PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The lymphoid neoplasms include an ever-increasing spectrum of disorders defined by a combination of morphologic, immunophenotypic, and genetic features.
PERSPECTIVE AND PATTERNS OF SPREAD
Hodgkin's Lymphoma
The first case described by Thomas Hodgkin, entitled “On some morbid appearances of the absorbent glands and spleen,” dramatically demonstrates the concept of contiguous spread of this lymphoid disorder (Fig. 54.1). This concept of “contiguous spread” was promulgated by Kaplan, who argued for a unicentric origin, along with other pioneer radiation oncologists who advocated for prophylactically treating the uninvolved contiguous nodal regions. Hodgkin's lymphoma (HL), which usually starts in a cervical lymph node, is believed to spread in an orderly fashion. Each contiguous nodal area is believed to be the next most likely site to be involved.
Each node, depending on its location, would involve the juxtaposed neighboring site (Fig. 54.2).
Three illustrations of cervical node involvement portray advancing stages: stage I, high cervical node (Fig. 54.2A); stage II, cervical node with mediastinal mass (Fig. 54.2B); and stage III, supraclavicular node with para-aortic node spread via thoracic duct (Fig. 54.2C). For the clinician, the patterns of spread of HL highlight the regional node-bearing areas and emphasize the need to know the location of the lymph nodes. HL can originate in any one of the different lymph node regions in the body and spread through adjacent normal lymphatic pathways. The more likely contiguous site of involvement is the one that is “upstream,” because lymph flows in prograde and centrifugal fashion from the peripheral limbs to the central core.
Lymphatic trunks gather the lymph and allow flow from different viscera and anatomic sites into lymph nodes. Once obstruction occurs, retrograde flow takes place in lymphatics, and contiguous sites may be the “downstream” lymph nodes.
Figure 54.1 | Water color painting by Robert Carswell (1793–1857) of a patient seen by him at postmortem examination in 1828; this case was the seventh described in Hodgkin's paper. Carswell's five magnificent water color paintings are the property of University College Medical School, University of London, and were rediscovered by Dr. Peter J. Dawson, who published three of them in an article in the Archives of Internal Medicine (1968;121:288–290).
PATTERNS OF SPREAD
Figure 54.2 | Patterns of spread in Hodgkin's lymphoma are due to contiguous involvement of adjacent node-bearing regions. A. High cervical nodes could retrograde to involve the parotid lymph node or Waldeyer's ring or prograde to the supraclavicular area. B. Mediastinal lymph nodes could spread to supraclavicular, infraclavicular, or cervical lymph nodes or involve hilar nodes as a gateway to pulmonary infiltration. C. Supraclavicular node retrograde can spread to epigastric and celiac para-aortic lymph nodes, as well as to ipsilateral axillary, cervical nodes, and contralateral supraclavicular nodes.
The common presentation of Hodgkin's disease is a unifocal painless enlargement of a lymph node (90%). Most often the nodal involvement is supradiaphragmatic: cervical and supraclavicular nodes can be involved in 60–80%. Primary mediastinal presentations are not very common despite mediastinal involvement often being present after staging work-up. Subdiaphragmatic involvement occurs in only 3–10% of clinical cases initially. The initial anatomic distribution of disease provides an overview of nodal vs. extranodal disease. The dissemination of HL is usually a late manifestation if the disease recurs (Fig. 54.2ABC).
Figure 54.2 | D. Anatomic distribution of sites of involvement. (From Kaplan HS, Dorfman RF, Nelson TS, et al: Staging laparotomy and splenectomy in Hodgkin's disease: analysis of indication and patterns of involvement in 285 consecutive cases, unselected patients. NCI Monograph 1973:36:291.)
In this illustration of the SIMLAP, construction of multidirectional spread, the presenting site of involvement is the anterior mediastinum (Fig. 54.2D).
The stage assumes the origin of the lymphoma in the anterior mediastinum.
To illustrate the SIMLAP construct of multidirectional spread, the presenting site of involvement is the anterior mediastinum (Table 54.2).
The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 54.2).
Non-Hodgkin's Lymphoma (NHL)
Diffuse large B cell lymphoma and follicular lymphomas are most prevalent, accounting for 50% of all cases. A large variety of associated disorders are noted that have an altered state of immunity—that is, autoimmune, immune suppression, or viral infections—and predispose the host to developing a secondary malignant lymphoma (Table 54.2A).
Understanding how lymphomas spread and advance in stage requires understanding the intricate structure of a lymph node. Lymph nodes consist of collections of lymphoid tissues, draining lymphatic vessels, typically lima bean shaped ovoids, normally ≤ 1.0 cm in size. The interstital fluid (lymph) enters via afferent channels in the convex cortex and exits via an efferent lymphatic at the hilus. This contains B and T cell domains and circulating lymphocytic cells enter via post capillary venules.
Although the cause of NHL is unknown, there are several genetic diseases and infectious agents that are believed to increase the risk. For example, some rare immunodeficiency states can result in 25% developing lymphomas. In Sjogren's syndrome there is a 30–40 times increase risk of developing lymphomas, usually in salivary glands as marginal zone NHL. In contrast T cell lymphomas are associated with celiac sprue disease (Table 54.2A).
Understanding how lymphomas spread and advance in stage requires an intimate knowledge of the intricate structures of lymph nodes and the function served by T cells and B cells.
• T cells remain in paracortex: T cells migrate to the thymus, where in T cell receptors, each recognize a single antigen and in their diversity, T cell receptors acquire CD3 and CD2 antigens define these lymphocytes as T cells. As other antigens appear, such as CD4 – defines helper cells and CD8 suppressor cells. The cells migrate from the thymus gland to lymph nodes. Once exposed to antigens specific for receptors, CD4 (helper) cells become activated. T lymphocytes once activated by antigen peptides become “killer cells”, eliminating viruses and foreign cells. A subpopulation of natural killer cells (NK cells) do not require antigenic recognition for their cytotoxic activity.
• B cells home to germinal centers: B cells acquire and collect cytoplasmic and cell surface antigens in the bone marrow i.e., CD19, CALLA, CD10, and a nuclear antigen TdT and mature expressing additional surface antigens CD22, plus lg heavy and light chains. Terminally differentiated B lymphocytes are plasma cells.
The numerous B and T/NK cell lymphomas are tabulated as to their incidence in Table 54.2B.
OVERVIEW OF LYMPHOID SYSTEM
The lymphoid system is represented diagrammatically in Table 54.3; Fig. 54.5 shows more explicit anatomic identification of lymph node stations and sites.
The term “variant lymphocytes” covers atypical lymphocytes and large granular lymphocytes. Atypical lymphocytes are large and exhibit deep blue to pale gray cytoplasm; they are seen in benign reactive processes. Large granular lymphocytes are medium-to-large lymphoid cells with some pink cytoplasmic granules. They are suppressor T lymphocytes, some with natural killer (NK) function, and may be increased in benign or malignant disorders. Plasmacytoid lymphocytes have abundant blue cytoplasm and are seen in some reactive disorders.
Figure 54.3 | A. Structure of a normal lymph node. B. Lymphocyte morphology. The term “variant lymphocytes” covers atypical lymphocytes and large granular lymphocytes. Atypical lymphocytes are large and exhibit deep blue to pale gray cytoplasm; they are seen in benign reactive processes. Large granular lymphocytes are medium-to-large lymphoid cells with some pink cytoplasmic granules. They are suppressor T lymphocytes, some with natural killer (NK) function, and may be increased in benign or malignant disorders. Plasmacytoid lymphocytes have abundant blue cytoplasm and are seen in some reactive disorders.
OVERVIEW OF HISTOGENESIS
Anatomically, the lymphoid system is ubiquitous in design and provides the immunologic function throughout the body, consisting of lymphatic channels, lymph node stations, and lymphoid extranodal sites. Lymphocytes can circulate in blood and lymphoid tissues and are characterized by preferentially homing to and from lymph nodes (Fig. 54.4A). Each lymph node has an outer cortex and inner medulla, as well as aggregations of lymphocytes in lymphoid nodules, which exhibit a lighter central area, called the germinal center. The medulla consists of cords and sinuses that are filled with lymphocytes, plasma cells, and macrophages. Lymph enters from afferent channels through the medullary sinuses in the node and exits from the hilus with the arteriole and vein into efferent channels (Fig. 54.4B). Lymphatic tissue in extranodal sites is part of other organs such as:
• GALT: gut-associated lymphoid tissue in small intestine, appendix (Fig. 54.4E)
• BALT: bronchus-associated lymphoid tissue in the respiratory system
• MALT: Mucosal-associated lymphoid tissue in mucous membranes of digestive septa or tonsil (Fig. 54.4C)
In the embryo and newborn, lymphocytes are generated as T cells in the thymus gland (Fig. 54.4D) and B cells in the bursa of Fabricius (as in the appendix; Fig. 54.4E), which populate bone marrow and peripheral nodal sites. The spleen can be viewed as a large node or an extranodal site with a more elaborate vascular supply (Fig. 54.4F). A connective tissue capsule with its fibrous septa divides the interior into incomplete compartments, that is, white and red pulp. The red pulp consists of splenic cords and sinuses, which interconnect, and eventually these blood channels exit via its vein. Perhaps the largest accumulation of lymphocytes is in peripheral lymph nodes and the central bone marrow, with rapid exchange among lymphoid sites.
Figure 54.4A | Overview of lymphoid system histogenesis. A. Total lymphoid system. B. Lymph node. C. Tonsil: mucosa-associated lymphoid tissue (MALT). D. Thymus. E. Small intestine and appendix: gut-associated lymphoid tissue. F. Spleen.
HISTOPATHOLOGY
To provide a basis for the classification of lymphomas, the histologic and physiologic elements of the structure of lymph node with its T cell and B cell lymphocyte domains are important. Lymphocytes mature in the thymus by virtue of developing CD3 antigen receptors. The large diversity in T cell receptors reflects the fact that each T cell recognizes a single antigen. Other key antigens are CD4 (helper) and CD8 (suppressor) lymphocytes.
• B lymphocytes mature in the bone marrow and express surface antigens CD19, CD20, and CD22, plus light and heavy immunoglobulin (Ig) chains.
• The cortex of a lymph node contains the T cell and B cell domains, and, circulating, they enter via the paracortex. T lymphocytes remain in paracortex; B cells migrate to the germinal centers (Fig. 54.3A).
Many different classifications of lymphomas have evolved over time. Currently, the revised European–American Classification of Lymphoid Neoplasms (REAL) has been adopted by the World Health Organization (WHO) and is standard for clinical trials. The list in Table 54.3 is defined by a combination of morphologic, immunophenotypic, and genetic aspects that have distinct clinical features. However, morphology is the most reliable and basic approach for classification, with immunotyping reserved for difficult cases. Some of the more common histopathologies are presented in Fig. 54.4A–E.
LYMPHOMAS
Malignant lymphomas are a very heterogeneous group derived from B cells and T cells. The REAL classification has been adopted by the WHO, which distinguishes between non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphomas. The more common histopathologic types are illustrated, as well as some less frequent types, to provide an overview of the spectrum of the lymphomas. The incidence is noted (%) for each group of lymphomas.
• (30%) Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of aggressive, potentially curable B cell neoplasms.
• (22%) Follicular lymphoma (FL) is the malignant counterpart of lymphocytes derived from follicle centers. Unlike any other type of lymphoma, FL mimics an entire functional unit of lymphocytes, including their ancillary cells. The opposite of FL is diffuse lymphoma.
• (7.6%) MALT lymphomas are indolent, malignant T lymphocyte proliferations of small to medium-sized lymphocytes, with frequent monocytoid features and variable admixtures of plasma cells.
• (6%) Mantle cell lymphoma is a B cell neoplasm of small to medium-sized lymphocytes with irregular nuclear features.
• (6.1%) Small-cell lymphoma is a malignant B cell proliferation of small, mature-appearing lymphocytes and a variable number of larger cells (prolymphocytes and paraimmunoblasts).
• (2.5%) Burkitt's lymphoma is one of the most rapidly growing malignancies.
Figure 54.4 | B. Diffuse large B cell lymphoma. Tumor cells show prominent nucleoli. C. Follicular lymphoma. The normal lymph node architecture is replaced by malignant lymph follicles. D. Mucosa-associated lymphoid tissue (MALT) lymphoma. Lymphoepithelial lesions of the stomach are present. E. Small lymphocytic lymphoma/leukemia. On microscopic examination, the lymph nodal architecture is replaced by a diffuse infiltration of normal-appearing small lymphocytes. F. Mantle cell lymphoma. A nuclear stain for BCL-1 is positive. G. Burkitt's lymphoma. Lymph node is effaced by neoplastic lymphocytes with several starry-sky macrophages (arrows).
HODGKIN'S DISEASE
Classic Hodgkin's disease is identified by the clonal proliferation of mononuclear cells that are multinucleated and express CD30; they were described by Reed and Sternberg and referred to by their names (Fig. 54.4H, I).
There are histopathologic varieties:
• Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) features Reed–Sternberg cell variants called “popcorn” of lymphohistocytic (LH) cells (Fig. 54.4I).
• Nodular sclerosis Hodgkin's lymphoma (NSHL) features a nodular architecture creating islands of lymphoid tissue surrounded by fibrosis (Fig. 54.4J).
• Mixed cellularity Hodgkin's lymphoma (MCHL) contains Hodgkin and RS cells against a mixed inflammatory background of eosinophils, neutrophils, macrophages, and plasma cells (Fig. 54.4K).
• Lymphocyte depleted HL shows a predominance of Reed–Sternberg cells with relatively low number of lymphocytes (Fig. 54.4L).
Figure 54.4 | H. Classic Reed–Sternberg cell. Mirror-image nuclei contain large eosinophilic nucleoli. I. Reed–Sternberg and Hodgkin cells. The cells are positive for CD30 (immunohistochemistry). J. Hodgkin's lymphoma; nodular sclerosis. A low-power photomicrograph demonstrates broad bands of fibrosis. K. Hodgkin's lymphoma; mixed cellularity. A photomicrograph of a lymph node shows classic, binucleated, and mononuclear Reed–Sternberg cells; lymphocytes; and mild diffuse fibrosis. L. Hodgkin's lymphoma; lymphocyte-depleted type. Two tumor cells are seen (arrows). The number of reactive lymphocytes in the fibrotic background is markedly reduced.
ANATOMIC STAGING SYSTEM—LYMPHOMAS
In 1971, the Ann Arbor staging system was introduced; it was internationally adopted with minor modification in Cotswold, England, in the earliest joint editions of the American Joint Committee on Cancer/International Union Against Cancer (Fig. 54.5). This classification has remained stable with minor modifications and is applicable to both HL and non-Hodgkin's lymphoma (NHL). Most classifications rate an extranodal site as “localized,” which deserves an “E” designation as part of the staging process. Briefly, stage I is one node-bearing region; stage II is two or more node-bearing regions on one side of the diaphragm; stage III is a node-bearing region on both sides of the diaphragm; and stage IV is dissemination to extranodal visceral sites. This anatomic classification was based on two new definitions: (1) a node-bearing region and (2) an extranodal site of involvement.
• Node-bearing regions: There are six major and five minor regions, but they do not have a foundation anatomically and have been assigned by consensus.
• The diaphragm is a critical landmark in the staging process, and supradiaphragmatic presentations carry a better prognosis than infradiaphragmatic ones. The diaphragm again is an anatomic but not a physiologic divide of the lymphoid system.
• Extranodal sites include Waldeyer's ring of pharyngeal lymphoid tissue, the spleen, Peyer's patches in the intestine, and bone. In immunosuppressed patients, when visceral sites are involved, such as brain, liver, lung, or bone marrow, these are considered to be disseminated sites similar to metastases.
For lymphomas, the TNM system could be visualized (similar to cancer) if “extranodal (E) sites” were the origin of the malignant lymphoid process and then spread to regional nodes. However, this parallel is not a common occurrence. Noncontiguous spread, which is less predictable and less orderly, occurs in NHL. The malignant lymphocyte is like the normal lymphocyte; it tends to enter the general circulation but homes back to lymphoid tissue and accounts for the random general spread pattern of lymphomas. The normal cellular migration streams have been diagrammed by Yoffey and are referred to as “the fourth circulation.” The therapeutic and diagnostic implications in treating lymphomas require a thorough evaluation of all lymphoid sites.
The lymphocyte is a highly mobile cell both when healthy and diseased. It can enter rapidly into the general circulation in the lymph nodes, which have rich beds of postcapillary venules, or move in a more orderly fashion from one nodal station to the next through lymphatic channels, eventually returning to the blood via the thoracic duct. Patterns of spread in lymphomas and HL are as follows.
• An early phase involves only lymphoid tissue and lymph nodes.
• In HL, the spread is more predictable, using lymphatic channels between contiguous sites.
• In lymphomas, the spread is random, confined to nodal and extranodal lymphoid tissues and organs.
• Virtually all lymphoid tissues can be involved and are at risk.
• Dissemination via hematogenous channels often is a late event, and transformation of lymphoma into a leukemic phase can be the terminal event.
Some clarification regarding extranodal sites:
• Spleen involvement is established if there is splenomegaly along with imaging of multiple focal defects.
• Liver involvement is due to hepatomegaly with multiple focal defects.
• Lung and bone involvement can be found as single infiltrates or multiple lesions. Both can be considered extranodal sites (E) if they are contiguous to a node. They need to be the only anatomic site involved to be considered focal extranodal (E) sites. If both or more sites are involved, the patient is stage IV.
• Neurologic involvement is considered disseminated disease and is common in advanced stages and/or immunosuppressed patients.
• Bone marrow involvement is distinguished from bone involvement and is always considered to be disseminated disease (stage IV).
• For the purposes of staging, some extranodal sites are considered as nodal sites—Waldeyer's ring, thymus, and spleen. NHL in 25% of presentations is an extranodal site.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
There are no changes to the stage groups in the seventh edition for Hodgkin's lymphoma and non-Hodgkin's lymphoma.
Primary cutaneous T cell lymphoma (CTLC): Mycoses Fundoides and Sezary Syndrome. Although there are no major changes in the staging of Mycosis Fungoides, when comparing the 6th vs. 7th edition of AJCC Manuals, there are more refinements in substages and peripheral blood involvement has been added and emphasized as a new feature. Erythematous patches progress to plaques, then tumors. Sezary syndrome is the aggressive leukemic and erythrodermic form of CTLC with circulating atypical malignant T lymphocytes with cerebriform nuclei (Sezary cells).
Figure 54.5 | ENM anatomic staging. Bars are color coded: stage I, green; II, blue; III, purple; and IV, red.
• Stage I: involvement of a single lymphatic site (i.e., nodal region, Waldeyer's ring, thymus, or spleen) (I), or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin's lymphoma).
• Stage II: involvement of two or more lymph node regions on the same side of the diaphragm (II), or localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by a subscript.
• Stage III: involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, S). Splenic involvement is designated by the letter S.
• Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.
N-ONCOANATOMY
OVERVIEW OF LYMPHOID N-ONCOANATOMY
For staging, lymph node regions are defined in Fig. 54.6A based on general agreement at the Rye, New York, and Ann Arbor, Michigan, meetings rather than any anatomic–physiologic principles. A more comprehensive overview is presented from an anatomic physiologic viewpoint (Fig. 54.6B).
The lymphoid and lymphatic system is diverse. The organization of this system is akin to a separate circulation, which allows lymphocytes, interstitial fluid, and plasma proteins from every tissue and organ system to be collected through lymphatic channels, at regional lymph node stations. Depending on the anatomic location of the organ, the collected lymph then passes through an array of distant lymph nodes and channels, coalescing first into the cisterna chyli below the diaphragm, into the thoracic duct, and finally into the bloodstream. Malignant lymphocytes follow the pathway of normal lymphocytes. An understanding of this normal pathway makes the concepts of both contiguous spread and random spread of lymphoid malignancies more readily appreciated.
The classic book on the anatomy of the lymphoid system is Anatomy of Human Lymphatics by H. Rouviere (1832). The drawings have been modified largely from his renderings of lymphatics and lymph nodes for each site. The lymphoid system has been of interest to many other anatomists and pathologists. Such sources as Cruikshank's The Anatomy of the Absorbing Vessels of the Human Body (1786), Kampmeier's Developmental Anatomy (1919), and Yoffey's Lymphatics, Lymph and Lymphomyeloid Complex (1970) are excellent historical references, which still apply today. Excellent renderings of regional node-bearing areas and anatomy exist in surgical dissection and resection diagrams for cancers of specific organs. The classic “en bloc” or “radical” operation of cancer surgery is the removal of first station or regional lymph nodes with the primary tumor. For example, a radical mastectomy is the removal of primary breast cancer, the breast, and axillary lymph nodes, as compared with a simple mastectomy, which usually does not remove lymph nodes. Simple hysterectomy versus radical hysterectomy emphasizes the removal of lymph nodes in addition to the cervix and uterus in the latter operation. Some key anatomic factors are summarized as follows.
• There are 12 so-called “lymph node bearing regions” as defined based on general agreement (Fig. 54.6A). However, if all specific lymph node stations are counted, there are 36 lymph node stations (Fig. 35.6B).
• Specific major lymphatic trunks drain each structure, site, and viscera, and generally coalesce in two major sites on either side of the diaphragm—the cisterna chyli or the thoracic duct. The cisterna chyli drains the abdomen and pelvis and empties into the thoracic duct, which drains the lungs, mediastinum, heart, breast, and head and neck.
• The first station (echelon) of lymph nodes comprises the “regional” lymph nodes that first receive the lymph from the major lymphatic trunks draining a structure, site, or viscera.
• The second station (echelon) of lymph nodes is referred to as “juxtaregional.” It is the next region to receive lymph from first-station nodes.
• Although bypass mechanisms and collateral channels exist, lymph generally flows from organs in a prograde fashion to their first-station regional nodes.
• The thoracic duct drains into the junction of the left subclavian vein and the internal jugular vein.
• The diaphragm is rich in lymphatics and drains the peritoneal cavity. The lymphatics, located on its undersurface, are greater on the right than on the left.
Lymph from the right side of the head, right upper extremities, and right upper thorax drain into the right subclavian duct, which empties into the venous circulation at the junction of the right subclavian and internal jugular veins. Lymph from the rest of the body drains alternately to the thoracic duct, which empties on the left side at the junction of left subclavian and internal jugular vein.
The staging of HL depends on biopsy of major lymph nodal sites below the diaphragm. One needs to identify the sites that commonly are sampled. These include any enlarged para-aortic or pelvic lymph nodes and the splenic hilar nodes and spleen (which are removed). The liver and the bone marrow are biopsied, the porta hepatis is explored, and the mesentery is biopsied, particularly in NHL.
Extranodal or extralymphatic sites (ENM) include the bone marrow, the gastrointestinal tract, skin, bone, central nervous system, lung, gonads, ocular adnexae (conjunctiva, lacrimal glands, and orbital soft tissue), liver, kidneys, uterus, etc. Hodgkin's lymphoma rarely presents in an extranodal site alone, but about 25% of non-Hodgkin's lymphomas are extranodal at presentation. The frequency of extranodal presentation varies dramatically among different lymphomas, however, with some (mycosis fungoides and MALT lymphomas) being virtually always extranodal, except in advanced stages of the diseases, and some (follicular lymphoma, B-cell small lymphocytic lymphoma) seldom being extranodal, except for bone marrow involvement. For the purpose of coding and staging, lymph nodes, Waldeyer's ring, thymus, and spleen are considered nodal or lymphatic sites.
Figure 54.6 | A. Lymph node–bearing regions. Diagram of the anatomic definition of separate lymph node regions adopted for staging purposes at the 1965 Rye symposium on Hodgkin's lymphoma (HL). B. N-oncoanatomy: human body. Anatomic distribution of major lymph node stations. Left. Anterior view. Right. Lateral view.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Histopathology
The lymphoid neoplasms include an ever-increasing spectrum of disorders. The large variety of sites affected and the systemic distribution of lymphomas reflects the ubiquitous distribution of the lymphocyte. The array of lymphomas and lymphoproliferative conditions has undergone a metamorphosis over the last five decades and has made their classification more accurate and perhaps more confusing. Morphologic criteria based on both the macropathology and micropathology of the lymph node have been supplemented by immunotyping and genetic features of the lymphocyte. These lymphoid neoplasms have a common ancestry with either B cells, T cells, or natural killer cells. Accordingly, the NHLs collectively include the neoplastic versions of these cells and in addition include HL and lymphoid leukemias. Currently, the Revised European–American Classification of Lymphoid Neoplasms (REAL) has incorporated the histopathology of the original Working Formulation of the International Lymphoma Study Group with the newer immunomolecular markers to define 50 different categories of lymphoid neoplasms in NHL (Table 54.3) whereas in HL there are 4 varieties histopathologically (Fig. 54.4H,I,J,K,L).
Clinical Staging and Imaging
Careful inspection and clinical palpation of all peripheral sites is mandatory: head and neck, upper limb (epitrochlear node) and axilla, inguinal/femoral area, and lower limb (popliteal and femoral nodes). Thoracic and abdominal nodes require imaging. Liver and spleen should be palpable if enlarged. Spiral computed tomography (CT) and magnetic resonance imaging (MRI) can provide cross-sectional anatomy. Suspicious nodes are defined with different size thresholds. Most nodes ≥1 cm and certainly 1.5- to 2-cm rounded nodes are considered positive and, if possible, deserve needle aspiration or excisional biopsy to confirm. Retrocrural nodes >0.5 cm are considered highly suspicious. Imaging can establish organ invasion of liver, spleen, lung, bone, and central nervous system. MRI is excellent to show bone marrow invasion, but aspiration biopsy is advised for confirmation (Table 54.4).
Pathologic Staging
Laparotomy, once routine in HL, allowed for histopathologic verification of lymphomatous invasion of liver, spleen, bowel, mesentery, omentum, accessible bone, and bone marrow. Currently, imaging and selected image-guided biopsy of suspicious areas can provide histopathologic verification for more accurate staging. Needle biopsy is limited in HL because aspiration of a Reed–Sternberg cell is essential for the diagnosis. An excisional biopsy of an enlarged node is preferred.
ONCOIMAGING ANNOTATIONS
Hodgkin's Lymphoma
• Generally, tumor is detected in cervical nodes when they are enlarged (≤10 mm), become more round, or increase in number.
• Lymphomas usually show homogeneous nodal enhancement. Central nodal necrosis is exceedingly rare.
• In the patient with low mediastinal or hilar abnormalities, CT is critical in verifying disease and better in defining the contiguous lung parenchyma for unsuspected involvement.
• Nodal size criterion is reduced to 6 mm for prevascular, internal mammary, posterior mediastinal, and anterior diaphragmatic nodes.
• HL primarily involves the upper abdominal and retroperitoneal nodes, whereas NHL may involve any of the nodes, including the mesenteric nodes. Retroperitoneal lymph nodes involved with HL rarely become grossly enlarged, detracting from the accuracy of CT.
Non-Hodgkin's Lymphoma
• On both ultrasonography and CT, a relatively specific finding of mesenteric NHL is the “sandwich” sign, in which tumor infiltrating the mesenteric leaves or nodes encase the mesenteric vessels.
• Waldeyer's ring is the most common head and neck site for extranodal NHL.
• Single or multiple submucosal nodules or masses are common in bowel lymphoma, and as the lesion outgrows its blood supply, mucosal necrosis may occur, leading to ulceration and cavitation.
• Diffuse infiltration of the submucosa causes wall thickening and enlargement of the folds.
• One of the unusual features of small-bowel lymphoma occurs after transmural extension of the lymphoma, resulting in aneurysmal dilation of the involved bowel.
• Lymphomatous involvement of the spleen occurs in three patterns: diffuse infiltration, small nodules 1 cm in diameter, and macronodules. Imaging typically detects only the macronodular form.
• Lymphomatous renal masses are frequently bilateral and often significant retroperitoneal lymphadenopathy is absent.
• MRI is exquisitely sensitive to bone marrow involvement, and in select patients, it may serve to guide biopsies.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
There are a number of prognostic indices that have been adopted by international and national investigators for lymphomas and used for clinical trials and treatment options (Table 54.5B).
Clinically significant:
• Associated with HIV/AIDS
• Symptoms at diagnosis (B symptoms)
• International Prognostic Index (IPI) score
• Follicular Lymphoma Prognostic Index (FLIPI) score
• International Prognostic Score (IPS)*
CANCER STATISTICS AND SURVIVAL
The NHL collective dominates the incidence of lymphoid neoplasms, with an estimated 65,000 new cases annually and increasing at an alarming rate, perhaps due to the increase in the aging population. This compares with a relatively stable population of approximately 8,000 new HL patients annually, which has been decreasing in the older age groups, again due to more accurate immunotyping. HL has a bimodal peak incidence of 15 to 35 years and a smaller peak between 40 and 60 years. NHL increases after age 45 years with each decade of age. HL was considered incurable 50 years ago and is now highly curable, particularly in the earliest stages of evolution. Fortunately, the advances in multimodal treatment, especially in multiagent chemotherapy added to shaped large radiation fields, have improved survival dramatically. Although NHL is considered to be a generalized condition, HL is thought to be unicentric in origin.
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 622.
The mortality rate is dramatically different; HL is highly curable, with only 1,000 deaths, compared with NHL, for which 20,000 (>30%) die annually. The dramatic gain in survival as shown over five decades was the first evidence that advances in all modalities when combined could conquer cancer. This was especially true for megavoltage irradiation and extended field techniques pioneered by Kaplan and combination chemotherapy (MOPP) by DeVita and Carbone. Numerous survival curves are presented by the International Non-Hodgkin's Lymphoma Prognostic Factors Project. The outcomes for low-risk patients are contrasted with high-risk disease: Complete remission rates are 87% versus 44%, and overall 5-year survival rates are at 73% versus 26%, respectively. Patients with low-grade follicular B cell lymphomas live with their disease, gradually dying over a decade, whereas high-grade B cell diffuse lymphoma patients tend to respond to therapy, as do anaplastic large T cell patients, and they reach a plateau and remain disease free (Figs. 54.7 and Fig. 54.8).
• FLIPI: For lymphoma treated patients, the low-risk versus high-risk complete response rates are 87% versus 44%. Overall survival rates are 44% versus 26%.
• IPS: For Hodgkin's lymphoma, low-risk versus intermediate-risk versus high–risk 10-year survival rates are 11% versus 51% versus 36%.
• Freedom from progression of disease according to number of risk factors is as follows: 0, 77%; 2, 67%; 3, 60%; 4, 51%; and 5 or more, 42%.
Figure 54.7 | A. Five-year survival. B. Trajectory of the curability of Hodgkin's lymphoma (HL), 1950 to 2000 (gain in survival, 65%; decrease in mortality, 65%). The curability of HL rose, with dramatic doubling in survival in the decade between 1960 and 1970, due to the introduction of megavoltage linear accelerator technology and advances in multiagent chemotherapy. (Data for part A from Edge SB, Byrd DR, and Compton CC, et al, AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)
Figure 54.8 | Survival for NHL. A. Follicular lymphoma. B. Extranodal B-cell lymphoma, MALT type. C. Diffuse, large B-cell lymphoma. D. Anaplastic large T-cell lymphoma. IPI, International NHL Prognostic Index Factors Project; FFS, Freedom from Relapse; OAS, Overall Actuarial Survival.
SECTION 7
Ophthalmic Primary
Sites
