboratories can also use fresh cells if they remain viable during transport and if the quality of DNA and RNA remains high. Some nonformalin fixatives are acceptable (e.g., Histochoice, Amresco, Solon, Ohio), but B5, Hollande, and Bouin fixatives denature the DNA and are not suitable for PCR analysis. There fore, care should be taken during prosection to include sufficient tissue in formalin to allow for molecular studies if preliminary findings on touch preparations or frozen section suggest an hematolymphoid process.48
Table 16.2 Cytogenetic Analyses Associated With Lymphoid Lymphomas and Leukemias That May Primarily or Secondarily Involve the Lung
|
Disease |
Abnormality |
Implicated Loci |
Percentage of Affected Cases |
|
B cell lymphoblastic lymphoma |
t(9;22)(q34;q11.2) |
bcr/ABL1 |
|
|
t(V;11q23) |
MLL |
||
|
t(12;21)(p13;122) |
TEL/AML1 |
||
|
t(1;19)(q23;p13.3) |
E2A/PBX1 |
||
|
t(5;14)(q31;q32) hyperdiploidy |
IL3/IgH |
||
|
T cell lymphoblastic lymphoma |
t(14;10)(q11.2;q24) |
TcR delta/HOX11 |
|
|
t(14;5)(q11.2;q35) |
TcR delta/HOX11L2 |
||
|
B cell chronic lymphocytic leukemia |
Trisomy 12 |
ATM |
20% of cases |
|
del (13)(q14.3) |
~15% of cases |
||
|
del (11)(q22-q23) |
~15% of cases |
||
|
del (17)(p13)(p53) |
~10% of cases |
||
|
T cell prolymphocytic leukemia |
inv 14(q11;q32) t(14;14)(q11;q32) |
TCL1 |
|
|
Follicle center cell lymphoma |
t(14;18)(q32;q21) |
IgH-bcl2 |
Common |
|
t(2;18)(p11;q21) |
IgL-bcl2 |
Rare |
|
|
t(18;22)(q21;q11) |
IgL-bcl2 |
Rare |
|
|
t(3;14)(q27;q32) |
bcl6-IgH |
Rare |
|
|
Mantle cell lymphoma |
t(11;14)(q13;q32) |
bcl1-IgH |
— |
|
Mucosa-associated lymphoid tissue/marginal |
Trisomy 3 |
API2-MLT |
20% of cases |
|
zone lymphoma |
Trisomy 18 |
IgH-MLT1 |
5%-10% of cases |
|
t(11;18)(q21;q21) |
30%-50% cases |
||
|
t(14;18)(q32;q21) |
5%-10% cases |
||
|
t(1 : 14)(p22q32) |
5% of cases |
||
|
Large B cell lymphoma |
t(3q27;V) |
bcl6—variable partners |
|
|
Double-hit B-cell diffuse large cell lymphoma |
(14;18)(q32;q21) with t(8;14)(q24;q32) |
— |
— |
|
High-grade B large cell lymphoma, not otherwise |
Complex karyotypes including c-myc |
See text |
— |
|
classified |
translocations |
||
|
ALK+ large B cell lymphoma |
t(2;17)(p23;q23) |
ALK/clathrin |
— |
|
Burkitt lymphoma |
t(2;8)(p12;q24) |
IgL-c-myc |
Almost always an isolated |
|
t(8;14)(q24;q32) |
c-myc-IgH |
karyotypic abnormality |
|
|
t(8;22)(q24;q11) |
c-myc-IgL |
||
|
T y/δ hepatosplenic lymphoma |
iso7q10 |
— |
— |
|
T cell anaplastic large cell lymphoma |
t(2;5)(p23;q35) |
NPM1-ALK (80% of cases) |
— |
|
t(1;2)(q25;p23) |
TPM3/ALK (10%-15% cases) |
PCR analysis may be used on formalin-fixed, paraffin-embedded material, or archived snap-frozen tissue to document clonality,49-52 define lineage, evaluate for certain translocation events, and assess for the presence of infectious agents. PCR may also be used to speciate mycobacterial organisms. Clonality is assessed by examination of areas of the immunoglobulin heavy- and light-chain loci or the T cell receptor a/p or у loci that are rearranged during normal lymphoid development.53 Specially designed primer sets that flank certain gene loci are used for PCR-based evaluations for certain translocations, a helpful solution when There are no commercially available FISH probes or if tissue suitable for FISH is not available.
As “objective” as they are, molecular genetic tests do not replace the thought process of diagnosis. These test results are adjunctive data that point in one direction or another, but the final diagnosis must be made by the pathologist.54 the results of molecular studies must be integrated into the “big picture” painted by the clinical setting, the morphologic findings, and the immunophenotypic results. Although clonality is used to define neoplasia, lack of clonality does not prove that a lesion is reactive. The finding of an oligoclonal band is meaningless to the treating physician unless the pathologist puts the result into the context of the morphologic and clinical data. Low tumor cell numbers in Hodgkin lymphoma, lymphomatoid granulomatosis, and T cell-rich B cell lymphoma may yield nonclonal results because of the dilutional effect of reactive cells. Similarly, non-B, non-T cell malignancies, such as natural killer cell lymphomas and myeloid leukemias, yield a polyclonal smear because the lesional cells are of neither B cell nor T cell lineage.
Frozen Section Issues
Because of the timeliness of diagnosis and the completeness of classification of hematolymphoid proliferations, special handling of the tissue is required. Routinely handled formalin-fixed tissue is often all that is necessary, but occasionally, lack of fresh tissue for flow cytometry or cytogenetic testing can delay the diagnosis or even prevent classification. By chance or design, those affected are often the sickest patients, and delay in diagnosis introduced by a lack of tissue appropriate for ancillary testing can be frustrating to both the clinician and the pathologist. When the quantity of lesional tissue is limited, performing a frozen section with the idea of delivering a preliminary diagnosis can have the unintended consequence of delaying the case. The frozen tissue is not suitable for flow cytometry, and the embedding material may contain interfering substances that decrease the sensitivity of FISH and reduce the interpretability of immunohistochemical stains.
Under ideal circumstances, there fore, it is important to talk to the patient’s pulmonologist as well as the surgeon. If a patient with known or suspected hematologic disease is undergoing thoracoscopic or open- lung biopsy, tissue should be set aside sterilely in the operating room for culture, cytogenetic testing, or both, and the remainder should be sent for immediate evaluation of the quantitative adequacy and distribution of tissue for all appropriate ancillary studies. Touch imprints stained with H&E or Diff-Quik (Dade Behring, Newark, Delaware) can quickly discriminate among necrotizing, granulomatous, and neoplastic infiltrates, and they are fine means of addressing the difficult differential diagnosis of lymphoblastic, Burkitt, Burkitt-like, and high-grade large B cell lymphomas. Air-dried or alcohol-fixed imprints can be used for enzyme histochemistry (myeloperoxidase) as well as for FISH, and most clinical microbiology laboratories have established protocols for pneumocystis, fungal, and acid-fast stains on smears.
If the lesion is cellular and lymphoid, and if at least 1 cm3 of tissue is available, then half of the tissue should be sent to the flow laboratory for analysis and the other half fixed in formalin or AZF fixative. The flow laboratory should retain unstained, unfixed disaggregated cells in tissue culture media so that it can be sent for FISH analysis if initial studies warrant. If There is more than 1 cm3 of lesional tissue, taking some for nonformalin fixation allows for assessment of nuanced cytologic detail.
Unless There is a compelling clinical question requiring resolution in the next 24 hours, frozen sections should be performed only when touch imprints do not provide sufficient information for triaging tissue. Important questions include: Of what value to the patient is this frozen section diagnosis likely to be? Am I ready to confidently diagnose or exclude lymphoma (or, for that matter, acute leukemia) from the diagnosis based on a frozen section? Can I distinguish MaZL from follicular lymphoma with marginal zone differentiation or an unusual hyperplasia without the help of flow cytometry? Am I ready to make a definitive distinction among a necrotizing infection, lymphomatoid granulomatosis, and high-grade lymphoma? If not, then the frozen tissue has not advanced the patient’s care significantly, but it has rendered a portion of the specimen suboptimal for permanent section histology and IHC.
Normal Lymphoid Tissue in the Lung and the Concept of Mucosa-Associated Lymphoid Tissue
The lung contains an extensive lymphatic network that channels antigen- rich lymph centripetally toward the parenchymal, septal, hilar, and mediastinal lymph nodes. Organized lymphoid tissue in the periphery of the normal lung is limited to sparse submucosal aggregates of lymphocytes and intrapulmonary lymph nodes, but it can be more substantial centrally and along bronchiolar branch points.55 Inhaled particulate matter is trapped in the mucus layer of the proximal airways, and some passes across patches of specialized epithelium, where it initiates primary and secondary immune responses. Inhaled irritants stimulate a principally monocyte/macrophage response, whereas inhaled immunogens promote a lymphocytic (or lymphoplasmacytic) response. In practice, inhalational exposures are seldom purely one or the other, and so the tissue response tends to be mixed and is not infrequently masked by fibrinous exudates and actively phagocytic macrophages. The lymphoid tissue proliferates as a result of nonexogenous stimuli as well. In autoimmune conditions and immunodeficiency states, there is an intrinsic dysregulation of lymphoid proliferation, and the lymphoid hyperplasia—acquired mucosa-associated lymphoid tissue (MALT) or bronchus-associated lymphoid tissue30,56-58 is less masked by acute-phase mucosal changes. Intrapulmonary lymph nodes, also a part of the pulmonary immune surveillance system, are uncommon, but when they are found, they are more often solitary, peripherally located, and located in the lower lung field. Their structure and immunoarchitectural compartments, and the diseases that affect them, are no different from those of extrapulmonary lymph nodes.
In addition, MALT has a close and specific relationship to the adjacent alveolar and bronchiolar epithelium, the lymphoepithelium, where antigen processing and presentation occur. Benign MALT has a distinctive immunoarchitecture with discrete compartments: the B cell-rich follicles, the mantle, and the T cell-rich interfollicular regions. In some cases and in some areas, a marginal zone of intermediate-sized cells with moderate to abundant amounts of cytoplasm may be interposed between the mantle and the interfollicular regions, although this marginal zone is never as well developed as it is where MALT was originally recognized in the spleen and Peyer patches (Fig. 16.1). The lymphocytes in these structures shuttle between the mucosa and the circulation to provide ongoing immune surveillance and response to antigens that diffuse through the airways. Between follicles, lymphocytes range from small and resting to intermediate in size and somewhat activated. Plasma cells may be commingled, but none have Dutcher bodies. Where immunoblasts are present, their regular size, round nuclear shape, and smooth nuclear contour support a benign interpretation.
Figure 16.1 (A) Benign mucosa-associated lymphoid tissue accumulates adjacent to the airways after exposure to immunogenic material. The proliferation represents a mixture of B and T lineage lymphocytes, with a structure that loosely recapitulates germinal centers. The marginal zone is seldom so well developed as it is in the spleen. (B) When it is developed, consideration should be given to an evolving lymphoproliferative disorder.
Table 16.3 Comparison of Marginal Zone Lymphoma With Benign Lymphoid Proliferations in the Lung
|
Nodular Lymphoid Hyperplasia |
Lymphoid Interstitial Pneumonia |
Marginal Zone Lymphoma |
|
|
Clinical features |
Adults > children ± altered immune state |
Common in children, association with immunodeficiency |
Adults > children, association with immunodeficiency |
|
Location of infiltrates |
Peribronchiolar, septal patchy, may be multifocal A few intraepithelial lymphocytes may be present |
Interstitial, patchy, may be multifocal A few intraepithelial lymphocytes may be present |
Masslike or patternless, typically unifocal Destructive lymphoepithelial lesions are present |
|
Architecture |
Diffuse effacement of lung parenchymal structures Germinal centers are often present and sharply defined |
Expansion of tissue planes by lymphoid infiltrate Germinal centers may be present and if so are sharply defined |
Complete effacement of the normal lung parenchyma Germinal centers are often present and usually frayed and disrupted (follicular colonization; discussed later) |
|
Cellular composition |
Polymorphous array of lymphocytes, plasma cells No Dutcher bodies |
Polymorphous array of lymphocytes, plasma cells No Dutcher bodies |
Germinal centers are surrounded by a broad marginal zone with variable proportions of centrocytoid, monocytoid, and plasmacytoid cells Plasma cells with Dutcher bodies may be present |
|
Immunophenotype |
Polytypic |
Polytypic |
Monotypic; clonal B cells are negative for CD5, CD10, CD23 Follicular colonization is present (influx of CD20+, bcl2+, bcl6- B cells into a network of dendritic cells defined by CD21) |
Very limited foci of lymphocytes likely have no clinical or radiologic correlate and may not require recognition with a diagnostic line in the report. However, lymphoid accumulations that either have a radiologic correlate or clearly associate with distortions of airways or air spaces should be mentioned (Box 16.3 and Table 16.3).
Reactive Lymphoid Proliferations
Clinicopathologic Patterns of Pulmonary Lymphoid Hyperplasia
Sustained hyperplasia of the MALT of the lung occurs in the setting of autoimmune or altered immune conditions (e.g., acquired immunodeficiency, connective tissue disorders, and congenital immunodeficiency). Biopsy is performed to distinguish among superimposed infection, treatment-related pneumotoxicity, and lymphoma.
The three main patterns of lymphoid hyperplasia, follicular bronchiolitis (FB), nodular lymphoid hyperplasia (NLH), and diffuse lymphoid hyperplasia (lymphoid interstitial pneumonia [LIP]), may be seen in isolation or may coexist in the same specimen.58,59 Much of the work in identifying specific benign and malignant lymphoid proliferations requires the diagnostician to recognize the intactness or the patterned disruption of the morphologic and immunologic landmarks of normal MALT (Fig. 16.2; see also Box 16.3 and Table 16.3).
Follicular Bronchiolitis
FB is slightly more common in males than in females, involves the lungs bilaterally, and produces a centrilobular reticulonodular pattern of involvement on radiologic studies.60,61 In exceptional cases, opacities up to 1 cm in size may be seen. FB is most commonly seen in patients with congenital or acquired immunodeficiency (HIV, common variable immunodeficiency, or immunoglobulin A deficiency), collagen vascular disease (especially rheumatoid arthritis), or chronic obstructive pulmonary disease,61-64 and it may also be seen at the periphery of localized infectious processes of the lung.
Microscopically, the key feature is multiple foci of eccentric peribronchiolar accumulations of lymphoid tissue that distort and may narrow the bronchiolar lumen (Box 16.4 and Fig. 16. 3).62,65-67 Confluent nodule-forming infiltrates larger than 1 cm should raise concerns about lymphoma. The structure of benign MALT is preserved with bcl2-germinal centers that are crisply demarcated by an immunoglobulin D-positive mantle zone and a polymorphous lymphocytic and histiocytic component at the interface with normal lung parenchyma. The proliferation may compress the airways, leading to postobstructive bronchiectasis in distal parenchyma. There is no interstitial involvement in the alveolar walls away from the bronchioles, and the air spaces are uninvolved (Fig. 16.4), which is a feature that distinguishes FB from LIP.60,61,66-68 Immunophenotypic findings in FB are identical to those seen in NLH (discussed later). In the vast majority of cases of FB, no special stains are required. However, in unusual cases, a useful immunohistochemical panel would include CD20, CD3, bcl2, bcl6, MUM1, and immunoglobulin D. The expected findings include a crisp immunoglobulin D-positive mantle at least partway around the germinal centers and germinal centers rich in bcl2-, bcl6+, MUM1- B cells, all enmeshed within a compact array of CD21+ follicular dendritic cells. A cytokeratin stain may be added to assess for destructive lymphoepithelial lesions. If even a modest degree of plasmacytic differentiation is evident on hematoxylin and eosin, kappa and lambda staining will mark enough cells to aid in assessing for clonality.
Differential diagnostic considerations include nonspecific chronic inflammation,69,70 which is not organized or airway-centered and which usually extends into alveolar walls. NLH may enter into the differential diagnosis, and the distinction is as much quantitative as it is a perception of a mass-forming process that compresses adjacent normal lung parenchyma.71 Constrictive bronchiolitis may be associated with lymphocytic accumulations around the bronchioles, but the cue to the correct diagnosis is concomitant peribronchiolar fibrosis with reduction in lumen size such that the bronchiole is significantly smaller in diameter than its accompanying arteriole. An elastin stain may be helpful in defining the architecture in such circumstances.
On transthoracic and transbronchial biopsy specimens, it can be difficult to distinguish a florid focus of FB from lymphoma, largely because of the limited nature of the specimen. Monocytoid morphologic features, Dutcher bodies, monotypic plasma cells or lymphoplasmacytoid forms, and molecular testing for clonality may suggest lymphoma in amply sampled cases, but full diagnosis with classification is probably best reserved for wedge biopsy.
Nodular Lymphoid Hyperplasia
NLH is an extremely rare condition, with multiple case reports and only one large series published, representing the Armed Forces Institute of Pathology experience over a decade. In older literature, NLH has been used synonymously with pseudolymphoma, an outdated and confusing term that should be discarded.71 It is a proliferation that is most commonly seen in adults, reported in the 2nd to 9th decade. Whereas There are reports of NLH in patients with an altered immune state, such as autoimmune disorders, collagen vascular disease, or acquired immunodeficiency, there was no special relationship with those conditions in the Armed Forces Institute of Pathology series.59,71,72
Patients come to clinical attention because of cough or reasons unrelated to respiratory symptoms. One or several discrete subpleural or peripheral nodules are detected on radiography.72 If There is a reticu- lonodular pattern in the remaining lung, clinical concern for lymphoma as well as infectious etiologies is greater. In contrast to the lymphoid lesions of FB, the nodules of NLH are typically larger than 0.5 cm, but they are seldom larger than 5 cm.
The lymphoid infiltrate of NLH forms a circumscribed nodule of lymphoid tissue (Box 16.5 and Fig. 16.5), with intact architecture, including germinal centers, a discrete mantle, and a preserved paracortical interfollicular zone. The process is not pleurally based, and There should not be a bronchiolar distribution.
Figure 16.2 the normal immunoarchitecture of bronchiolar lymphoid tissue follows that seen elsewhere. Germinal centers are negative for bcl2 (A) and rich in CD21+ follicular dendritic cells (B) and bcl6+ centrocytes and centroblasts (C). (D) Ai low power, some of the follicles are polarized into light and dark zones. (E) At high power, there is a rich and heterogeneous mix of centrocytes and centroblasts, without a discernible increase in plasma cells or monocytoid cells. (F) It may be irregular in contour, but an immunoglobulin D-positive mantle is often present.
Figure 16.3 (A) Eccentric accumulation of lymphocytes around airways is the principal morphologic finding in follicular bronchiolitis. (B) the proliferation may protrude into the lumen, causing symptoms.
Figure 16.4 In follicular bronchiolitis, there is abrupt termination and a discrete boundary of the proliferation, which does not track along alveolar septa as lymphoid interstitial pneumonitis often does.
Within the mass, a follicular architecture predominates.71,73 Cells within nodules retain centrocytic and centroblastic morphologic features, and the mantle zone retains its population of small cells with deeply basophilic round nuclei and scant cytoplasm. Small resting lymphocytes, stromal elements, and plasma cells fill the interfollicular zone, which may also contain patchy accumulations of histiocytes. Lesional foci of NLH remain sharply circumscribed from the surrounding lung parenchyma, with at least a partial immunoglobulin D-positive mantle (Fig. 16.6), without significant extension along the lobar septa or into the alveolar walls, in contrast to LIP. Plasma cells with Russell bodies and Mott cells may be present, but destructive lymphoepithelial lesions, Dutcher bodies, and follicular colonization74 should not be identified.
If the nodule was not sampled for flow cytometry, a useful immunohistochemical panel includes CD20, CD21, CD3, bcl2, bcl6, and immunoglobulin D, as well as kappa, lambda, MUM1, and cytokeratin. The immunoglobulin D-positive mantle should be present and fairly crisply demarcated from the immunoglobulin D-negative germinal center inside and the immunoglobulin D-negative paracortex beyond. The germinal center cells should have a bcl2- bcl6+ phenotype. The bcl6+, CD20+ B lymphocytes within the follicles are definitionally polytypic, as are the plasma cells and immunoglobulin D-positive mantle cells. The interfollicular areas are rich in CD3+ T cells. CD21 staining in NLH highlights the compact nature of the follicular dendritic cell network (Fig. 16.7). A disrupted appearance, particularly if associated with a significant bcl2+, bcl6- or MUM1+ population of B cells within the follicles or an increase in the number of interfollicular B cells, suggests the diagnosis of MaZL (Table 16.3).59
Because of its rarity, NLH is a diagnosis that should be approached with caution and made only after all necessary studies to exclude lymphoma are performed. In practice, if neither flow cytometry nor IHC yields a secure diagnosis, molecular studies are a reasonable final step. Principal microscopic differential considerations in transbronchial or transthoracic biopsy specimens may include a particularly robust FB, LIP, and various low-grade lymphomas. In contrast to FB, NLH is mass-forming and displaces significant amounts of lung parenchyma.71 LIP is readily excluded by radiologic correlation, because it is generally diffuse and bilateral and is not mass-forming, and it is primarily interstitial, with extensive infiltration of the alveolar walls, whereas NLH displaces normal lung tissue as a mass.
In contrast to follicular lymphoma, the germinal centers of NLH are widely spaced, vary in size, exhibit light zone/dark zone polarity, and are demarcated by a distinct immunoglobulin D-positive mantle zone composed of cytologically bland small lymphocytes.47 the finding of bcl2 positivity within nodules in excess of what CD3+ intrafollicular T cells would yield, or the finding of significant numbers of bcl6+, CD20+ B cells outside of the germinal centers should raise concern about follicular lymphoma. If flow cytometry is not available, assessment for clonality and disease-defining translocations should be pursued (PCR, FISH). MUM1 immunostaining may be helpful in distinguishing follicular lymphoma from MaZL.
Marginal zone lymphoma is the most challenging element of the differential diagnosis. Because MaZL is much more common than NLH, it can be argued that molecular studies should be pursued in all cases before a benign diagnosis is rendered. The architecture may be identical to that of NLH, or There may be some blurring of the mantle zone separating the germinal centers from the intervening cellularity. A significant population of monocytoid cells (intermediate size, round or reniform nucleus, sufficient quantities of pale cytoplasm that nuclei are widely spaced on routine sections), either within or between nodules, favors MaZL. The nodules may exhibit follicular colonization by MaZL,74 which is seen as displacement of the CD20+, bcl6+, bcl2-, MUM1- centrocytes and centroblasts of the normal follicle by the MaZL cells (CD20+, bcl6-, bcl2+, MUM1+; discussed later). The mantle zone in MaZL is eroded or distorted on immunoglobulin D stain, and the follicular dendritic cell meshwork is diffused through the dilutional effects of the infiltrating MaZL cells. Although they are not diagnostic of MaZL, destructive lymphoepithelial lesions should be sought on cytokeratin stain.
Lymphoid Interstitial Pneumonia and Diffuse Lymphoid Hyperplasia
The pattern of LIP may be seen in both children and adults, and up to 40% of cases are eventually attributable to a specific underlying condition.
Figure 16.5 Nodular lymphoid hyperplasia is a discrete mass-forming lymphoid proliferation that is spherical or ovoid, in contrast to the linear parabronchial distribution of follicular bronchiolitis. (A) Germinal centers are widely spaced, vary in size, and maintain the benign immunoarchitectural landmarks seen in Fig. 16.2. (B) Pale-staining monocytoid cells seen in marginal zone lymphoma are not present.
Figure 16.6 A thin immunoglobulin D-positive mantle zone is seen in nodular lymphoid hyperplasia. Because of the close overlap with marginal zone lymphoma, even when the immunoarchitecture is reassuringly intact, flow cytometry or molecular studies are needed to confirm the polyclonal nature of the process.
Figure 16.7 the CD21 + follicular dendritic meshwork of nodular lymphoid hyperplasia is sharply circumscribed, in contrast to the ragged appearance of the network in marginal zone lymphoma, which is seen in Fig. 16.17B.
It is more common in the setting of altered immune states, such as autoimmune conditions and connective tissue disorders (especially Sjogren syndrome)75, AIDS,76,77 and congenital immunodeficiency states,75 and after bone marrow transplant. It may also be a tissue response pattern to infections such as mycoplasma, chlamydia, EBV, and Legionella7 In some series, females are affected disproportionately,60 perhaps because of the common collagen vascular disease association. Older literature doubtless includes cases of MALT lymphoma, which may skew both outcome and the clinicopathologic parameters that have been associated with LIP.
Patients with LIP present with a cough and slow but progressive shortness of breath, and radiologic studies usually show bilateral basilar patchy opacities or reticulonodular infiltrates.60,77,78-80 Cysts have been reported in LIP,81 but correlation with clinical findings suggests that the cysts are more likely a manifestation of the underlying condition (Sjogren syndrome) than of LIP. Some patients have systemic symptoms, such as fever and weight loss, and many (70%) have polyclonal hypergammaglobulinemia; both the clinical and laboratory abnormalities likely reflect the underlying altered immune state.
In contrast to architecturally disrupting pattern of FB and NLH, the infiltrate of LIP has a dominant interstitial pattern of distribution, although the constituent cellular components are otherwise similar. Small, cytologically bland lymphocytes and intermingled plasma cells distend the alveolar walls, with accentuation along the bronchovascular bundles and lobular septae (Box 16.6 and Fig. 16.8). Aggregates of histiocytes or poorly formed granulomas may be present, but neutrophils and eosinophils are scarce. A few germinal centers may be present.64,77,79 An intraepithelial component mimicking the lymphoepithelial lesions of MALT lymphoma and a coalescence in and around the microvasculature have been described, but truly destructive changes are not part of LIP (Fig. 16.9).
An LIP-like pattern has been described in the lung in the setting of atypical infectious mononucleosis.82-84 In these few reports, the alveolar walls and interstitium were expanded by a mixture of lymphocytes, plasma cells, and transformed lymphocytes (immunoblasts), and There was a patchy alveolar exudate. In situ hybridization for EBV-encoded ribonucleotides (EBERs) is the most sensitive and specific means of identifying the virally mediated nature of the process. Immunosuppressed patients are at increased risk for EBV-related lymphoid proliferations, and biopsy is usually undertaken to assess for a specific infectious process. In the transplant setting, the terminology of posttransplant lymphoproliferative disorders (PTLDs) should be used (discussed later).
'I he cellular phase of nonspecific interstitial pneumonitis may be a differential consideration in patients with an LIP-like pattern of fibroblasts and an extracellular matrix in the alveolar walls. Hypersensitivity pneumonitis may lead to cellular interstitial infiltrates, but on scanning view, the process should show bronchocentricity, and loosely formed granulomas or at least multinucleated giant cells are likely to be more prominent. Organizing pneumonia would be less typical of LIP, and if more than an occasional focus is noted, a descriptive diagnosis of chronic interstitial pneumonia with organizing pneumonia might be most appropriate.
Occasional germinal centers and focal intraepithelial accumulations of lymphocytes may prompt consideration of MaZL/MALT lymphoma, but the bilateral and interstitial (rather than unifocal and mass forming) nature of LIP, as well as the lack of a dominant B cell population in the interfollicular areas, provides a strong and objective means of excluding this possibility. Because of the interstitial distribution, dominant T cell population, and cytologic heterogeneity of LIP, distinction from pulmonary presentation of systemic lymphomas, such as small lymphocytic lymphoma, mantle cell lymphoma, or follicle center cell lymphoma, is seldom an issue. In difficult cases, or when diagnostic material is limited, IHC (CD20, CD3) usually permits a definite diagnosis (discussed later; Box 16.3 and Table 16.3).
Outcome for patients with an LIP pattern of lung disease is variable and relates largely to the underlying condition. Some patients may have spontaneous resolution, and others achieve a good response to a trial of steroids. Morbidity and mortality are most often seen in patients with superimposed infection or other comorbid conditions, such as renal failure. A subset of patients, generally with a difficult-to-control connective tissue disease, progress to end-stage fibrosis with honeycombing; thus in some cases, the prognosis is worse than that of its neoplastic lookalike, MaZL. The reported increased risk of lymphoma likely relates at least in part to the fact that some cases previously diagnosed as LIP were in fact lymphoma ab initio.
Castleman Disease
Castleman disease includes two distinct conditions. One, the hyaline vascular variant, almost invariably presents via mass effect of a solitary mediastinal mass or central lymphadenopathy in otherwise asymptomatic individuals and is cured by complete resection. The other, the plasma cell variant, has protean manifestations and multifocal disease and has significant associated morbidity and mortality. What brings them together85 is that, in historical examples, the two histologies may coexist in the same lymph node, and second, they were characterized in separate publications by the same individual, Benjamin Castleman.
Hyaline Vascular Variant
The hyaline vascular variant of Castleman disease (HVCD) arises in axial node groups of the mediastinum and abdomen, although it may extend along the hilum to involve peribronchial lymph nodes. Most patients have no systemic symptoms and present because of mass effect (e.g., airway compression or superior vena cava syndrome) or have mediastinal adenopathy detected during radiologic studies performed for other reasons.86-88 A patient who has B symptoms and diffuse adenopathy likely has a mixed type of Castleman disease, in which the histologic features of the plasma cell variant are present elsewhere (discussed later). In contrast to the plasma cell variant of Castleman disease (PCCD), there is no consistent abnormality in laboratory findings.
Figure 16.9 Lymphoid interstitial pneumonia shows composition by morphologically mature lymphocytes. Most are CD3+ T cells, a helpful feature in distinguishing this condition from marginal zone lymphoma. Lymphocytes may abut the epithelium of the distal airways, but they do not form destructive aggregations, as seen in marginal zone lymphoma and in Fig. 16.15.
At low power, the architecture is nodular, composed of small and involuted germinal centers with expansive immunoglobulin D-positive mantles formed of small lymphocytes, often in a laminated or “onion skinning” array. Multiple germinal centers may be found in the boundaries of a single mantle zone, and in opportune sections, the lymphoid depletion in the germinal centers unmasks the radially penetrating high endothelium, the “lollipop” motif (Box 16.7 and Fig. 16.10). Sinuses between the regressed follicles are imperceptible, usually because they are absent. At high power, the germinal centers are depleted of lymphocytes and contain both extracellular matrix and abundant follicle dendritic cells. The interfollicular zone includes plasmacytoid monocytes, stromal myoid cells, histiocytes, dendritic cells, and lymphocytes.89-91
Follicle dendritic cells within the germinal centers are CD21+ and S100-, and they are distributed as dense aggregates rather than as circumscribed meshworks with intermingled centrocytes and centroblasts. Their processes extend in a laminar array beyond the germinal center border such that the mantle cells align along them. The lymphocytes of the mantle zone represent a mixture of CD20+ B cells, and the plasmacytoid monocytes are both CD4+ (but CD3-) and CD68+.89’90’92 Plasmacytoid monocytes aggregate in clusters between regressed follicles, and they are demonstrable on CD123 and other stains such as HECA452 (Fig. 16.11).
Figure 16.10 (A) One of the subtle and least appreciated histologic findings in the hyaline vascular variant of Castleman disease is the absence of the sinuses that weave in between follicles. (B) the hypervascular nature of the intervening tissues, often creating the radially penetrating lollipop motif is the classic feature of Castleman disease. (C) It is also seen in other settings in which There are regressed germinal centers (e.g., HIV-related changes).
Figure 16.11 Plasmacytoid monocytes, which appear as pale lavender aggregates of cells between regressed follicles in the hyaline vascular variant of Castleman disease, are easiest to see on HECA-452 stain.
Differential diagnostic considerations may include a Castleman-like reaction to tumor93,94 and a variety of non-Hodgkin lymphomas. Mantle cell lymphoma is clonal and positive for cyclin D1, and in partially involved nodes, the sinuses may be compressed but still present. Follicular lymphoma rarely (if ever) has an immunoglobulin D-positive mantle zone that is broader than the follicle within, and the nodules are cellular and rich in bcl6+ B cells, rather than depleted. HIV-related lymph node changes, particularly the depleted form, which has regressed germinal centers, may enter the differential diagnosis and may be difficult to exclude, but the laminated array of mantle cells is generally undeveloped, plasmacytoid monocytes are few or absent, and sinuses are present and generally congested with histiocytes. The angioimmunoblastic lymphadenopathy (AILD) type of peripheral T cell lymphoma is discussed in the differential diagnosis with HVCD, because both have abnormal follicular structures, but in AILD-peripheral T cell lymphoma (PTCL), the follicles are generally enlarged and fragmented (not compressed or regressed) and flow cytometry may show the loss of a pan T cell antigen on T cells. IHC shows bcl6 expression in CD3+ T cells. Molecular studies often document at least a clonal T cell population and sometimes also a clonal B cell population. Double antibody immunostains highlight a special population of bcl6+ T cells in perivascular areas. If There is cytoatypia or a mass-forming coalescence of follicular dendritic cells, consideration should be given to an evolving follicular dendritic cell tumor (discussed later).
Outcome is excellent in patients with fully resected localized HVCD.95
Plasma Cell Variant
The PCCD is most frequently encountered in HIV-positive patients and the elderly, and presenting pulmonary symptoms include shortness of breath, productive cough, and fevers. When it involves the chest structures, PCCD is more often found in the central lymph nodes, with secondary extension into the centrilobular regions of lung tissue. Radiologic studies may show adenopathy alone or concurrent with bilateral interstitial infiltrates.96 Laboratory studies may show cytopenia, an elevated erythrocyte sedimentation rate, and hypergammaglobulinemia, hyper-IL-6 syndrome.990,97
Both localized and multicentric expressions of PCCD occur. Taken together, they are far less common than HVCD. When localized, the adenopathy is typically axial (mediastinum or abdomen and, less commonly, in the neck) and node-based. When the disease is multicentric, patients typically have generalized lymphadenopathy and hepatospleno- megaly, and they may have symptoms fitting polyneuropathy, organomegaly, endocrinopathy, M spike, skin disorder syndrome (POEMS syndrome).98
The low-power appearance is that of follicular hyperplasia with marked interfollicular plasmacytosis (Box 16.8 and Fig. 16.12). In contrast to HVCD, the subcapsular and medullary sinuses remain patent; the germinal centers are hyperplastic and large and contain amorphous eosinophilic material and have a discrete, if thinned, mantle zone.89 Because the potential for lymph nodes to be involved by more than one process (e.g., Castleman disease and Hodgkin lymphoma or plasmablastic non-Hodgkin lymphoma), a careful search for a second diagnosis should be made before the solo diagnosis of PCCD is rendered.
Flow cytometric analysis identifies only polytypic B lymphocytes and phenotypically normal T cells. Routine immunostaining shows a polytypic population of plasma cells. Careful scrutiny of the lambda light-chain stain may show a population of immunoblasts in the perifollicular region. These, all immunoglobulin M-lambda, may be monoclonal on PCR and part of a microlymphoma or polyclonal at the genetic level.89,99,100
In lymph nodes, the differential diagnosis includes rheumatoid arthritis-related lymphadenitis, syphilitic lymphadenitis, lymphoplas- macytic lymphoma, HIV-related lymphadenitis, and reactive lymph nodes draining sites of carcinoma. In the lung parenchyma itself, PCCD may closely mimic the LIP pattern, and MALT lymphoma is also an important element of the differential diagnosis. Clinical correlation, good histologic sections, and sufficient tissue to assess for follicular colonization and perform clonality studies are key to resolving this set of differential considerations.
Figure 16.12 Although the germinal centers in the plasma cell variant of Castleman disease may be depleted of lymphocytes (A), the interfollicular regions are rich in plasma cells (B) and the sinuses are preserved.
Clinically, PCCD may be smoldering or aggressive, but it is inexorable and is associated with a high rate of morbidity and mortality as a result of infection and progressive renal, hepatic, or immune system dysfunction.86,101,102 Median survival time is 2 to 3 years for patients with multicentric disease. A subset of patients has Kaposi sarcoma (approximately 10%), large cell B cell lymphoma, Hodgkin disease, plasmacytoma, myeloma, or POEMS syndrome (up to 20% in HIVpositive patients).
IgG4-related lung disease is often manifested as a mass-forming process in the lung parenchyma, though it can also present as a mediastinal mass, pleural thickening, airway thickening with narrowing, or as alveolar interstitial disease. Key histologic features in any site are (1) a dense and confluent lymphoplasmacytic infiltrate; (2) fibrosis that is at least in part storiform patterned; and (3) obliterative phlebitis. The lymphocytes are small and cytologically bland. Though the plasma cells may be numerous and some may be multinucleated, they are polytypic on tissue stains with in situ hybridization and severe nuclear pleomorphism is not expected. Eosinophils vary in number and can be prominent. Identifying the lymphangitic distribution of the lymphocytes and plasma cells and the vascular changes may be challenging, but an elastin stain can help identify the remnants of vessel walls. Importantly, the vessel lumen is obliterated, but There is no active/acute or necrotizing vasculitis.103,104 Well-formed granulomas should steer the diagnostic work-up towards infection as they are not characteristic of IgG4-related lung disease. Differential diagnostic considerations in the lung include infection (chronic bacterial, fungal, or acid-fast bacterial), granulomatosis with polyangiitis, and inflammatory myofibroblastic tumor; a sarcomatoid carcinoma is also a possibility. If the specimen has been sent fresh, reserving a piece sterilely for microbiological culture (or snap freezing for possible 16S ribosomal RNA sequencing) is prudent. An IHC panel that includes IgG4, CD20, kappa and lambda (ISH), CD3, cytokeratin, and ALK will assist in excluding alternative possibilities and aid in establishing the diagnosis.
Neoplastic and Malignant Lymphoid Proliferations
Classification of extranodal B lineage lymphomas involves an assessment of both patterned architectural disruptions and phenotypic parameters, some of which relate the lesional cells to normal stages of B cell and T cell development. By this paradigm, for instance, the characteristic features used to diagnose follicular lymphoma (a monotypic mixture of centrocytes and centroblasts, usually with CD10 and bcl6 expression) resemble those of the cells of benign follicular hyperplasia (a polytypic mixture of centrocytes and centroblasts, usually with CD10 and bcl6 expression). In contrast, those of mantle cell lymphoma and MaZL recapitulate specific aspects of mantle cell and marginal zone lymphocytes of normal tissues, respectively, though similarities may be incomplete (e.g., cyclin D1 is negative in the benign mantles of reactive lymph nodes). No such developmental principle provides structure to the classification of T lineage lymphomas, which remain more of a “laundry list” of ontogenically unrelated entities.
Primary Lung Lymphomas
Regardless of the histologic type, adults are most commonly affected, and primary pulmonary lymphoma is rare in the pediatric population. The designation of primary pulmonary lymphoma is restricted to de novo lymphomas that present with lung-limited disease. Other than hilar node involvement, no evidence of extrapulmonary disease is evident on staging at presentation or on restaging studies repeated after a short period of observation. Strictly defined, patients with primary pulmonary lymphoma should have little disease-related morbidity and mortality60,105, unless the disease acquires systemic manifestations or progresses to involve extrathoracic sites.
Mucosa-Associated Lymphoid Tissue Lymphoma
MaZL of MALT type is the most common type of primary pulmonary lymphoma. Unlike MaZL of the stomach, thyroid, and salivary gland, however, it has an inconstant association with infectious agents or specific autoimmune conditions.106-108 Recent studies have shown that 40% of cases contain a t(11;18) involving API2 and MALT1.38 Although some patients are entirely asymptomatic, many present with cough, fever, or unexplained weight loss,106-108 and radiologic studies most commonly show solitary or multiple discrete nodules.109,110 Serum protein electrophoresis is positive in up to 30% of patients, and staging shows extrathoracic disease in one third of patients. The disease is almost entirely restricted to adults. Pulmonary pathologists may encounter MALT lymphomas on thymic biopsies and resections as well.111
Following the paradigm of benign MALT, MaZL is composed of cells that morphologically and phenotypically resemble the mature B cells that form the outer rim of the malpighian corpuscles of the spleen and their counterpart in the organized lymphoid tissue of Peyer patches in the terminal ileum.106,112-114 At low power, MaZL may have a nodular or diffuse pattern, and at the periphery, the lesion may extend along intact alveolar walls in discontinuous fashion (Fig. 16.13), occasionally with a low-power beading motif. Nodularity may be inconspicuous, but where it is present, it corresponds to residual benign germinal centers that have been infiltrated (“colonized”) to a greater or lesser degree by tumor cells.74 Much of the neoplastic proliferation is present between the nodules and is composed of a mixture of small, resting lymphocytes, monocytoid cells (oval or reniform nuclei, condensed chromatin, and moderate amounts of pale-staining cytoplasm), and plasmacytoid forms (Box 16.9 and Fig. 16.14).
Figure 16.13 (A and B) Marginal zone lymphoma may involve the lung in a reticulo- nodular pattern within the interstitium. (C) These generally coalesce centrally in larger lesions to form a diffuse mass.
Figure 16.14 Although the histologic features of marginal zone lymphoma are often described as heterogeneous, in any given high-power field, a fairly uniform population of cells is present. In some areas, this is centrocytoid (A); in others, it is plasmacytoid, with Dutcher bodies (B); and in yet others, it is monocytoid (C). In all of these patterns, even the centrocytoid pattern, the heterogeneous mix of centrocytes, centroblasts, dendritic cells, and tingible body macrophages of normal germinal centers (as seen in Fig. 16.2E) is not present.
Figure 16.15 Although they are not diagnostic of marginal zone lymphoma, destructive lymphoepithelial lesions are often present and appear as aggregations of 5 to 10 small lymphocytes with sufficient cytoplasm that the nuclei stand apart (A). These can be highlighted with cytokeratin stain (B).
Because of their ontogenic relationship to lymphocytes that home to mucosal surfaces, tumor cells in MaZL have a tendency to form destructive lymphoepithelial lesions (Fig. 16.15), a characteristic feature of this disease, although one that is not independently diagnostic of neoplasia in general or MALToma in particular.59 In some cases, monocytoid morphologic features dominate, whereas in others, the cells more closely resemble centrocytes (The small cleaved cells within germinal centers). A MALToma diagnosis based on transbronchial biopsy should be approached cautiously because plasmacytoid differentiation may be so striking superficially that the differential diagnosis includes plasmacytoma115 (Fig. 16.16). With fuller representation (e.g., on wedge biopsy), a concomitant lymphoid component is often identified, however, permitting accurate classification. Occasional cases may have a few cells with intracytoplasmic crystalline immunoglobulin116119 or amyloid deposits.120-124
The lesional cells of MaZL are CD19+ and CD20+ and do not coexpress CD5, CD10, or CD23, Tdt, cyclin D1, or bcl6. In small biopsy specimens, a cytokeratin stain may help to identify lymphoepithelial lesions, and the combination of CD21, bcl2, and bcl6 stains highlights germinal centers colonized and overrun by tumor cells59,106’114 that are bcl2+, bcl6- and have a disrupted network of follicular dendritic cells (Fig. 16.17).74 Bcl10 protein expression has been shown to correlate with the presence of the t(11;18)(API2/MALT1) translocation, and a positive result by paraffin section IHC can be a helpful adjunct to classification.38
Figure 16.16 In marginal zone lymphoma, when plasma cells are present (A), immunohistochemical studies for kappa and lambda light chains should be performed. (B and C) In this case, the kappa-to-lambda ratio is greater than 10: 1, a compelling documentation of the clonality of the proliferation.
Figure 16.17 Flow cytometry in marginal zone lymphoma shows the nonspecific CD5-, CD10-, CD23- profile. The finding of follicular colonization on immunohistochemical studies helps in classification. The process is composed of CD20+ B cells (A) that are present both within and between CD21+ dendritic cell aggregates (B). The latter have ragged and moth-eaten borders, and There is no evidence of retained bcl2—, bcl6+ benign centrocytes within (C representing bcl2 stain and D representing bcl6 stain).
Although MaZL resembles NLH, the latter has a polymorphous population of lymphocytes and histiocytes in the interfollicular areas. In addition, it contains benign, “uncolonized” germinal centers with a CD20+, bcl2-, bcl6+ phenotype and has interfollicular areas rich in T cells, not B cells (Box 16.3 and Table 16.3).59 Importantly, there is no evidence of a monotypic population of B cells on flow cytometry, and NLH is nonclonal on PCR-based molecular studies. Small biopsy specimens of MaZL may have some degree of morphologic overlap with LIP, but MaZL tends to overrun normal structures and does not have the predominant interstitial localization associated with LIP. Distinction from other lymphomas rests on the findings of immuno- phenotyping studies (Boxes 16.2 and 16.3 and Table 16.3),47 although colonization of the germinal centers and heterogeneity of the lesional infiltrate are two features that favor MaZL. Distinction from follicular lymphoma with florid marginal zone differentiation125 requires careful attention to immunohistochemical assessment for follicular colonization and may also require FISH for the t(14;18) and t(11;18) translocations. It is important to be attentive to the possibility that the biopsy specimen contains more than one lymphoma, because “collisions” occur.126
Diffuse Large B Cell Lymphoma, Variants, and Subtypes
Large cell lymphoma of B cell type (B-LCL) is the second most common type of primary pulmonary lymphoma47,127,128 and most commonly affects older adults in the 6th and 7th decades. Patients present with cough or dyspnea. Most lesions are solitary, solid, and off-white, and they have a discrete border with adjacent normal lung parenchyma. A subset of B-LCL arises in patients with a preexisting or concurrent low-grade lymphoma, such as MaZL, small lymphocytic lymphoma, or follicular lymphoma. Rapidly proliferating tumors may have central cavitation as a result of tumoral necrosis.
The neoplastic nature of B-LCL is readily evident from the dominant population of large cells as well as the destructive manner in which it obliterates the lung parenchyma. The lesional cells are large (20-30 pm) and form confluent, discohesive sheets of cells. Cytologic features vary from case to case, although usually the tumor cells have coarse chromatin, distinct nucleoli, and abundant cytoplasm (Fig. 16.18). Essentially all are CD19+, CD20+, and CD79a, and those with a follicle center cell origin also express CD10 and bcl6.47
Figure 16.18 Although large B cell lymphoma most often involves the lung in a mass-forming nodular manner, on occasion, it may also have a selectively pleural distribution (A). As in the lymph nodes, pulmonary diffuse large B cell lymphomas may have centroblastic (B), polylobated (C), or large cleaved (D) histologic features.
Differential diagnostic considerations can include primary or metastatic carcinoma, metastatic melanoma, and other epithelioid malignancies (especially large cell neuroendocrine carcinoma), all resolvable with IHC. Some cases of B-LCL may have a high content of reactive T cells or histiocytes (T cell-rich large B cell lymphoma [TcRBCL]; Fig. 16.19)129 and may mimic metastatic lymphoepithelioma-type nasopharyngeal carcinoma or Hodgkin lymphoma.
Several histologic and immunophenotypic variants bear mentioning because of specific differential considerations. Although most have been reported first in lymph nodes, there is no reason why the same tumor could not involve the lung. The immunoblastic variant of B-LCL has vesicular chromatin, thick nuclear membrane, a prominent and centrally placed eosinophilic nucleolus, and abundant amphophilic cytoplasm. A morphologic variant may confer a worse prognosis47 (Fig. 16.20) and may mimic anaplastic myeloma, plasmablastic lymphoma,130 carcinoma, and melanoma as well as some dendritic cell tumors. A panel including CD138, cytoplasmic immunoglobulin (cIg), pancytokeratin, CD45, MART1, S-100, and CD21 may be helpful in such cases. The presence of CD5+ B-cell diffuse large cell lymphoma (B-DLCL)131 is rare but recognized, and where this phenotype occurs, cyclin D1 staining and well-prepared slides of well-fixed tissue can be helpful in excluding mantle cell lymphoma. ALK+ B-DLCL, although rare, is now well characterized3 (Fig. 16.21), and similar to the T cell counterpart, may mimic carcinoma, histiocytic malignancy, and melanoma. These rare variants are usually negative for CD20, CD30 (unlike their T cell counterpart), CD45, and PAX5, and positive for epithelial membrane antigen. Negative pancytokeratin results help to exclude carcinoma, and positive results for CD138, MUM1, cytoplasmic ALK1, and cytoplasmic immunoglobulin light chains point toward the correct diagnosis. FISH or PCR for the t(2;17)(ALK/clathrin) translocation is confirmatory.
In some cases, a substantial reactive population of T cells or histiocytes may disperse the lesional large B cells such that flow cytometry and molecular studies do not identify a B cell clone. T cell/histiocyte-rich large B cell lymphoma is the prototype in this category,129 and consideration can be given to lymphoepithelioma, metastatic nasopharyngeal carcinoma, and Hodgkin lymphoma of either the classic or the nodular lymphocyte-predominance type. Pancytokeratin, CD30, CD21, CD57, PAX5, and Oct2 can be used to identify such cases. Believed to reflect clonal escape of virally infected cells in older patients with age-related deterioration of immunity, EBV+ DLCL of the elderly132,133 also includes a mix of small and large cells. A cue to this diagnosis is the finding of a polymorphous spectrum of large immunoblasts, Reed-Sternberg (RS)-like cells, and medium-sized transitional lymphoplasmacytoid forms, all diluted by small, reactive lymphocytes in a patient older than 70 years. CD30 findings may be positive, making the exclusion of classic Hodgkin lymphoma difficult, although EBER/EBV-ISH positivity and strong expression of CD20 or CD79a in the large cells help to secure the diagnosis. Lymphomatoid granulomatosis is another special subtype of EBV-related B-LCL, as described later.
Figure 16.19 T cell-rich large B cell lymphoma forms masses rich in histiocytes and relatively poor in neoplastic cells. (A) Well-prepared sections are necessary to avoid misinterpreting such lesions as granulomas. (B) CD20 immunostaining shows large lymphoma cells.
Figure 16.20 the immunoblastic variant of large B cell lymphoma mimics both carcinoma and melanoma.
There are also several subtypes of B-DLCL with distinctive clinical aspects that should be addressed. An intravascular variant of B-LCL134 presents without adenopathy, organomegaly, or mass-forming lesions in solid organs and may only be recognized when the patient undergoes biopsy of sites without clinical evidence of lymphomatous involvement, including the lung (Figs. 16.22 and 16.23). The vessels are filled with aggregations of large cells with coarse chromatin and a high nucleus- to-cytoplasm ratio, clearly different from resting lymphocytes or monocytes. Although it may have a prominent pulmonary component, the disease is never restricted to the lung and should be regarded as an aggressive, systemic lymphoma from the outset.
Primary thymic/mediastinal large B cell lymphoma usually presents with mass-related symptoms (e.g., superior vena cava syndrome) in young patients, and when it disseminates, it tends to involve extranodal sites (kidney, adrenal, liver) as much as or more than the development of generalized adenopathy with marrow involvement. The tumor can closely mimic classic Hodgkin lymphoma.134,135 Because of tumor-related fibrosis (Fig. 16.24), the fragility of cells, and the known lack of surface immunoglobulin display in these tumor cells, flow cytometry may be inconclusive. Because many patients with primary thymic/mediastinal large B cell lymphoma express CD30, exclusion of classic Hodgkin lymphoma relies on assessment of the expression of Oct2, PAX5, CD20, CD79a, and CD23 and on identifying the packeting of tumor cells within long, thin slips of collagenous fibrosis (Fig. 16.25). Treatment for DLCL and treatment for classic Hodgkin lymphoma are fundamentally different, so when There is any degree of ambiguity, gene rearrangements can be pursued. This adjunctive study may not allow for complete clarity in all cases, leaving some in a “gray zone.”47
Figure 16.21 Anaplastic large B cell lymphoma is rare and can be distinguished from conventional diffuse large B cell lymphoma by the presence of hallmark cells with eccentrically placed horseshoe-shaped nuclei (A and B) and ALK expression in large CD20+ B cells.
Figure 16.22 Intravascular lymphoma is an aggressive systemic large B cell lymphoma that may present with a confusing array of signs and symptoms, including shortness of breath. The radiologic findings may be normal or may show accentuated interstitial markings. (A) Histologically, at low power, the lung may appear entirely normal. (B) At high power, and especially on immunohistochemical staining, numerous CD20+ large B cells are seen plugging the vasculature.
Lymphomatoid Granulomatosis
Although the vast majority of the cellularity of lymphomatoid granulomatosis (LyG) is of T lineage, studies have shown that the neoplastic cells in this process are a clonal population of EBV-infected B cells.136138 Consequently, LyG belongs in the category of B lineage lymphoproliferative disorders. It affects primarily adults, and many cases arise in the setting of immunodeficiency.139 Most patients have a prodromal phase of fever and nonspecific symptoms that may relate to pulmonary or sinonasal disease (cough, epistaxis). Skin, subcutaneous tissues, and the central nervous system may also be involved,140 all cues to the correct diagnosis. Radiologic studies usually show multiple opacities and nodules, with or without cavitation.141 Mediastinal adenopathy is rare. In resection specimens, the tumoral masses are centrally located within the lung and have a homogeneous off-white appearance on cut section.
Transbronchial and transthoracic biopsy specimens usually yield insufficient diagnostic material to secure the diagnosis, and a wedge biopsy is usually required. Extensive necrosis, angio occlusion, and vascular damage (Box 16.10 and Fig. 16.26) in the context of a mixed lymphohistiocytic infiltrate are the histologic hallmarks of LyG.136,140 the lymphoid component includes small cytotoxic T lymphocytes,142 intermediate-size activated forms, and large neoplastic B cells that closely resemble centroblasts or immunoblasts. The large lesional B cells are diffusely dispersed and have coarse chromatin, distinct or prominent nucleoli, and moderate amounts of cytoplasm. The process is both angiocentric (accumulations of viable cells around the arterioles and venules) and angiodestructive (mural invasion, luminal occlusions, and disruption of vessel walls), and the endothelial cells are plump and activated. Necrosis may be present and is usually focal. Diagnostic RS cells are not present, although some cells may have features reminiscent of mononuclear variants.
Figure 16.23 Some cases of intravascular lymphoma expand the interstitium, and although the findings of hematoxylin and eosin staining may be less than compelling (A), immunostaining for CD20 shows the neoplastic cells (B).
Figure 16.24 (A) In primary mediastinal large B cell lymphoma, the lymphoma cells are enmeshed within slips of collagenous fibrosis. (B) the lesional cells are large, with coarse chromatin and scant cytoplasm.
Figure 16.25 Because of the fibrosis and delicate nature of lymphoma cells, flow cytometry may yield false negative results in primary mediastinal large B cell lymphoma. Fortunately, the necessary stains for diagnosis can be performed on paraffin sections. These include positive results for both CD20 (A) and CD23 (B).
Grading is achieved by assessing the density of large lesional B cells. At the low end of the spectrum, in grade I LyG, the proliferation is polymorphous and is composed of cytologically bland small lymphocytes, plasma cells, histiocytes, and very rare large lesional cells that may be evident only on CD20 stains (Fig. 16.27) and EBER-ISH. Although EBV+ cell count would create objective and reproducible boundaries between grades, the WHO Classification of hematologic malignancies does not include this recommendation. Grade I assignment on biopsy samples should be approached with caution, since the possibility of undersampling of a higher-grade process cannot be excluded.
Greater numbers of large lesional cells (in the range of 5 to 20 cells) and more abundant levels of necrosis (Fig. 16.28) distinguish grade II LyG from grade I LyG, although the large centroblastic/immunoblastic cells remain widely dispersed and may be difficult to find on routine stains. Grade III LyG has all of the hallmark features of a high-grade lymphoma, high content of mitotically active large atypical cells and necrosis (Fig. 16.29), often in sheets and syncytia, although the small lymphoid component persists. When the angiocentric component takes on a monomorphic quality and moderate or marked atypia is noted in the small lymphocytes, the process is best classified as grade III.61,83,84
The majority of the small lymphoid component is composed of CD4+ T helper cells, with lesser numbers of CD8+ T killer cells and CD16/CD56+ natural killer cells. CD79a and CD20 staining is present in the large-cell component only, and it helps to identify lesional cells that may not be readily evident on H&E stains. Latent membrane expression and EBERs are present in the lesional large B cells but not the T cells of LyG (Fig. 16.30).141143 CD30 may be expressed, and in difficult cases, CD15, PAX5, Oct2, and other markers may be helpful in excluding classic Hodgkin lymphoma. Because lung involvement by classic Hodgkin lymphoma is rare without mediastinal involvement, radiologic correlation may also be helpful.
Figure 16.26 (A) the lymphoid infiltrate in lymphomatoid granulomatosis engulfs and infiltrates small- and medium-caliber vessel walls. (B) the media and intima are both expanded by small lymphocytes, with relatively few large neoplastic cells apparent in low-grade lesions. (C) As the process progresses, it becomes mass-like.
Figure 16.27 CD20+ neoplastic large B cells are more abundant outside of vessel walls than within the walls. In this case, overall, there were sufficient numbers of large cells to warrant the diagnosis of grade II/III disease.
Differential considerations include poorly confined fungal or bacterial infection, necrotizing viral infections such as varicella zoster or herpes infection in immunosuppressed patients, and systemic vasculitic processes such as polyarteritis nodosa and granulomatosis with polyangiitis. Granulomatosis with polyangiitis lacks the large CD20+ B cells and has neutrophil-rich necrosis with histiocyte-rich granuloma-like formations and multinucleated giant cells. Other inflammatory conditions that resemble LyG include bronchocentric granulomatosis, although the latter lacks the vasocentric and lymphocyte-rich, neutrophil/eosinophil-poor qualities that typify all grades of LyG. Because of The bimorphic population oflarge cells set within a polymorphous background lymphoid population, classic Hodgkin lymphoma (cHL) T cell/histiocyte-rich large B cell lymphoma should also be considered in the differential diagnosis with LyG. TcRBCL rarely has necrosis and does not exhibit angiocentricity with angiodestruction. The lung is an unusual site for primary presentation ofcHL; reviewing radiologic studies to assess for extrapulmonic disease and the finding of a CD15+, CD30+, OCT2(-) phenotype are helpful cues to the correct diagnosis.
Figure 16.28 Even at the point at which lymphomatoid granulomatosis is mass-forming, there are no granulomatous foci.
Figure 16.29 Grade III lymphomatoid granulomatosis has both necrosis and an abundance of large cells that are evident even on routine stains.
Figure 16.30 the lesional large cells of lymphomatoid granulomatosis are positive for Epstein-Barr virus, best evaluated by in situ hybridization for Epstein-Barr-encoded ribonucleotides.
In contrast to LyG, peripheral T cell lymphoma lacks the atypical large CD20+ cells and instead has significant cytologic atypia of small, intermediate, and large cells; patches of cells with small nuclei and abundant pale-staining cytoplasm; tissue eosinophilia; aberrant loss of a stage-specific pan T cell marker (CD2, CD3, CD5, or CD7) (Box 16.11; see also Box 16.2); and usually clonal T cell gene rearrangements by PCR analysis. If There is sinonasal disease, T/natural killer (NK) cell lymphomas of the nasal type enter the differential diagnosis. Because these T/NK lymphomas can be angiocentric and angiodestructive as well as EBV+, the presence of CD20+ lesional large cells is the distinguishing feature. An abundance of CD56+ cells and an absence of CD20+ large cells favor NK cell lymphomas of the nonnasal type.
Hodgkin Lymphoma
Hodgkin lymphoma is a tumor of lymphoid lineage144,145 in which the neoplastic cells are in the vast numeric minority. 'There are two categories, classic Hodgkin disease and lymphocyte-predominance Hodgkin lymphoma (LPHL), with the distinction based on the phenotype of the lesional cells as well as the nature of the background infiltrate. Most patients with pulmonary Hodgkin lymphoma present with concomitant node-based or mediastinal disease, and the diagnosis is established by lymph node biopsy. In occasional cases, however, clinical, pathologic, and radiologic staging shows only pulmonary involvement, invariably mass-forming rather than interstitial (Box 16.12 and Fig. 16.31).145
Distinguishing RS cells from mimics can be difficult, and when the cells are few in number, using CD30 immunostains may be necessary to find diagnostic forms. RS cell nuclei are large enough that they are evident to the trained eye at scanning (10x) power and may be round, polylobated, or wreath-shaped, with a thick nuclear membrane. They have a thick nuclear membrane and a nucleolus that often approaches the size of the whole nucleus of a resting lymphocyte. The nucleolus is often rimmed by a halo of pale nonstaining chromatin146,147(Fig. 16.32). Cytoplasm is abundant and may be homogeneously eosinophilic or feaThere d and retracted (The lacunar variant; Fig. 16.33). RS-like cells may be seen in other clinical contexts, including primary mediastinal large B cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and acute infectious mononucleosis; thus, their presence in addition to an appropriate milieu is required for diagnosis.
The milieu of Hodgkin lymphoma varies from area to area and from case to case. In classic Hodgkin lymphoma, the background infiltrate ranges from a monotony of cytologically bland small T lymphocytes to a polymorphous mixture of lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. When sclerosis is present, it consists of broad bands of collagenized fibrosis that partitions the cellularity into nodules and is evident grossly and microscopically (Fig. 16.34). This gross partitioning differentiates the fibrosis of cHL from the delicate slips of collagen that encircle packets of cells in primary mediastinal large B cell lymphoma. In the lung, the mixed inflammatory milieu of Hodgkin lymphoma may overlap substantially with reactive conditions, such as hypersensitivity pneumonitis, collagen vascular disease, and infection. Apart from infection, however, these conditions are not mass-forming, and none of them contain diagnostic RS cells.
Figure 16.31 (A) At low power, this example of pulmonary Hodgkin lymphoma has overlap with both marginal zone lymphoma and lymphomatoid granulomatosis. (B) the suggestion of a bimorphic population of small and large cells (e.g., the large cell just to the right of the center) may be the only cue to the correct diagnosis.
Immunophenotypic staining of RS cells typically yields a CD30+, CD20-, LCA- Oct2-, BOB.1- phenotype (Fig. 16.35). CD15 expression is reported in 60% to 70% of cases, depending on the series; thus it is not an essential finding to establish the diagnosis. Weak and granular CD20 reactivity may be present in some cases (Table 16.4),146-149 as is weak nuclear staining for PAX5. CD79a expression, however, should be lacking. In the lung, differential diagnostic considerations for cHL with abundant sclerotic stroma include inflamed solitary fibrous tumors of the pleura, inflammatory myofibroblastic tumor, sclerosing mediastinitis, and infection. Without the sclerosis, consideration should be given to senile EBV+ B-LCL of the elderly, LyG, and potentially reversible lymphoproliferative disorders arising in the setting of immunosuppression (methotrexate, Remicade, transplantation).
Table 16.4 Immunophenotypical Comparison of Classic Hodgkin Lymphoma and Differential Considerations
|
CD30 |
CD45 |
CD15 |
CD20 |
CD79a |
PAX5 |
cIg |
Oct2 |
EBV |
EMA |
ALK1 |
CD138 |
|
|
cHL |
+ |
0 |
± |
w, f, g |
0 |
w, d |
0 |
0 |
± |
0 |
0 |
± |
|
LPHL |
0 |
+ |
0 |
++ |
++ |
++ |
± |
+ |
0 |
± |
0 |
0 |
|
TcRBcL |
0 |
+ |
0 |
++ |
++ |
++ |
± |
+ |
0 |
0 |
0 |
0 |
|
LyG |
± |
+ |
± |
++ |
++ |
++ |
± |
+ |
+ |
0 |
0 |
0 |
|
PMBL |
+ |
+ |
0 |
++ |
++ |
++ |
0 |
0 |
0 |
0 |
0 |
0 |
|
B-ALCL |
0 |
+ |
0 |
0 |
0 |
0 |
+ |
0 |
0 |
+ |
+ |
+ |
|
T-ALCL |
+ |
± |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
± |
± |
0 |
B-ALCL, B cell anaplastic large cell lymphoma; cHL, classic Hodgkin lymphoma; d, diffuse (present in >80% of lesional cells); f focal (present in <20% of lesional cells); g, granular (noncontinuous beaded staining along the membrane or in the cytoplasm); LPHL, lymphocyte-predominance Hodgkin lymphoma; LyG, lymphomatoid granulomatosis; PMBL, primary mediastinal large B cell lymphoma; T-ALCL, T and null cell anaplastic large cell lymphoma; TcRBcL, T cell-rich large B cell lymphoma; w, weak (clearly faint relative to the intensity of nuclear staining in benign small lymphocytes).
Figure 16.33 Mononuclear variants of diagnostic Reed-Sternberg cells are most common in the mixed cellularity subtype of classic Hodgkin lymphoma (A), whereas the lacunar variants are most commonly found in the nodular sclerosis type (B).
Figure 16.34 Tissues involved by the nodular sclerosis type of classic Hodgkin lymphoma have a nodular architecture grossly (A) as well as microscopically (B).
The “nonclassic” or lymphocyte-predominance subtype of Hodgkin lymphoma, LPHL, has not been reported as a primary lung tumor or as the primary localized mediastinal disease. This disease is often restricted to a single lymph node at presentation, and it pursues an indolent clinical course. In the vast majority of patients, survival is similar to that of age-matched individuals without LPHL.112 Great care should be taken in evaluating lung biopsy specimens with features suggestive of LPHL. The phenotype of the lymphocytic-histiocytic (L&H) RS cell variants in LPHL (CD15-, CD30-, CD20+, PAX5+, CD45+ Oct2+, BOB.1+; Table 16.4) is identical to that seen in the more aggressive TcRBCL.113,114,150,151 A large specimen is essential in resolving such a differential diagnosis because the B cell-rich and folliculocentric immunoarchitecture is as much a part of the disease definition as the lesional cells (Fig. 16.36).
Figure 16.35 (A) Although the classic phenotype associated with Reed-Sternberg (RS) cells is CD30+, CD15+, CD20-, the sine qua non is CD30 expression. Between 30% and 40% of classic Hodgkin lymphoma cases are negative for CD15 (B), and 10% to 20% may express CD20 (C) in a weak and partial granular manner. PAX5 expression is expected in RS cells (D), although Oct2 is not (E). The latter is a helpful means of distinguishing classic Hodgkin lymphoma from T cell-rich large B cell lymphoma.
Table 16.5 Immunophenotypical Comparison of B Cell Lymphomas Composed of Small Cells
|
TdT |
CD19 |
CD20 |
CD79a |
bcl2 |
bcl6 |
cyD1 |
CD5 |
CD10 |
CD23 |
Other* |
|
|
B-LBL |
+ |
+ |
0 |
+ |
+ |
0 |
0 |
0 |
± |
0 |
FISH |
|
B-SLL/CLL |
0 |
+ |
dim |
+ |
+ |
0 |
0 |
+ |
0 |
+, d |
FISH |
|
MCL |
0 |
+ |
+ |
+ |
+ |
0 |
+ |
+ |
0 |
0 |
FISH |
|
FL |
0 |
+ |
+ |
+ |
+ |
+ |
0 |
0 |
+ |
var |
FISH |
|
BL |
0 |
+ |
+ |
+ |
0 |
+ |
0 |
0 |
+ |
0 |
Ki67 >95% |
|
MaZL |
0 |
+ |
+ |
+ |
+ |
0 |
0 |
0 |
0 |
0 |
foll col |
|
HCL |
0 |
+ |
+ |
+ |
0 |
0 |
0 |
0 |
0 |
0 |
CD103, DBA |
|
LPL |
0 |
+ |
+ |
+ |
+ |
0 |
0 |
0 |
0 |
0 |
clg, CD138 |
|
PCY |
0 |
0 |
0 |
+ |
± |
0 |
± |
0 |
0 |
0 |
clg, CD138 |
*CD103, lesional cells are CD103+; CD138, lesional cells are CD138+; clg, plasma cells have monotypic cytoplasmic kappa or lambda; DBA, lesional cells are DBA.44+; FISH, in situ hybridization may be helpful in classifying difficult cases or may provide clinically relevant prognostic information (see text); foll col, follicular colonization present (see text); Ki67, proliferation index >95%.
BL, Burkitt lymphoma; B-LBL, B cell lymphoblastic lymphoma; BSLL/CLL, B cell small lymphocytic lymphoma/chronic lymphocytic leukemia; cyD1, cyclin D1; FISH, fluorescence in situ hybridization; FL, follicular lymphoma; HCL, hairy cell leukemia; LPL, lymphoplasmacytic leukemia; MaZL, marginal zone lymphoma; MCL, mantle cell lymphoma; PCY, plasmacytoma; var, variable results; some cases may be positive.
Systemic Lymphoproliferative Disorders That May Secondarily Involve the Lung, Pleura, or Mediastinum
Secondary pulmonary lymphoma is a lymphoma diagnosed in the lung of a patient who either has a previous or concurrent nodal diagnosis of lymphoma or has evidence of systemic lymphoma during a relatively short interval after presentation. The diagnostic criteria for lymphoma in lymph node biopsies should be applied.47,152
In the United States, follicular lymphoma, systemic large B cell lymphoma, small lymphocytic lymphoma, and mantle cell lymphoma (Fig. 16.37) are the most common systemic lymphomas to secondarily involve extranodal sites. Careful attention to cytologic detail, a broad IHC panel, and above all, the clinical history, should permit complete diagnosis in most cases (Table 16.5). Although all of these lymphomas may remain localized for a period, all have a significant risk of disseminating to other sites. Cues to the diagnosis offollicular lymphoma include a mixture of small, intermediate, and large cleaved cells, including cells with irregular, cleaved, elongated “twisted towel,” and gourd-shaped nuclei. Mantle cell lymphoma, by contrast, is composed of uniform small lymphocytes with condensed chromatin and a minimally irregular nuclear profile. Pink histiocytes are often evenly commingled. Small lymphocytic lymphoma is usually composed of small cells with round nuclei with a smooth nuclear contour. Some patients have a greater degree of nuclear contour irregularity (“atypical” chronic lymphocytic leukemia) that is similar to mantle cell lymphoma cytologically. However, the cue to the correct classification is a second cell population of paraimmunoblasts and immunoblasts, which often accumulate together in pale-staining areas (“proliferation centers”).36,153,154 MaZL (discussed in detail earlier) may involve the lung secondarily after presentation in other mucosal sites. As in secondary B-LCL, MaZL cannot be distinguished from a primary lung lymphoma on purely morphologic grounds, and the diagnosis requires correlation with clinical history and full radiologic staging. Immunohistochemical studies are central to the accurate diagnosis and classification of all of these conditions (Table 16.5).
High-Grade Lymphomas
While the differential diagnosis of small lymphoid proliferations is challenging, a subset of aggressive lymphomas is equally difficult to identify, and the diagnosis is usually far more clinically pressing. These are clinically high-grade lymphomas, and There are obvious frozen section and specimen triaging issues. A timely diagnosis requires excellent histologic material and adequate material for IHC (flow cytometry seldom has sufficient viable cells for accurate results) and cytogenetic analysis.
Figure 16.36 the CD30-, CD15-, CD20+ immunophenotype of the lesional cells in the lymphocyte-predominance form of Hodgkin lymphoma (LPHL) helps to distinguish it from classic Hodgkin lymphoma, but it is identical to that seen in T cell-rich large B cell lymphoma. Because the latter is not uncommonly seen in the lung, whereas LPHL is vanishingly rare, a large biopsy or resection specimen to assess the milieu is essential for making the correct diagnosis.
The histologic features characteristic of Burkitt lymphoma (BL) include uniform, intermediate cell size; uniformly round or ovoid nuclei, with coarse chromatin and dispersed, often peripheral, small nucleoli; and a rim of amphophilic cytoplasm with crisp separation from the adjacent cells (sometimes called squaring off of cytoplasm).155157 the proliferation is uniform, with no commingled small cells (Fig. 16.38). Either apoptotic single-cell necrosis or geographic tumoral necrosis may be present, often accompanied by dispersed tingible body macrophages. Exceptional cases may show tumoral pneumonia, a consolidative picture radiologically because of alveolar filling by tumor cells, extravasated serum, and fibrin.58 This can also introduce confounding background staining into immunostains. A CD20+, CD10+, bcl6+, bcl2- profile with more than 95% of tumor cells exhibiting nuclear positivity for Ki67 is characteristic. In some cases, CD10 expression may be weak or absent, but bcl6 expression confirms the follicular stage of maturation. When the morphology is characteristic of BL but an other-than-characteristic immunophenotype is obtained, a MYC-simple cytogenetic result should direct the final classification as BL.
B cell lymphoma, unclassifiable with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL (BCL-U) is a heterogeneous category proposed by the WHO Classification.47 While cytogenetics are pending, this term can be applied to cases that have the characteristic morphologic features of Burkitt lymphoma and a phenotype that is not characteristic of BL or when the morphology points to classification as DLBCL (greater degree of variation in cell size and nuclear contour irregularity; Fig. 16.39) but the Ki67 and BCL2 staining results are more characteristic of BL. An isolated c-myc translocation with a permissive BL morphology but nonconforming phenotype supports a BL diagnosis. A complex karyotype or a c-myc translocation with a gene other than immunoglobulin H or immunoglobulin L should prompt the use of BCL-U or reconsideration of the diagnosis of B-DLCL (Table 16.6).
Figure 16.37 (A) the lung may be secondarily involved by any type of B cell lymphoma. Follicular lymphoma is seen in which the tumor cells have folded or twisted nuclear profiles. (B) Another example of intrapulmonary follicular lymphoma, showing irregular nuclear contours.
Figure 16.37—cont'd (C) Mantle cell lymphoma of the lung, showing composition by relatively mature and monomorphic small lymphoid cells. This tumor has also been known as centrocytic lymphoma or lymphocytic lymphoma with intermediate differentiation. A chromosomal translocation t(11;14) in mantle cell lymphoma involves the bcl1 locus on chromosome 11 and the immunoglobulin heavy-chain locus on chromosome 14. It leads to overexpression of the PRAD-1 gene, which encodes cyclin D1. Hence, nuclear immunolabeling for the latter protein is a reproducible diagnostic marker for mantle cell lymphoma. (D) Small lymphocytic lymphoma (SLL) is shown involving the lung. It is morphologically similar to mantle cell lymphoma but is often accompanied by a leukemic component. Moreover, SLL lacks cyclin D1 immunoreactivity and instead shows labeling for CD5, CD20, and CD43. Flow cytometric studies of SLL also should show positivity for CD23. (E and F) the similarity of tumor cells in SLL to mature nonneoplastic B lymphocytes is well shown. (G) Peripheral T cell lymphoma of the lung, growing in an interstitial pattern with a tendency to confluence. (H) Interalveolar septa are expanded and distorted by obviously atypical lymphoid cells in peripheral cell lymphoma of the lung. Continued
Figure 16.37—cont'd (I) the morphologic triad of a spectrum of small, intermediate, and large atypical cells with pale cytoplasm; hypervascularity; and eosinophilia is often present in peripheral T cell lymphoma, as shown. (J) Markedly irregular nuclear contours and nuclear hyperchromasia are present in the tumor cells of this intrapulmonary peripheral T cell lymphoma. (K) Expression of the pan T cell marker CD3 is present in the vast majority of tumor cells in this intrapulmonary peripheral T cell lymphoma. (L) Many cases of peripheral T cell lymphoma show a selective loss of one or more pan T cell markers, as detected in paraffin section immunostains. CD7 is lacking in the tumor cells (left), but CD5 is present (right).
Table 16.6 Correlation of the Morphologic Features, Phenotype, and Cytogenetics in Burkitt and Burkitt-Like High-Grade Lymphomas
|
Phenotype |
Cytogenetics |
||||
|
bcl2 |
bcl6 |
CD10 |
Ki-67 |
||
|
Burkitt morphologic features with bcl2 expression |
+ |
+ |
+ |
>90% |
Isolated IgH or IgL translocation with c-myc should prompt classification as Burkitt lymphomaA c-myc translocation involving a non-Ig partner or a complex karyotype including a c-myc translocation and other translocations (e.g., t[14;18], t[3q27;V]) should prompt classification as high-grade B-NHL-UC |
|
Burkitt morphologic features without CD10 expression ( The same may be applied to a patient with Burkitt morphologic features without bcl6 expression) |
0 |
+ |
0 |
>90% |
Isolated IgH or IgL translocation with c-myc should prompt classification as Burkitt lymphomaA c-myc translocation involving a non-Ig partner or a complex karyotype including a c-myc translocation and other translocations (e.g., t[14;18], t [3q27;V]) should prompt classification as high-grade B-NHL-UC |
|
Intermediate morphologic features |
± |
± |
± |
>90% |
Isolated IgH or IgL translocation with c-myc should prompt classification as Burkitt lymphoma; because treatment planning differs if the pathologist remains unsure, sending the patient for external consultation is always appropriate; patients with a complex karyotype, including a c-myc translocation, a double hit of a c-myc translocation with either t(14;18) or t(3q27;V), or an isolated t(14;18) or t(3q27;V) should be diagnosed as having B-NHL-UC or DLCL |
|
Large-cell morphologic features |
+ |
± |
± |
<80% |
If the patient has clear-cut morphologic features of large-cell lymphoma, it should be classified as B-DLCL, regardless of the results of cytogenetic testing; cytogenetic testing may be of clinical use in treatment planning because patients with double-hit B-DLCL do worse than those with B-DLCL without this abnormality |
Burkitt morphology: Uniformly intermediate-sized cells without nuclear contour irregularity; homogeneous eosinophilic cytoplasm with clear-cut edges between cells (“squaring off”); several peripheral small nucleoli. Classic Burkitt phenotype: bcl2-, bcl6+, CD10+. Intermediate morphology: Mixture of intermediate-sized and larger cells, with mild or moderate nuclear contour irregularity in some; prominent solitary centrally placed nucleoli in some cells; commingled small, resting lymphocytes may be present.
Large-cell morphology: Mixture of large and very large cells with moderate or striking nuclear contour irregularity, or cells with immunoblastic or polylobated nuclei; indistinct cell borders; commingled small lymphocytes with either resting cytology or features of centrocytes.
B-DLCL, B-cell diffuse large cell lymphoma; B-NHL-UC, B-cell non-Hodgkin lymphoma, not otherwise classified; DLCL, diffuse large cell lymphoma.
Figure 16.38 Burkitt lymphoma (BL) may involve the lung, usually secondarily. (A) the key features of BL include intermediate cell size, coarse chromatin with multiple peripherally located small nucleoli, and scant deeply basophilic cytoplasm. (B) the cells are not especially adherent to one another, creating a sense of discohesion and a squaring off of cell borders. (C) the mitotic rate is brisk, and There is apoptotic single-cell necrosis. (D) Nuclei are monotonously round and smooth.
High-grade large B cell lymphoma, in contrast to BL, is more heterogeneous, with a minor population of commingled small cells. In the lesional cell population, there is wide variation in cell size, including cells 3 to 4 times the size of small resting lymphocytes; cells with irregular, notched, bilobed, or polylobated nuclei; and usually a blurring of cell borders (no “squaring off”; Fig. 16.40). An additional cue to the diagnosis is commingled small resting lymphocytes among the large lymphoma cells. More variable results for CD10 and bcl6 are reported in this setting, and at least 20% of the tumor cells are bcl2+. The majority of these cases have translocations involving either the bcl2 or bcl6 gene or a complex karyotype, and they only rarely have isolated c-myc translocation (Table 16.6).158
Immunoproliferative Disorders
Plasmacytoma
Extraosseous plasmacytoma is uncommon and usually involves the upper (rather than lower) aerodigestive tract.159 Primary pulmonary plasmacytomas, which are far less common than secondary pulmonary involvement by a disseminated plasma cell dyscrasia (i.e., multiple myeloma), have discretely demarcated edges and are brown or dark tan on cut section.160163 Amyloid deposition may be grossly evident as white nodules or streaks in large tumors. Microscopically, the typical plasmacytoma is composed of syncytia of plasma cells with no residual germinal centers and with negligible numbers of intermingled small lymphocytes. Occasionally, lesional cells of plasmacytomas have a pleomorphic or anaplastic appearance (Fig. 16.41A) and may mimic bronchogenic carcinoma or metastatic melanoma. The amphophilic cytoplasm and paranuclear clear zone are preserved in sufficient numbers of cells to suggest the correct diagnosis in most cases.
If only surface marker analysis is performed, flow cytometric analysis of plasmacytomas yields confusingfalse negative results. These terminally differentiated B cells are usually negative for CD45 (leukocyte common antigen) and the B cell markers PAX5, CD19, and CD20, and they do not have sufficient quantities of surface immunoglobulin expression to appear positive on standard flow cytometry (Box 16.11), though they would be positive with cytoplasmic marker analysis. The diagnosis depends on the finding of CD138 expression (Fig. 16.41B) and a restricted pattern of cytoplasmic immunoglobulin expression, which can be showed on IHC or via cytoplasmic protocols for flow cytometry. Other markers that may be positive include CD30 and epithelial membrane antigen, but neither is lineage-specific, and both should be interpreted in the context of cytokeratin, S-100 protein, and other marker results.
When more than 20% to 30% of a plasmacytic proliferation is composed of small lymphocytes, consideration should be given to small lymphocytic lymphoma, lymphoplasmacytic lymphoma (Fig. 16.42), and MaZL.164166 All have a CD45+, CD20+, surface immunoglobulin (sIg+) profile for the lymphoid population, whereas plasmacytomas are negative for these markers (Table 16.5). Findings that favor MaZL include colonized germinal centers and a polymorphous array of monocytoid, centrocytoid, and plasmacytoid cells. If residual germinal centers are detected in the setting of extreme plasmacytosis, consideration should be given not only to the possibility of MaZL, but also to PCCD. Because it is impossible to distinguish between a solitary plasmacytoma and pulmonary involvement by a systemic plasma cell dyscrasia (multiple myeloma), all patients with biopsy-proven pulmonary plasmacytoma should be fully evaluated with serum and urine protein electrophoresis, skeletal survey, and bone marrow biopsy.
Figure 16.40 Diffuse large B cell lymphoma can have histologic features indicative of high grade, including a brisk mitotic rate, apoptotic or tumoral cell necrosis, and cytoplasmic amphophilia. However, careful scrutiny of viable, well-preserved areas shows the fundamentally large cell size and the irregular nuclear shape of the tumor.
Patients with a previously diagnosed plasma cell dyscrasia (or MaZL) may have nodular deposits of amyloid within the lung. These may be solitary or multiple on chest radiograph, and the patient is usually asymptomatic. The material is homogeneously eosinophilic and nonfibrillary, and it may contain intermingled lymphocytes, plasma cells, and transitional lymphoplasmacytoid forms. Congo red stain shows oran- geophilia in regular light and green birefringence in polarized light in most cases, although noncongophilic amyloidosis occurs (Fig. 16.43). Although accumulations of amyloid are most closely associated with plasma cell dyscrasias, such as multiple myeloma, they also may be seen in association with MaZL and lymphoplasmacytic lymphoma as well as in benign settings.120124
Crystal storing histiocytosis is a rare but distinctive manifestation of immunoglobulin deposition that mimics adult rhabdomyoma. Bone, spleen, lymph node, stomach, thymus, and sinonasal mucosa as well as lung have all been sites of infiltration by this mass-forming proliferation of large polygonal histiocytes that contain large periodic acid/Schiff-posi- tive, phosphotungstic acid-hematoxylin-positive crystalloids (Figs. 16.44 and 16.45). The tumor can be distinguished from rhabdomyoma and plasmacytoma phenotypically by its CD68+, SMA-, CD138- phenotype; the cytoplasmic crystalloids are positive for immunoglobulin light-chain stains, usually of the kappa type (Fig. 16.46).116-119
Immunodeficiency-Related Lymphoproliferative Disorders
Posttransplant Lymphoproliferative Disorders
The immunosuppressed posttransplant state predisposes solid-organ transplant recipients to the development of lymphoid proliferations, often EBV-related and of B lineage (Table 16.7).167’168 For most patients, the disease is systemic at the time it is detected clinically, but for many patients who undergo lung transplant, PTLD arises in and remains localized to the graft. Radiographic findings vary from bilateral reticu- lonodular infiltrates to discrete single or multiple nodules or masses, with the latter most common in patients with high-grade histologic features.169
Figure 16.41 (A) Plasma cell neoplasms can closely mimic carcinoma, although cellular dyshesion is a clue to the hematologic nature of the process, as is the presence of a prominent Golgi zone in some of the lesional cells. (B) Although it is CD45- in most cases, plasmacytomas are strongly CD138+.
Figure 16.42 In lymphoplasmacytic lymphoma, there is a heterogeneous mix of clonal small B lymphocytes, transitional lymphoplasmacytoid forms, and plasma cells. Because of the lymphoid component, flow cytometry findings are positive, and because of the plasmacytic component, paraffin section studies for clonality are also positive.
Figure 16.43 Amyloid deposition in the lung may be nodular and mass-forming, as in this case, or may be more subtle and restricted to the alveolar septal walls.
Figure 16.44 the lesional cells of crystal-storing histiocytes are massively enlarged because of the phagocytosis of needle-like shards of crystalline immunoglobulin. When no history of lymphoma or myeloma is given, unusual epithelial malignancies and adult rhabdomyoma are differential considerations.
Figure 16.45 Marginal zone lymphoma with crystal-storing histiocytosis.
Table 16.7 Histologic, Phenotypic, and Genetic Characteristics of Posttransplant Lymphoproliferative Disorders
|
P-BCH |
P-BCL |
M-BLCL |
M-BL |
M-BPCY |
|
|
Cellular composition |
Mixture of small |
Mixture of small |
Uniform population of |
Uniform population of intermediate- |
Uniform population of |
|
lymphocytes, plasma cells, |
lymphocytes, plasma cells, |
centroblastic or immunoblastic |
sized cells with coarse chromatin, |
plasmacytic or |
|
|
and occasional large |
and occasional large |
large cells and moderate |
multiple distinct nucleoli, moderate |
plasmablastic cells |
|
|
centroblastic and |
centroblastic and |
quantities of eosinophilic or |
or abundant quantities of |
with coarse chromatin |
|
|
immunoblastic cells |
immunoblastic cells |
amphophilic cytoplasm |
amphophilic cytoplasm |
||
|
Histologic grade |
Low (occasional mitoses, |
Low (occasional mitoses, |
High (increased mitoses); |
High (numerous mitoses); necrosis |
May be low or high |
|
no necrosis) |
no necrosis) |
necrosis may be present |
often present |
(no necrosis) |
|
|
sIg expression |
Polytypic |
Monotypic |
Monotypic |
Most cases sIg- |
Some cases sIg- |
|
cIg expression |
Polytypic |
Monotypic |
Usually cIg- |
Usually cIg- |
Monotypic |
|
Clonal IgH/IgL loci |
None |
Present |
Present |
Present |
Present |
|
rearrangements |
|||||
|
Outcome |
May resolve spontaneously |
May resolve spontaneously |
Less likely to resolve without |
Unlikely to resolve without systemic |
Unlikely to resolve |
|
with reduced |
with reduced |
systemic chemotherapy |
chemotherapy; often fatal |
without systemic |
|
|
immunosuppression |
immunosuppression |
chemotherapy |
cig, Cytoplasmic immunoglobulin; M-BL, monomorphous Burkitt lymphoma; M-BLCL, monomorphous B cell large-cell lymphoma; M-BPCY, monomorphous B cell plasmacytoma; P-BCH, polymorphous B cell hyperplasia; P-BCL, polymorphous B cell lymphoma; sig, surface immunoglobulin.
Figure 16.46 Immunoglobulin in crystal-storing histiocytosis is more often of the kappa subtype than chance would allow, as shown in this immunostain for kappa light chains.
Early lesions include plasmacytic hyperplasia type PTLD, infectious mononucleosis like PTLD, and florid follicular hyperplasia type PTLD. More established lymphoproliferations include polymorphous PTLD and forms that for all intents and purposes resemble either non-Hodgkin lymphoma ( The monomorphous PTLD and cHL-PTLD). Classification integrates morphologic, phenotypic, and genetic data (Table 16.7).169 Polymorphous PTLD is composed of a mixture of lymphocytes, plasma cells, and transitional lymphoplasmacytoid forms (Fig. 16.47). In this setting, a polytypic pattern of light-chain expression and the lack of clonality are compatible with early lesions and nonclonal polymorphous PTLD. With these early lesions, the lymph node architecture is preserved and the disease is usually more localized, so dissemination with lung involvement is uncommon. If There is a monotypic population of B-cells seen on flow cytometry, or if gene rearrangement studies identify a clonal population, the proliferation is best classified as polymorphous B cell lymphoma or clonal polymorphous PTLD. Clonal processes are more commonly associated with architectural distortion of the lymph node architecture and may be more likely to involve the lung. Monomorphous PTLDs have a uniform appearance and histologic features identical to those of large cell lymphoma, Burkitt lymphoma, or plasmacytoma occurring in an immunocompetent patient (Fig. 16.48). Most cases, though not all, contain EBV, which can be detected with either IHC or in situ hybridization. T lineage PTLDs with no relationship to EBV also occur, and a number have been shown to be of a special T y/S hepatosplenic type.
Classification plays an important role in initial treatment planning, and it is also an important indicator of prognosis.169 Because of the propensity for PTLD to involve more than one site, the level of intervention must consider the possibility that though the biopsy demonstrates a low grade or early process, there may be a higher grade PTLD at another site.
Differential diagnostic considerations are few, because the lymphoid nature of the proliferation is readily apparent histologically, and immu- nophenotypic studies rarely yield ambiguous results. Difficulty may arise if a transbronchial biopsy specimen has been obtained. For example, the quantity of lesional infiltrate may be too limited to allow a meaningful histologic classification into polymorphic or monomorphic categories or to fully exclude other diseases, such as lymphomatoid granulomatosis (discussed earlier), Hodgkin lymphoma, or nonneoplastic disorders, such as cytomegalovirus (or other viral) pneumonia.
T Lineage Lymphoid Malignancies
Most patients with PTCL are clinically ill with disseminated disease at presentation, and they may have features such as spiking fevers, rash, and lung infiltrates.7 Radiologic findings may show bilateral miliary nodules or reticulonodular infiltrates simulating interstitial disease, although the finding of one or more masses is most common. There is a systemic distribution of disease at presentation, and the initial diagnosis is usually based on lymph node biopsy.7 Lung biopsy may be performed at any point during presentation or treatment to distinguish among infection, treatment-resistant lymphomatous infiltrates, and medication- related interstitial lung disease. The histologic hallmark of most cases of PTCL is the following triad: (1) a spectrum of atypical small, intermediate, and large cells with irregular nuclear shapes and clear cytoplasm; (2) hypervascularity; and (3) tissue eosinophilia (Fig. 16.49).3,170 Phenotypically, there may be an aberrant loss of a pan T cell marker (CD2, CD3, CD5, or CD7), which may be easiest to detect on flow cytometry, where the tumor cells can be studied for three or four markers at the same time. However, IHC on serial sections from paraffin blocks can also show this phenotypic alteration.3,170
Figure 16.47 Polymorphous posttransplant lymphoproliferative disorder (PTLD) in the lung, showing an alveolar (A) and interstitial infiltrate of hematopoietic elements with lymphoplasmacytic features (B). (C) Polymorphous PTLD may show an admixture of atypical mononuclear cells, plasma cells, and Reed-Sternberg cell-like elements, or a prominent histocytic component together with lymphocytes and plasma cells (D). This process is driven by infection with Epstein-Barr virus; it is polyclonal and is not associated with mutations of proto-oncogenes, such as c-myc.
Specific T lineage lymphomas have distinctive clinicopathologic profiles (Box 16.13), some principally marrow-based and others principally nodal and parenchymally based, but primary or predominant lung or mediastinal involvement is uncommon. Of these, T cell lymphoblastic lymphoma and T cell anaplastic large cell lymphoma (T-ALCL) are the only two malignancies encountered in chest or lung biopsy specimens with any frequency.
T Cell Lymphoblastic Lymphoma/T Cell Acute Lymphoblastic Leukemia
T cell lymphoblastic lymphoma (T-LBL) often presents in adolescent boys with a mediastinal mass, hepatosplenomegaly, and generalized lymphadenopathy. The liver, spleen, marrow, and blood are often involved.47 In fully involved tissues, the architecture is diffuse and the blasts are intermediate in size (~1.5 times the size of a benign lymph node), although There may be a surprising degree of variation in cell size, with some blasts approximately twice the size of a benign lymph node. The nuclear contours may be smooth or convoluted, and the blasts may have fine or evenly condensed chromatin, often with a distinct nucleolus (Fig. 16.50). With good fixation and thinly sectioned slides, the neoplastic and blastic nature of the infiltrate is seldom in doubt, although with therapy, necrosis and apoptosis may make the diagnosis more difficult.
Figure 16.48 (A) High-grade monotypic posttransplant lymphoproliferative disorder (PTLD) in the lung showing an infiltrate of atypical larger cells in a field of geographic necrosis. (B) the lesional cells of high-grade monotypic PTLD expand and distort the interalveolar septa. (C) They show obvious nuclear anaplasia and were monoclonal genotypically and immuno- phenotypically. (D) In situ hybridization for Epstein-Barr virus-related ribonucleic acid (left) or immunostaining for Epstein-Barr virus latent membrane protein (right) usually yields positive results in PTLD of the lung.
Figure 16.49 the morphologic triad of a spectrum of small, intermediate, and large atypical cells with pale cytoplasm, hypervascularity, and eosinophilia are often present in peripheral T cell lymphoma, as shown here.
In most cases, the leukemic cells are positive for TdT, CD2, and CD7, with variable expression of CD34, CD5, CD1a, and CD10 (Box 16.14 and Fig. 16.51). Surface expression of CD3 may be slight to absent, so the cells may appear to be negative on flow cytometry, although immunohistochemical stains show cytoplasmic positivity. There are few to no cytokeratin-positive cells commingled with the blastic infiltrate, and no lobulation is seen on routine or special stains.
Differential diagnostic considerations for T-LBL in the mediastinum include benign thymus and lymphocyte-rich thymoma, and an adequate sample size is the only way to assess for effacement of the thymic architecture, which would favor T-LBL. Because benign thymic tissues can have an identical phenotype, attempting an initial diagnosis of T-LBL based on the findings of cytology or needle-core biopsy alone can be treacherous. Cytokeratin stains show an intact lobulated array of thymic epithelial elements in benign thymus and lymphocyte-rich thymomas, but these are absent or rare in T-LBL (Fig. 16.52). Neuroendocrine carcinomas, including carcinoids and small cell carcinoma, can mimic T-LBL, although immunophenotypic studies readily show the correct diagnosis. B lineage lymphoblastic lymphoma and acute myeloid leukemia are histologically indistinguishable, but the former is positive for PAX5, CD19, CD79a, or CD22, while the latter is positive for CD13, CD33, and myeloperoxidase.
Figure 16.50 (A) Lymphoblastic lymphoma creates diffuse proliferations of small cells that leave the tissue planes intact. (B) the cells have evenly dispersed or fine chromatin, with indistinct nucleoli, irregular (convoluted) nuclear shapes, and scant agranular cytoplasm.
Figure 16.51 TdT stain is the most important stain in evaluating a lymphoid proliferation for the possibility of lymphoblastic lymphoma. In this case, the lymphoma cells distend the alveolar walls (TdT stain).
Figure 16.52 the differential diagnosis for blast-like proliferations in the mediastinum includes both lymphoblastic lymphoma and lymphocyte-rich thymoma. The latter, seen here, has abundant cytokeratin-positive thymic epithelial cells that form a network among the thymocytes, whereas lymphoblastic lymphoma is free of this native cell population (cytokeratin stain).
T Cell Anaplastic Large Cell Lymphoma
The lung is a common site of secondary involvement by systemic T-ALCL, and several cases of primary pulmonary ALCL of T or null cell type have also been reported.171-176 Presentation is via mass effect, with cough, hemoptysis, or symptoms referable to pleural effusions.176-178
Microscopically, ALCL is formed of diffuse sheets of large and very large cells with pleomorphic nuclei and abundant cytoplasm, and the similarity to carcinoma or melanoma may be striking. Careful attention to the periphery may show a dyshesive array of intraalveolar tumor cells, a helpful cue that the disease may be of hematolymphoid origin (Box 16.15 and Fig. 16.53). There are multiple histopathologic variants or patterns (Box 16.16), and more than one pattern can be seen in a single patient or a single biopsy specimen. The uniting elements are the very large hallmark cells (Fig. 16.54), which are especially numerous in the common or pleomorphic form.178 Hallmark cells have reniform, or U-shaped nuclei, and abundant amounts of cytoplasm compared with other lymphomas. In some cases, the nuclear indentation is in the plane of view, such that the nucleus appears as an O (donut cells). Nucleoli are distinct but generally are not the size of a small lymphocyte and lack the perinucleolar halo characteristic of RS cells. The remainder of the cellularity includes medium and large cells with round, irregular, lobated, and folded nuclear shapes, dispersed chromatin, distinct nucleoli, and moderate or abundant amounts of glassy eosinophilic cytoplasm (Fig. 16.55).174,175,178
Figure 16.53 Anaplastic large T cell lymphoma can mimic carcinoma, melanoma, or even sarcoma. The cue to the correct diagnosis is often found at the edges of the tumor or within open spaces, where the discohesive nature of the tumor is seen.
Figure 16.54 the hallmark cells of T cell anaplastic large cell lymphoma are large and have centrally placed, reniform nuclei.
ALCL is reliably CD30+ (Fig. 16.56A), and the majority of these cases are positive for a pan T cell marker, such as CD2, CD3, or betaF1, although some may be negative for these antigens (null cell phenotype) or negative for leukocyte common antigen. ALK expression can be documented immunohistochemically in many but not all cases of ALCL, and it correlates with the presence of the t(2;5) translocation involving the nucleophosmin and ALK genes.179 Although There are exceptions,180 ALK expression is associated with better overall survival47,179 and should be tested in every lymphoma that shows anaplastic morphologic features. B cell lineage markers including PAX5 and CD15 are negative (Fig. 16.56B).
Differential considerations may include metastatic carcinoma, melanoma, and epithelioid sarcoma, and so a panel of stains including pancytokeratin, S-100, MART1, actin, desmin, and vimentin will be helpful. Some cases have a degree of morphologic overlap with classic Hodgkin lymphoma, and PAX5, which has weak to moderate intensity relative to small resting B cells, which helps to resolve this gray zone differential. Exceptional cases of T-ALCL are rich in neutrophils, raising a differential with suppurative inflammation; and the presence of CD30+ large cells effectively excludes a reactive process. There is also the potential for morphologic overlap with true histiocytic malignancies, which are negative for CD3, CD30, and ALK, and positive for CD68, CD31 (PECAM-1), and CD163. The rare B lineage ALCL, which tends to be negative for CD20, enters into differential consideration, but most cases are negative for CD30, a helpful cue, and are positive for CD138 or MUM1.181 Despite ALK expression, these cases of B lineage ALCL have a more aggressive clinical course than ALK+ T and null cell ALCL, and should There fore be distinguished with the appropriate stains.
Myeloid Proliferations
Extramedullary Myeloid Tumors
Extramedullary myeloid tumors (EMTs; granulocytic sarcomas) are masses composed of neoplastic (clonal) precursors of the granulocytic lineage. Cell types include blasts, promyelocytes, and myelocytes, as well as monocytes and promonocytes. Myeloid malignancies, such as idiopathic myelofibrosis (agnogenic myeloid metaplasia), may, instead of producing discrete tumefactive masses, produce a radiologic picture similar to that of interstitial lung disease.182-184 Both the clinical context and the histologic composition are important: in the pediatric setting, most extramedullary accumulations of hematopoiesis are benign and arise because peripheral demand for red cells and neutrophils is in excess of what the marrow space can provide.185 However, in an adult with an established diagnosis of a chronic myeloproliferative disorder, the same histologic features suggest a neoplasm and should raise concern that the disease is progressing to a more aggressive phase.186-188
Figure 16.55 Many variants of T cell anaplastic large cell lymphoma (T-ALCL) have been reported, including a small-cell variant. The cells are small relative to the usual size for typical ALCL, but are large overall. (A) Hallmark cells are the key to the diagnosis. (B) Reed-Sternberg-like cells may also be present in T-ALCL, and although CD30+, they are PAX5+ and ALK-.
Figure 16.56 (A) CD30 expression is the expected result in T cell anaplastic large cell lymphoma (T-ALCL), but interestingly, it is not seen in B lineage ALK+ ALCL (CD30 stain). (B) the lesional cells of T-ALCL are negative for PAX5.
By definition, EMTs arise outside the bone marrow. Although they usually develop during the course of systemic myeloproliferative disease, either as a complication or as a transformation from the chronic to the acute phase,182,183,189 on occasion, they are a presenting sign or the first sign of relapse.187,188 the underlying condition may be myelodysplasia or acute or chronic leukemia, including hypereosinophilic syndrome/ chronic eosinophilic leukemia.189-196 ’tterefore, examination of the peripheral blood is a necessary part of the work-up (Fig. 16.57). When the peripheral blood is free of blasts but the bone marrow meets the criteria for acute leukemia, the process is often referred to as aleukemic leukemia.190,191
The demographic features of EMTs match those of chronic myeloid neoplasms. Most patients with both of those conditions are adults, with a median age of 60 years at presentation. The overall incidence of EMT is estimated at 0.7 cases per million children in the general population per year and 2 cases per million adults per year, a feature that reflects the fact that myeloid neoplasms overall are much less common in children than adults.189 Organs that normally harbor hematopoietic cells (bone, spleen, and lymph nodes) are often involved, but a significant proportion of EMTs occur elsewhere—including the lungs.190,192 Associated pulmonary symptoms and signs include pleural effusions, chest pain, and cough. On cut section, most EMTs are a homogeneous off-white color, but some will show a pale green hue for a few minutes as the blasts’s cytoplasmic enzymes (including myeloperoxidase) oxidize.
Figure 16.57 Extramedullary myeloid tumor can arise in a variety of settings. Review of the peripheral blood is a necessary part of the work-up of such cases. The morphologic features of the blasts can be a helpful guide in ordering immunohistochemical studies.
There is a substantial risk of misdiagnosis of EMTs arising in the lungs and chest structures, because they may occur out of the context in which hematologic malignancy is suspected and because the morphologic features and phenotype overlap with more common solid tumors in those sites. Ewing sarcoma, rhabdomyosarcoma, Langerhans cell histiocytosis, neuroendocrine carcinomas, perivascular epithelioidcell tumors (PEComas), and multiple myeloma can all show some degree of morphologic overlap. When the process is associated with sclerosis, inflammatory pseudotumor may also be considered.
Histologically, three morphologic patterns of EMT can be recognized: blastic, intermediate, and differentiated.192 In the first pattern, sheets of round or polyhedral cells that infiltrate around or sometimes efface the architecture of the native tissue are seen. The neoplastic cells generally have medium or large vesicular nuclei, sometimes with folded nuclear membranes, discernible nucleoli, and amphophilic or basophilic cytoplasm (Fig. 16.58A). In poorly fixed tissue, these subtle features may be concealed by artifact. A few small scattered cells with sparse cytoplasmic granulation are always present. Background inflammatory cells in the blastic form of EMT are banal, usually comprising mature lymphocytes and histiocytes. This “hiatus” between the tumor cells and the reactive elements is a helpful clue to the nonlymphoid nature of the lesion in cases initially believed to be lymphoma. Compared with blastic EMT, the intermediate morphologic features show a balanced mixture of immature (blastic) and maturing cells (promyelocytes, myelocytes, and eosinophilic myelocytes; see Fig. 16.58B). The “differentiated”histologic pattern of EMT may be the easiest to overlook or to interpret as reflecting a nonneoplastic, inflammatory process.
If air-dried touch preparations of fresh tumor have been prepared, a histochemical stain for myeloperoxidase can be performed. A negative result does not exclude the diagnosis of EMT, since monoblasts and some myeloid blasts can be negative for this enzyme. In tissue sections, the von Leder stain can be performed, with reactivity seen in fewer than 30% of blastic EMTs, 30% to 50% of “intermediate” tumors, and more than 50% of differentiated lesions. The IHC menu for this differential has expanded, and now, in addition to TdT, CD34, CD45, and CD15, there are antibodies for CD14, myeloid cell nuclear differentiation antigen (MNDA), and CD33 that work well in paraffin sections. Immunostains for CD163, lysozyme, and myeloperoxidase can also be used, but they are somewhat more limited in their sensitivity in blastic proliferations.193,197-199
Figure 16.58 In extramedullary sites, it can be difficult to identify myeloid neoplasms. Blast-like cytologic features (A) and commingled eosinophilic myelocytes (B) are helpful findings.
Very nicely described by Goldstein and colleagues197 is the fact that the decisive factor in the diagnosis of EMTs is not in the availability of fresh tissue for flow cytometry or the breadth of one’s IHC lab; instead, it is in thinking of EMT in the first place. It is in not misinterpreting negative or weak focal results on a screening CD45 stain as excluding a myeloid neoplasm. If the initial IHC panel on a poorly differentiated neoplasm yields negative results in a thoughtfully constructed screening panel, including CD43, CD14, CD15, CD34, TdT, and CD33 on a follow up panel may rescue the day.
Self-assessment questions and E Cases related to this chapter can be found online at ExpertConsult.com site for this title.
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1. Which of the following represent immunoprofiles that support the presence of a neoplastic lymphoid population?
A. CD3+/CD4+/CD5-/CD7+/CD8-/CD43+/CD20-/CD79a-/PAX5-
B. CD3-/CD5-/CD20+/CD43+/CD79a+/PAX5+
C. CD3+/CD4+/CD5+/CD7+/CD8+/CD43+
D. CD3-/CD5+/CD20+/CD43-/CD79a+/PAX5+
E. All of the above
ANSWER: E
2. What is the principal advantage of studying the immunophenotype of a lymphoid population with flow cytometry (FC) compared with immunohistochemistry (IHC)?
A. FC provides superior morphologic detail.
B. The antibodies used for FC are more specific than those for IHC.
C. FC allows for evaluation of multiple antigens simultaneously.
D. FC is much less expensive.
E. FC requires less technological equipment.
ANSWER: C
3. Which ONE of the following lymphoproliferative disorders is expected to show negative results in molecular evaluations for immunoglobulin and T-cell gene-receptor rearrangements?
A. Follicular lymphoma
B. Small-lymphocytic lymphoma
C. Immunoblastic large cell B cell lymphoma
D. Natural killer-cell lymphoma
E. Peripheral T cell lymphoma, not further specified
ANSWER: D
4. Granulocytic sarcoma is expected to show molecular evidence of rearrangement of the:
A. Immunoglobulin heavy-chain gene
B. Immunoglobulin light-chain gene
C. Alpha/beta T cell receptor gene
D. Gamma T cell receptor gene
E. None of the above
ANSWER: E
5. Which of the following pairs is mismatched?
A. Small lymphocytic B-cell lymphoma—1(14;18)
B. Mantle cell lymphoma—1(11;14)
C. Marginal zone lymphoma—t(11;18)
D. Burkitt lymphoma—t(8;14)
E. Anaplastic large cell lymphoma—t(2;5)
ANSWER: A
6. Follicular bronchiolitis:
A. Does not produce any radiographic abnormalities in the lungs
B. Is an idiopathic condition with no known disease associations
C. Produces lesions that may narrow bronchiolar lumina
D. Is associated with multifocal interstitial pulmonary fibrosis
E. Demonstrates a marked predominance in females
ANSWER: C
7. Nodular lymphoid hyperplasia of the lung is characterized by:
A. Wide spacing of germinal centers
B. Formation of intrapulmonary masses
C. Plasma cells in intercellular zones
D. Sharp demarcation from the surrounding parenchyma
E. All of the above
ANSWER: E
8. Which ONE of the following conditions is NOT associated with lymphoid interstitial pneumonia?
A. Autoimmune diseases
B. Infection with human immunodeficiency virus (HIV)
C. Paraneoplastic response to visceral carcinomas
D. Chronic infection with Epstein-Barr virus
E. Mycoplasma pneumonia
ANSWER: C
9. Primary pulmonary lymphomas:
A. Are not allowed to involve hilar pulmonary lymph nodes
B. Are all aggressive, high-grade tumors
C. Are associated with chronic infection by Borrelia
D. May be associated with abnormal serum protein electrophoregrams
E. All of the above
ANSWER: D
10. In cases of pulmonary marginal-zone lymphoma, small transbronchial biopsy specimens often result in a misdiagnosis of:
A. Plasmacytoma
B. Small cell carcinoma
C. Carcinoid tumor
D. Malakoplakia
E. None of the above
ANSWER: A
11. Which ONE of the following conditions is associated with the formation of histologic lymphoepithelial lesions?
A. Nodular lymphoid hyperplasia
B. Lymphoid interstitial pneumonia
C. Marginal zone lymphoma
D. Follicular lymphoma
E. Mantle cell lymphoma
ANSWER: C
12. Which of the following statements regarding primary large-cell lymphomas of the lung is/are TRUE?
A. They are predominantly B cell tumors.
B. Lesions may be centrally necrotic on chest radiographs.
C. A subset is immunoreactive for CD10.
D. Their immunoblastic variant may be particularly aggressive.
E. All of the above
ANSWER: E
13. Which ONE of the following does not belong in the differential diagnosis of primary large cell B cell lymphoma of the lung?
A. Metastatic melanoma
B. Large-cell undifferentiated carcinoma
C. Lymphoepithelioma-like carcinoma
D. Syncytial Hodgkin lymphoma
E. Rosai-Dorfman disease
ANSWER: E
14. Plasmacytoma in the lung:
A. Is more likely to be secondary than primary
B. Is immunoreactive for CD45
C. Only rarely shows light-chain immunoglobulin restriction
D. Almost always has an anaplastic cytologic appearance
E. Are recognized definitively by flow cytometric analysis
ANSWER: A
15. Crystal-storing histiocytosis in the lung has a histologic resemblance to:
A. Hermansky-Pudlak syndrome
B. Malakoplakia
C. Adult rhabdomyoma
D. Gaucher disease
E. Byssinosis
ANSWER: C
16. Lymphomatoid granulomatosis of the lung:
A. Shows integrated nucleic acid of Epstein-Barr virus in lesional cells
B. Is actually a form of T cell lymphoma
C. Is associated with serologic positivity for antineutrophil cytoplasmic antibodies
D. Does not involve extrapulmonary tissue sites
E. Is virtually identical histologically to necrotizing sarcoidal granulomatosis
ANSWER: A
17. Posttransplant lymphoproliferative disease:
A. May be limited in distribution to the allograft itself
B. Can be polymorphous genotypically
C. Is driven by infection with Epstein-Barr virus
D. Usually shows B cell differentiation
E. All of the above
ANSWER: E
18. Pulmonary anaplastic large cell lymphoma:
A. Is characteristically CD20+
B. May show immunoreactivity for ALK-1
C. Contains a t(3;8) chromosomal translocation
D. Shows CD30-reactivity in 40% of cases
E. Is an indolent tumor type
ANSWER: B
19. Follicular dendritic cell tumor of the lung:
A. Often resembles a fibrohistiocytic neoplasm histologically
B. Is a rapidly progressive lesion with fatality in less than 1 year
C. Presents in the lung more often than in lymph nodes
D. Shows aberrant immunoreactivity for keratin in 80% of cases
E. Has been seen only in adolescent males to date
ANSWER: A
20. Extramedullary myeloid tumors:
A. Comprise a mixture of metamyelocytes, megakaryocytes, and plasma cells
B. Are seen only in patients with overt leukemia
C. Show no evidence of B cell or T cell-related gene rearrangements
D. Lack immunoreactivity for all lymphocyte-associated markers
E. Are reactive for leucine aminopeptidase histochemically
ANSWER: C
Case 1
eSlide 16.1
Clinical History
The patient is a 17-year-old young man who presents to his pediatrician with a month long history chronic nonproductive cough and fatigue that has prevented him from being a senior starter on his high school football team. He says that he could feel a wheeze with deep expiration and had tried using his sister’s asthma inhaler, but he got no improvement from it. Apart from this he has no other symptoms. A chest x-ray demonstrates a 5.0-cm discrete mass in the hilum of the right lung.
Pathology Findings
The mass is composed of a polymorphous array of small cytologically bland lymphocytes, neutrophils, eosinophils, macrophages, and histiocytes. Also present, and apparent even at 20x, are scattered very large cells that are 4 or more times the size ofa small lymphocyte and that have a nucleolus that is similar in size to a small lymphocyte. There are bands ofpaucicellular fibrosis that separate the proliferation into nodules. In some areas, the large cells aggregate, but large syncytia are not a conspicuous feature. The tumor abuts bronchiole but There is no epithelial dysplasia.
Final Diagnosis
Classic Hodgkin lymphoma, mixed cellularity (extranodal) Discussion
Differential: On hematoxylin and eosin (H&E), at the top of the differential is classic Hodgkin lymphoma, and diagnostic Reed-Sternberg cells are present in the expected milieu, but it is important to also consider the possibility of non-Hodgkin lymphoma (e.g., inflamed diffuse large B cell lymphoma or anaplastic large B cell lymphoma), extension from a thymic neoplasm, and metastasis from an as yet unrecognized primary site such as a sinonasal carcinoma.
Work-up: An immunohistochemical panel including CD30, CD15, PAX5, CD20, CD3, OCT2 and/or BOB1, CD45, and cytokeratin (e.g., AE1/3) is an excellent initial panel that would secure the diagnosis in the vast majority of cases. If The lymphocytes have unusually fine chromatin, TdT may be applied to evaluate for thymocytes and lymphoblasts. IfThere are syncytia of pleomorphic large cells including some with features of hallmark cells, adding on ALK and betaF1 may be useful to address the possibility of anaplastic large cell lymphoma (ALCL) up front.
Is a minimally invasive approach likely to yield a complete diagnosis? In this setting, probably not. In older patients, in whom the likelihood of bronchogenic carcinoma is higher, a needle core biopsy or other minimally invasive approach might be undertaken as an initial diagnostic step. While it is likely that the work up would allow for the exclusion of carcinoma, the quantity of lesional cells for phenotyping might be too low to allow for certain distinction between classic Hodgkin lymphoma (cHL), ALCL, and large B cell lymphoma (BLCL).
What information should be conveyed to the surgeon at the time of intra-operative consultation? A safe approach is to limit the comments to what is certain, “Lesional tissue obtained and distributed for appropriate studies; favor hematologic malignancy.” Unless you know your surgeon very well, it can be risky to mention any specific condition by name. Sometimes the patient’s family presses the surgeon so strongly that they present what you have said is “possible” in a way that the family take as “probable” or “actual.”
What information should be conveyed in the final pathology report? the final diagnosis should be expressed with unambiguous terminology, such as is present in the WHO Classification of Haematologic Neoplasms: “classic Hodgkin lymphoma, mixed cellularity type” Since this is an unusual primary neoplasm in the lung, it is helpful to highlight the testing done that excludes more common primary lung tumors (“negative results on the cytokeratin stain exclude the diagnosis of carcinoma”, or “ The negative results by flow cytometry help in excluding the possibility of non-Hodgkin lymphoma”).
Case 2
eSlide 16.2
Clinical History
The patient is a 54-year-old woman who presented to her gynecologist with dysfunctional uterine bleeding. At initial presentation, the patient had a mildly elevated heart rate and respiratory rate, and a complete blood count (CBC) documented mild microcytic anemia. There was no lymphadenopathy or organomegaly. The patient admitted that she felt short of breath and could not play a full set of tennis anymore, and so a chest x-ray was done as part of the work up and it demonstrated bilateral coarse reticulo-nodular infiltrates. These did not resolve with antibiotic therapy, and after a series of intermediate attempts at diagnosis, a wedge biopsy of involved lung was obtained.
Pathology Findings
The normal lung architecture is distorted by an extensive lymphoid infiltrate that tracks along bronchovascular bundles, lobular septae, and that has a nodular architecture perceptible even at 4x. At higher power, the neoplastic cells are small, have clumped chromatin, and just enough cytoplasm to keep the nuclei from overlapping. This small lymphoid population surrounds and compresses residual germinal center structures, and in a few areas begins to enter the germinal centers and commingle with the centrocytes and centroblasts.
Final Diagnosis
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
Discussion
Differential considerations: at first blush, infection, collagen vascular disease, and sarcoidosis might all be favored initially over lymphoma. But with closer scrutiny, most of proliferation between the follicles is exceptionally monotonous rather than the usual mix of cells that typifies paracortical zones in benign lymph nodes. Consequently, lymphoma
chance increases a little higher, and chronic lymphocytic leukemia / small lymphocytic leukemia (CLL/SLL), follicular lymphoma (including the pediatric FL and IRF4-related lymphoma), mantle cell lymphoma, and marginal zone lymphoma are all possible.
Work-up: If approaching the diagnosis with flow cytometry first, key markers to look at by flow are kappa, lambda, CD19, CD20, CD5, CD10, and CD23, and a case like this would yield a relatively nonspecific CD19+, CD20+, CD5(-), CD10(-), CD23(-) light chain restricted result on screen. At this point, further flow could be done (FMC7, CD11c, CD25, CD103), but paraffin section immunohistochemical stains will also be important (bcl6, cyclin D1, bcl2, CD21) to firmly exclude mantle cell lymphoma, CLL/SLL, and follicular lymphoma.
It is always helpful to review a peripheral smear obtained concurrently with the surgery. CLL/SLL has a distinctive bimorphic population of small CLL cells plus larger prolymphocytes, whereas follicular lymphoma (FL) and mantle cell lymphoma (MCL) do not. Marginal zone lymphoma (MaZL) in leukemic phase can sometimes be missed by automated CBC analyzers if The cells, which will have moderate amounts of cytoplasm and sometimes plasmacytoid features, are scored as monocytes.
What is the ideal distribution of tissue to allow for complete characterization of the disease from both the diagnostic and predictive/prognostic perspective? Intraoperative evaluation with either touch preparations or frozen section will push non-Hodgkin lymphoma to the top of the list of possibilities, and so a screening flow cytometry panel is appropriate. In this case, flow would be positive, which will allow you to complete the lymphoma work-up with the remainder of the flow panel and immunohistochemical stains.
What is the role of cytogenetics? Unless the patient is on a protocol that requires conventional karyotyping, it not likely to yield useful information in establishing diagnosis. Fluorescence in situ hybridization (FISH) cytogenetics can be quite informative, though, and should be pursued whenever There is ambiguity regarding classification in low-grade or high-grade neoplasms.
What information should be conveyed in the final pathology report? If the morphology and immunophenotype point to an unambiguous diagnosis, it should be top-lined using clear terminology based on consensus documents such as the WHO Classification. For this case, “Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)” is appropriate. The report should also contain pertinent predictive / prognostic information relating to the neoplasm (e.g., is There any histological evidence of large cell transformation) and relating to any underlying comorbid conditions that the patient may have (if the patient has a history of a collagen vascular disease, is There any evidence of vasculitis or viral cytopathy if the patient has received any form of immunosuppression)
Case 3
eSlide 16.3
Clinical History
The patient is a 61-year-old Russian immigrant with a two-and-a-half year history of atypical chest pain and says through an interpreter that he had been worked up for a heart attack but it was always negative. He has a 30-pack-year history of cigare The smoking. In recent months, he had developed a cough that would not go away with maximum use of over-the-counter cough suppressants. Radiologic studies demonstrated at least five coalescing nodules in the left mid lung field and one in the left upper lung field. ’Лю largest showed central cavitation. Blood cultures were repeatedly negative, and a transbronchial biopsy yielded only necrotic debris. The patient underwent a wedge resection of a peripheral nodule for diagnosis.
Pathology Findings
The necrotic core of the tumor is rimmed by sheets of small, cytologically bland lymphocytes, which, though not encapsulated, make an abrupt transition to essentially normal lung parenchyma. Scattered large cells with vesicular chromatin are present, but they represent less than 1% of the total cellularity and There are no syncytia. The skeletal remains of several blood vessels that have been entirely overrun by lymphocytes can be seen adjacent to and away from the necrotic core.
Final Diagnosis
Lymphomatoid granulomatosis
Discussion
Differential considerations: Given the cavitation, infection is an important consideration, but bronchogenic carcinoma and lymphoma are also possibilities. Because of the propensity for tumoral necrosis, minimally invasive approaches are unlikely to establish the diagnosis, and may produce misleading results. In addition, the scattered large cells may be mistaken for Reed-Sternberg cells and steer thinking towards classic Hodgkin lymphoma, and the necrosis may lead the unwary diagnostician to favor infection.
Work-up: If flow cytometry was done on a case similar to this, negative results may be obtained, the T cells would have a normal phenotype, and There are to o few B cells to evaluate for clonality. The presence of necrosis should be the reminder that further work is needed to exclude malignancy. With the increasing availability of molecular microbiology (i.e., 16S Ribosomal RNA analysis), favoring formalin fixation to allow for morphologic assessment does not burn as many bridges as it once did.
Paraffin section immunohistochemical stains are necessary, and a panel that includes CD3, CD20, CD30, CD15, CD45, PAX5, OCT2 or BOB1, and EBV-ISH would be appropriate. Also, the enzyme histochemistry for infectious agents (AFB, GMS, PAS) and structural elements (elastin, trichrome looking for blood vessel remnants) would be very helpful. If There are cells suspicious for viral cytopathy, it may be prudent to include viral immunostains (HSV, VZV, CMV).
What is the ideal distribution of tissue to allow for complete characterization of the disease from both the diagnostic and predictive/prognostic perspective? Touch preparations of the fresh specimen may yield both necrosis and some viable small benign appearing lymphocytes. If the amount of viable, nonnecrotic lesional tissue is limited, it can be difficult to know how best to triage the tissue. The combination of small cytologi- cally bland lymphocytes and the abundant necrosis should be a cue to steer away from flow, since small cell lymphomas seldom cause necrosis and large cell malignancies are quite often fully characterizable with paraffin section immunohistochemistry.
What information should be conveyed in the final pathology report? If diagnostic features are present, the case should be top-lined as Lymphomatoid granulomatosis with a grade applied. Grading ofLyG integrates the enumeration of large lesional EBV+ cells with semiquantitation of necrosis. Although necrosis is extensive in this portion of the sample, the large EBV+ are not; thus, it would best be graded as grade II.
Case 4
eSlide 16.4
Clinical History
The patient is a 48-year-old woman being followed for elevated liver function tests complains of shortness of breath and is found to have reticulonodular infiltrates on a chest x-ray. These did not resolve with antibiotic therapy, and the respiratory symptoms worsened, so the patient underwent wedge biopsy for diagnosis.
Pathology Findings
Both pleura and interstitium are involved by a fibrosing process that includes lymphoid aggregates, germinal centers, and plasma cells. The germinal centers are polarized, widely separated, and not encircled by atypical, monotonous, or monocytoid lymphocytes. The fibrosis is relatively patternless in most areas, but focally, it forms small cartwheel-like arrays. Some blood vessels seem patulously expanded by the encasing fibrosis, and it is important to note that some of the lobular septa lack vascular elements, such as bronchovascular bundles, seem underrepresented.
Final Diagnosis
IgG4-related lung disease
Discussion
Differential considerations: With a predominant interstitial and fibrosing pattern, interstitial lung disease is the principle element of the differential for this particular case. The pattern does not, however, fit neatly into either idiopathic pulmonary fibrosis (IPF) or nonspecific interstitial pneumonitis (NSIP) or follicular bronchiolitis (FB). If the case had been mass-forming, the mix of fibrosis and inflammation would prompt consideration of inflammatory myofibroblastic tumor, solitary fibrous tumor, lymphomatoid granulomatosis, and granulomatosis with polyangiitis.
Work-up: In cases such as this, establishing the diagnosis of IgG4 disease first requires just considering it a possibility. Depending on the size of the biopsy, the density of the inflammation may be high or low, and in the lung, the storiform pattern of fibrosis and obliterative phlebitis may be subtle or even lacking. Consequently, ordering an elastin stain on one or more blocks will help in identifying obliterative phlebitis, and ordering an IgG4 stain will help in identifying the unique plasma cell population. CD20 can also be an aid: IgG4+ plasma cells have been shown to be positive for this marker, which would be negative in plasma cells outside of this context.
ttere is too much fibrosis for this to represent FB, and the patchy rather than uniform distribution of inflammation and fibrosis would be unusual for NSIP. While the uneven distribution of diseased lung might resemble temporal heterogeneity, without fibroblastic foci, the diagnosis of IPF should be approached with great caution.
Granulomatosis with polyangiitis or lymphomatoid granulomatosis may enter the differential, but the lack of vasculopathy/vasculitis and necrosis and the chronic rather than acute inflammatory component is more typical of IgG4 related disease.
What is the ideal distribution of tissue to allow for complete characterization of the disease from both the diagnostic and predictive/prognostic perspective? If, on triaging the fresh specimen with touch preps and frozen section, the lymphoid infiltrate is especially dense, it may be useful to set aside some tissue for flow cytometry. If not, then the entirety of the work-up can be performed with paraffin-embedded tissue.
What information should be conveyed in the final pathology report? If all three cardinal features are present and There is supporting immunohistochemical evidence of increased serum IgG4 and increased tissue IgG4+ plasma cells, a top line diagnosis of “IgG4-related lung disease can be rendered” Ifless than the full complement of features are present, then nomenclature such as “highly suggestive of” or “probable” might be used. It is important to include the fact that IgG4 disease is systemic, and other organ systems may be affected synchronously or metachronously.
Case 5
eSlide 16.5
Clinical History
The patient is a 16-year-old girl with common variable immunodeficiency who gradually developed shortness of breath to the point that it limited
her ability to participate in physical education. Radiologic studies have demonstrated bilateral reticulonodular infiltrates. She began to develop intermittent fevers and was noted to have splenomegaly on CT scan. Out of concern for the possibility of lymphoma, diagnostic biopsy was performed.
Pathology Findings
The peribronchiolar tissues are expanded by lymphoid aggregates containing germinal centers that compress and distort the bronchial lumens. The lymphocytes are small and cytologically bland, and There is no necrosis, no angiocentricity, and no angiodestruction. Plasma cells are few and far-between, and There is no significant fibrosis.
Final Diagnosis
Follicular bronchiolitis
Discussion
Differential considerations: Lymphoid interstitial pneumonitis (LIP), nodular lymphoid hyperplasia, hypersensitivity pneumonitis, and IgG4 disease might all be considered. Incomplete sampling of a low-grade lymphoma is also a theoretical possibility, although it would be unusual in a patient of this age.
Work-up: If the lymphoid component seems suspicious in density or cytomorphology, a screening panel of immunohistochemical stains that includes CD20, CD3, CD5, CD20, CD21, cyclin D1, TdT (in young patients), bcl2, and bcl6 can be employed. The B cell predominant pattern
expected for FB contrasts with the T cell predominance in LIP, and There will be no aberrant phenotype for either B cells or T cells. Well- stained, thinly cut H&E stained sections should demonstrate cytologic monotony and other helpful features (proliferation centers in CLL, Dutcher bodies, and plasma cells in marginal zone lymphoma) in most lymphomas. Close scrutiny of the bcl6 stain in interfollicular areas is important, and finding too many bcl6+ cells outside of the context of germinal centers should prompt further work up for follicular lymphoma.
The distribution of the lymphoid infiltrate provides the key to excluding other reactive lymphoid proliferations in FB, the lymphoid infiltrate is confined to the peribronchiolar zone, without extension into the alveolar septae, as is typical in LIP. Nodular lymphoid hyperplasia forms discrete masses or nodules in the lobules, which is not present in this case.
The peribronchial chronic inflammation can indicate hypersensitivity pneumonitis, which may be difficult to exclude since not all cases of HP exhibit granulomas and chronic interstitial pneumonitis. A good clinical history and high level of clinical suspicion are keys to recognizing this possibility.
What information should be conveyed in the final pathology report? the pattern of the process should be carefully described and correlated with the available clinical information. If the specimen is quantitatively limited, or if it contains any features unusual for FB that suggest a more specific condition (e.g., hypersensitivity), this should be clearly stated.