Alain C. Borczuk, MD
Introduction and General Considerations
Neuroendocrine tumors are grouped together based on common morphologic features and the finding of ultrastructural neurosecretory granules whose presence we detect using immunohistochemistry (IHC). There has been movement toward uniformity of nomenclature for these tumors, especially within the gastrointestinal tract and pancreas. This has resulted in a grading schema that incorporates low-grade, intermediate-grade, and high-grade neuroendocrine tumors. However, in the lung, the terminology remains carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma because that is what is used in the International Association for the Study of Lung Cancer/World Health Organization (IASLC/WHO) classification.1
The origin of these tumors remains a topic of discussion. The earliest investigations of scattered cells within secretory mucosa of the gastrointestinal tract had in common the recognition that There were cells within the mucosa oriented away from the lumen and identifiable through histochemical reactions with silver salts. These first observations raised issues as to the possibility of secretion into the vasculature rather than the luminal space, and also allowed for a method of detection in various organs. These cells were given different names including enterochromaffin, argentaffin, and Kulchitsky cells based on their staining characteristics and the histologist who studied them. Oberdorfer coined the term Karzinoid tumoren and Masson raised the possibility that these tumors were related to Kulchitsky cells with a secretory endocrine nature. Feyrter suggested that such cells were diffusely distributed among mucosal surfaces, and introduced a diffuse neuroendocrine system.2,3
Pearse and colleagues brought forth the concept that biochemical reactions in these cells—amine precursor update and decarboxylation (APUD)—were common to this cellular system and also postulated a neural crest origin for these cells. However, experimental evidence mounted that these cells were not of neural crest origin, and further studies showed that thyroid C-cells, melanocytes, myenteric plexus, and paraganglia were of neural crest origin, but not the neuroendocrine cells of various mucosal linings. Instead it is postulated that these cells are derived from local precursors. However, the relationship of these cells to both epithelia and neural structures is a critical functional interface, and the spectrum of differentiation within these cells shows their own ability to straddle epithelial and spindle/neural-like differentiation.2
Neuroendocrine cells are present in adult lung as scattered, mostly single cells, within large airway epithelium. These cells are thought to be important during lung embryogenesis and in fact are more plentiful in fetal lung. Achaete-Scute Family (ASCL1) Transcription Factor 1 (BHLH) expression, a transcription factor important for neuronal cell lineage commitment and differentiation, is critical to the generation of neuroendocrine cells.4
The ultrastructural feature of neuroendocrine cells and tumors is the neurosecretory granule. Sometimes called dense core granules, these structures are round and characterized by an electron dense center surrounded by an outer membrane.5 They vary from 100 to 300 nm, and their number varies based on the grade of the tumor—more numerous in carcinoids and scarcer in small cell carcinoma.6 Because their detection requires electron microscopy (EM), this approach has been largely replaced by IHC techniques that detect proteins associated with these dense core granules.7
Chromogranins are proteins that are directly associated with dense core granules. As a result, their detection is most specific for the presence of these granules, but detection is dependent on the number of these granules within the tumor. Although both chromogranin A and chromogranin B can be present, the IHC assay commonly used has an antibody toward chromogranin A. There fore, in addition to the number of granules present, the composition and balance between chromogranin A and B determines the sensitivity of this marker.8
Synaptophysin is a membrane protein of 38,000 daltons that is associated with synaptic vesicles, both neuronal and neuroendocrine.9 In this regard, this marker can be used to detect neuroendocrine differentiation, with the understanding that other cell types produce this protein. In practice, some tumors will produce synaptophysin without detection of chromogranin, whereas others produce chromogranin without synaptophysin. However overall, synaptophysin is more sensitive than chromogranin and somewhat less specific. In one series, 27% of morphologically squamous carcinomas and adenocarcinomas were synaptophysin positive,10 a finding common to other series.11 This indicates caution in using immunochemistry independent of morphologic assessment in the classification of tumors.
Neural cell adhesion molecule (CD56) is also a widely used marker because it is immunoreactive in a wide range of neuroendocrine tumors.12 This is a cell membrane protein found in the nervous system, but also in neuroendocrine cells and tumors. Although the sensitivity of this marker is often highest among the commonly used neuroendocrine markers, nonneuroendocrine carcinomas may be positive for this protein, including ovarian stromal tumors, endometrial stromal sarcoma, synovial sarcoma, thyroid neoplasms, and natural killer cells. This lack of specificity is a problem when CD56 is used in situations where morphologic assessment is limited (small or crushed sample) or when tumors are sufficiently undifferentiated to require a broader differential diagnosis than carcinoma. In this regard, CD56 as a single positive marker among the three commonly used markers is most useful in well-sampled and morphologically suspected neuroendocrine tumors.
IHC as a technique has improved to include enhanced methods of antigen retrieval, antibodies effective in formalin-fixed paraffin- embedded tissues, and detection reagents developed to reduce background. Three markers—CD56, chromogranin, and synaptophysin—have emerged as technically reproducible neuroendocrine markers. However, other antibodies have been used in the past. Neuron-specific enolase is an enzyme found in neurons and neuroendocrine cells, and for a time it was the only consistent marker of neuroendocrine differentiation.13 Unfortunately, this protein may be found in combination with other proteins in its family, and these combinations may be found in other cell types. As a result, the most sensitive reagents will cross-react with many nonneuroendocrine tumors,14 and attempts to create more specific reagents have resulted in loss of sensitivity or technically difficult protocols. Protein gene product 9.5 (PGP9.5) is commonly expressed by neuroendocrine cells but also suffers from common expression in tumors without morphologic neuroendocrine differentiation or ultrastructural evidence of dense core granules.14
The detection of specific peptides such as adrenocorticotropic hormone or calcitonin, while feasible, is generally relegated to situations in which tumors produce associated endocrine symptoms.
As a result of its documented importance in neuroendocrine cell differentiation, IHC for ASCL1 has been investigated in tumors. Although neuroendocrine tumors are immunoreactive, a subset of nonneuroendocrine tumors is also positive for this marker. In addition, some cells that are synaptophysin positive are ASCL1 negative. Overall, although ASCL1 may be useful in determining cells that are destined to be neuroendocrine, its role in diagnosis remains uncertain.15
Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia
Definitions and Synonyms
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is currently defined by the 2015 WHO classification as “generalized proliferations of pulmonary neuroendocrine cells, scattered single cells, small nodules or linear proliferations of pulmonary neuroendocrine cells that may be confined to the bronchial or bronchiolar epithelium.” These can protrude into the lumen. Because it is found in association with tumorlets and carcinoids, this definition goes on to include these entities. Carcinoid tumorlets are nodular proliferation of neuroendocrine cells, usually with an invasive growth pattern through the airway wall, measuring 5.0 mm or less.
Neuroendocrine cell hyperplasia can be seen in association with a variety of chronic pulmonary conditions including infection, bronchiectasis, smoking-associated diseases, and high altitude, but DIPNECH itself is a bilateral condition that is considered a primary pulmonary process of neuroendocrine cell proliferation. The definition becomes increasingly complicated in settings where the background chronic lung disease can lead to histologic neuroendocrine hyperplasia, but where multifocality cannot be assessed or when imaging or clinical manifestations are not present. This is compounded by publications of both symptomatic and asymptomatic presentations of DIPNECH.
DIPNECH syndrome or DIPNECH with airways disease has been proposed as the term to encompass patients with the combination of clinical, radiologic, and pathologic findings of the symptomatic disease.16 Patients with physiologic manifestations of airway obstruction as well as imaging associated with airways disease would be included, but incidental hyperplasia and hyperplasia associated with multiple nodules would not.17 These latter categories would be defined as secondary neuroendocrine cell hyperplasia and DIPNECH without airways disease, respectively.
History
DIPNECH, as a pulmonary process associated with clinical obstructive lung disease, was described in 1992 by Aguayo et al18 in six patients in whom clinical and histologic findings were characteristic of what has ultimately been classified under this term.
Incidence and Demographics
Patients with DIPNECH are usually women in their fifth or sixth decade, with an age range from the mid-30s into the mid-70s. Although it can occur in both smokers and nonsmokers, most series show a higher frequency of nonsmokers, largely never smokers.19
Although not typically associated with tumor syndromes, it is noteworthy that one reported patient had multiple endocrine neoplasia (MEN) type 1 syndrome,20 and that another had a pituitary adenoma that was not documented as being part of a syndrome.21
Clinical Manifestations
Many patients are asymptomatic, but cough or increasing dyspnea may be present. In one review of 24 published cases, the majority were symptomatic, including cough, wheezing, or dyspnea.22 the proportion of asymptomatic patients varies by study and may reflect disease definition or study design; for example, one series divided patients based on symptomatic presentation versus imaging detection. In this series, age, gender, and smoking status were similar in both groups.20
It is common for patients to carry a diagnosis of chronic obstructive pulmonary disease (COPD), asthma, or bronchiolitis prior to the definitive diagnosis of DIPNECH.23 Pulmonary function tests may demonstrate obstructive lung disease; this was seen in about 60% of patients in one review of 100 patients.19 This also varies by series, including one in which all patients had obstructive physiology.23 In that series, over 50% of patients had oxygen desaturation to under 88% during a 6-minute walk test.
Cushing syndrome has been rarely described in multiple carcinoid tumorlets;24 in some cases, multiple tumorlets are associated with a carcinoid tumor in these cases.25,26
Radiologic Features
DIPNECH is not identified on chest radiographs unless associated with nodules.22 Computed tomography (CT) findings are described. The disease is most often bilateral. An airway-based process may be associated with thickening of bronchial and bronchiolar walls and airway dilatation may also be present. However, one critical finding is mosaic perfusion.27,28 Mosaic attenuation is the description of patchwork regions of variable attenuation. In areas of airway constriction, hypoxic vasoconstriction results in decreased perfusion and lower attenuation. This finding may not be assessed in CT studies without expiratory views.29
In addition to these observations, CT scans from patients with DIPNECH may show nodules that are associated neuroendocrine proliferations, ranging from tumorlets under 5.0 mm to carcinoids, 5.0 mm and larger. The presence of nodules varies by study, but in one retrospective series based on pathologic diagnosis, nodules were found in all cases.30
The multinodular appearance may be mistaken for a variety of other entities including metastatic carcinoma. The presence of mosaic attenuation can be due to vascular disease, but in this circumstance, the lack of air trapping on expiration assures that the heterogeneity seen does not increase in expiratory views. Other causes of small airway disease, for example constrictive bronchiolitis due to collagen vascular disease or graft versus host disease, will also result in similar CT findings.
Gross Pathology
In the absence of carcinoid tumors or carcinoid tumorlets, DIPNECH is not grossly evident. Carcinoid tumorlets can be grossly visible (Fig. 14.1). Secondary changes, such as airway dilatation and mucous plugging, can be seen.
Microscopic Pathology
The hallmark of DIPNECH is neuroendocrine cell proliferation in the airway epithelium. The neuroendocrine cells are relatively uniform and can be round, oval, or spindled. Their cytoplasm can be pale and eosinophilic or relatively clear. Their distribution is variable. The patterns of growth can include single cells that are increased in number, aggregates of cells, and confluent expansions raising overlying respiratory epithelium (Fig. 14.2). These proliferations can be sufficiently exuberant as to cause small aggregates and intraluminal projections (Fig. 14.3). When the cells extend and invade the underlying basement membrane of the epithelium extending into the airway wall, the eccentric nodularity is a carcinoid tumorlet (Fig. 14.4). Carcinoid tumorlets are defined as being less than 5.0 mm; once such nodular proliferations exceed 5.0 mm, they are defined as carcinoid tumors.
Figure 14.1 Tumorlet: Gross image of lung wedge shows a tan nodule near a bron- chovascular bundle measuring about 3.0 mm, which was a histologically proven to be a carcinoid tumorlet.
Figure 14.2 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Bronchiole with diffuse basal-oriented cellular proliferation of uniform cells, round to spindled, with smooth nuclear contour and fine “salt-and-pepper” chromatin.
Figure 14.3 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Bronchiole with nodular aggregates of neuroendocrine cells, with thinning of the surface respiratory epithelial lining.
Figure 14.4 Carcinoid tumorlet. The neuroendocrine cell hyperplasia in the bronchiole is accompanied by a nodular proliferation of neuroendocrine cells next to the airway.
A significant proportion of cases of DIPNECH will have associated carcinoid tumorlets. An additional finding that can be observed is the presence of airway wall scarring (eSlide 14.1), which can be significant, warranting a designation of constrictive bronchiolitis. This fibrosis can be in airways with DIPNECH or in adjacent airways without proliferation. However, a wide spectrum of airway findings has been reported, including airway dilatation, mucous plugging, airway inflammation, and airway wall fibrosis. In some cases, fibrosis was fairly focal, whereas in others it was multifocal and obliterative.20
There is a proposal to define criteria of at least five neuroendocrine cells in a minimum of three bronchioles associated with three or more carcinoid tumorlets. This minimum definition has not been fully tested, so it is not yet adopted17’31 in the current WHO classification.
Special Studies
Although serum chromogranin A, serum serotonin, and urinary 5-hydroxyindoleacetic acid levels can be increased, these findings are not sufficiently sensitive to warrant use in the diagnosis of DIPNECH in lieu of tissue sampling.23
The cells of DIPNECH are sometimes relatively inapparent and can be mistaken for airway basal cells or inflammatory cells. As a result, immunohistochemical markers can be useful to highlight the proliferation; these can include chromogranin, synaptophysin, or CD56 (Fig. 14.5). In relatively normal lung tissue biopsies in patients with severe obstructive lung disease, IHC may be a useful adjunct to avoid underdiagnosis of DIPNECH.
Grading and Staging
DIPNECH is a preinvasive lesion.
Differential Diagnosis
The histology of neuroendocrine cell hyperplasia in association with a variety of chronic lung diseases is the same as that of DIPNECH. There fore the multifocality of the lesions, clinical presentation, and imaging need to be combined to confirm a DIPNECH diagnosis. As a result, small samples, such as transbronchial biopsy, might demonstrate neuroendocrine cell hyperplasia, but without evidence of multifocality histologically, this observation needs to be evaluated in the context of clinical and radiologic findings.
Figure 14.5 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Immunohistochemistry for synaptophysin highlights the neuroendocrine proliferation eccentrically involving the airway wall with projection into the lumen.
Genetics
Little is known about the genetics of DIPNECH.
Treatment and Prognosis
In a summary of 55 patients with DIPNECH in whom follow-up was available, 62% had stable disease, whereas 27% had progressive disease with worsening pulmonary function; mortality in that review series was unrelated to disease.19 In a review of 17 patients with clinical follow-up, 76% of patients had either stable disease or showed improvement; a subset of these patients was treated with inhaled corticosteroids and bronchodilators.22 Octreotide therapy in patients in whom progression occurs and in whom There are hormonal manifestations has been tried with reported success.19’32-34 In some instances, symptomatic improvement (cough) was reported.23 Lung transplantation may be an option in patients with severe obstructive lung disease.35’36 Two series reported a death due to progressive lung disease.20’23
Although DIPNECH is considered a preinvasive condition, this is based on the similar appearance of the cells in these lesions to those of carcinoid tumor, the presence of carcinoid tumorlets, and the finding of DIPNECH in association with carcinoid tumor resections.37 In fact, considering the stability of DIPNECH in most patients, subsequent neuroendocrine tumors in these patients is only rarely reported. It has been noted that the frequency of neuroendocrine hyperplasia is higher in lungs harboring neuroendocrine tumors when compared to nonneuroendocrine tumors, and was the highest in carcinoid tumors.38
Carcinoid Tumor
Definitions and Synonyms
Carcinoids tumors are neuroendocrine malignant neoplasms defined by histologic features associated with neuroendocrine differentiation, a low mitotic rate of fewer than two mitoses per 2 mm2 (10 HPF), and the absence of necrosis. In the first Armed Forces Institute of Pathology (AFIP) fascicle authored by Avril Liebow,39 these tumors were called bronchial adenoma, carcinoid type, with suggested commonality with bronchial glands and ducts; however, there was some recognition of their similarity to carcinoid tumors of the ileum. The identification of a relationship of carcinoid tumor cells to neuroendocrine cells led to synonyms such as Kulchitsky cell tumor, argentaffin tumor, well-differentiated neuroendocrine carcinoma, and Grade 1 neuroendocrine carcinoma. Although these latter terms acknowledge their malignant potential (albeit low grade), these terms are not recommended by the IASLC/WHO lung tumor classification system.1
Incidence and Demographics
Analysis of the surveillance, epidemiology, and end results (SEER) program registry in the United States from an 8-year period during the 1990s identified an incidence rate of carcinoids of the lung and bronchus at 0.45 per 100,000, similar to the rate in the small intestine.40 A subsequent study has shown a consistent increase in incidence, with 1.4 per 100,000 having been reached in 2003.41’42 It has been proposed that the rate is currently as high as 2.0 per 100,000 with a rate of increase of 3% to 6% per year. The peak age for this tumor is in the fourth to sixth decade of life, with a lower age of presentation for typical carcinoids than atypical carcinoids.43’44 A female predominance is noted, although the female-to-male ratio varies, up to 2: 1.40,45’46 the incidence of pulmonary carcinoids is highest in Caucasian populations. Smoking does not increase risk in either men or women, and alcohol ingestion does not increase carcinoid risk. A family history of cancer, not specifically of carcinoid tumor, however, imparts a higher risk of carcinoid tumor.47
Carcinoid tumors are the most common pulmonary neoplasm in children and adolescents.48-51 the majority are centrally located typical carcinoids, and conservative lung-sparing excisions are recommended in these patients. However, as many as 30% have a peripheral location.52
Although most carcinoid tumors are sporadic (>95%), some patients have carcinoid tumors in the setting of the MEN 1 syndrome.53
Clinical Manifestations
Many patients with typical carcinoids are asymptomatic, and the tumor is identified incidentally;54 this rate varies by clinical series in which half to all patients are symptomatic. When symptoms are present, they are usually related to large airway irritation such as cough or wheezing, and in some patients, hemoptysis. Obstruction of the airway can lead to atelectasis and pneumonia.55
Neurosecretory symptoms in carcinoids of the lung occur with lower frequency than in tumors of the gastrointestinal tract. Cushing syn- drome,56,57 carcinoid syndrome (usually in patients with liver metastasis),58 and acromegaly59 can occur; in carcinoid syndrome, this can be associated with an adverse outcome. Pulmonary carcinoid tumors represent a significant proportion of ectopic Cushing syndrome cases, and overall account for 1% of all Cushing syndrome patients.60
Laboratory Findings
In patients with a biochemical/endocrine syndrome, laboratory testing may include 24-hour urinary 5-hydroxyindoleacetic acid (carcinoid syndrome), serum cortisol, adrenocorticotropic hormone level, and 24-hour urinary cortisol (Cushing syndrome).43 In cases of acromegaly, serum growth hormone, growth hormone releasing hormone, or insulinlike growth factor 1 can be measured.
Chromogranin A serum levels can be measured at diagnosis, and these levels can be used to monitor for recurrence postoperatively.43
Radiologic Features
Although carcinoid tumors can be identified on chest x-ray, CT scan is the gold standard. High-resolution CT can be used, and contrast enhancement on CT can be exploited due to the high vascularization of these tumors.61’62 They are usually round or ovoid with a smooth contour; they are generally slow-growing tumors.63 Calcification, nodules with hyperlucency, atelectasis, or bronchiectasis can be associated findings.
For staging purposes, imaging of the chest and abdomen should be performed.
Somatostatin receptor scintigraphy may be more sensitive at the determination of stage in carcinoid tumors and can help identify a primary tumor.64 Although sensitive, it is of note that other tumors, including carcinomas, may be positive. It has been proposed that flu- deoxyglucose (FDG) positron emission tomography (PET) may be able to distinguish carcinoid tumors from atypical carcinoids with higher proliferation rates; this technique may be most helpful in distinguishing carcinoids from high-grade neuroendocrine tumors such as small cell or large cell neuroendocrine tumors.65-67
The sensitivity of FDG-PET in detection of nodal disease in typical carcinoid is low.68 Despite the fact that N2 nodal disease does not preclude surgery, a mediastinal dissection as part of the surgical resection of the primary tumor should be performed even in FDG-PET negative cases. In individual patients in which N2 nodal status would influence surgical decisions, preoperative nodal sampling (e.g., endobronchial ultrasound guided sampling) could be warranted. Octreotide singlephoton emission CT and other novel imaging techniques such as gallium-labeled somatostatin analogues may be more sensitive at disease detection.69’70
In patients with carcinoid syndrome, echocardiography is needed to assess both right- and left-sided valves; left-sided valvular disease should be evaluated if the syndrome is seen in the absence of liver metastasis.71
Gross Pathology
Carcinoids are found in the large conducting airways including trachea and bronchi. Central location is more common, although peripheral location is seen in up to 30% of cases. By definition, carcinoid tumors are larger than 5.0 mm.
Bronchial carcinoids are, as the name implies, bronchial wall based and can protrude to varying degrees into the bronchial lumen. They are often covered by bronchial epithelium in a dome-like protrusion. The cut surface varies from tan to yellow tan (Fig. 14.6). Carcinoid tumors can also be peripheral where they are often round rather than spiculated. Multicentric forms of carcinoid tumor (not carcinoid tumorlets, which are often multiple) are reported at a rate of about 5%.72
Microscopic Pathology
Of resected carcinoids, the majority (75% to 80%) are typical carcinoids. In one series, small sample diagnosis misclassified carcinoids as small cell or non-small cell carcinomas in 10% of bronchoscopic biopsy or cytology, and in 43% of peripheral tumors in which adenocarcinomas were the reported but incorrect diagnosis. It is unclear whether ancillary studies were routinely performed in this series.73
The classic cytologic features of carcinoid tumors include loose clusters and scattered uniform cells with low to moderate amounts of cytoplasm. Nuclear features are critical; nuclei are round to ovoid, uniform and smoothly contoured, with salt-and-pepper chromatin (Fig. 14.7). Nucleoli are absent or inconspicuous, and necrosis is absent. Mitoses should be rare if identified at all. In challenging cases, errors in diagnosis are caused by cellular smears, hyperchromatic nuclei, presence of small nucleoli, and microglandular arrangements. The presence of macronucleoli should suggest a different diagnosis such as poorly differentiated carcinoma.74
Figure 14.6 Carcinoid tumor. This lobulated yellow-tan tumor is associated with a bronchus, growing out into the adjacent lung parenchyma. Lung tissue distal to the tumor shows patchy consolidation, likely due to obstruction.
Figure 14.7 Carcinoid cytology: Clusters of uniform cells with round nuclei with fine chromatin ("salt and pepper”) and smooth nuclear contour are characteristic of a carcinoid tumor.
The histology of typical carcinoid tumors includes characteristics associated with neuroendocrine morphology, which encompass architectural and cytomorphologic features. The cells of typical carcinoid tumors have nuclear uniformity with generally round nuclei with smooth nuclear contour (Fig. 14.8A). The chromatin is described as salt and pepper—that is, the chromatin is relatively uniform, without prominent chromocenters or nucleoli—and without a vesicular chromatin in the background. However, while this is seen in the majority of cells, individual cells can be larger and show small nucleoli (Fig. 14.8B). In some instances, the nuclei will be ovoid or elongated, and this may be seen with cellular elongation in spindle cell carcinoids (Fig. 14.8C). Although spindle cell carcinoids may be more often atypical, spindle cell histology does not equate with atypical carcinoid tumors, that is, mitotic rate or necrosis criteria must be met. A moderate amount of cytoplasm is seen in most tumors, although more abundant cytoplasm is a feature of oncocytic tumors (Fig. 14.8D). Despite a wide variety of architectural patterns, the uniformity of the cells is the most striking feature among these tumors and within a particular tumor.
The architecture of carcinoids can be quite varied, even within the same tumor. The classic description is an organoid pattern, that is, solid islands of cells with an intervening vasculature or delicate stroma (Fig. 14.9A). However carcinoid patterns can be solid, trabecular (Fig. 14.9B), gland-like, and rose The (Fig. 14.8A and B) forming; their stroma can be fibrous, calcified, ossified, or amyloid containing (Fig. 14.9C).
Figure 14.8 Cellular and architectural features of carcinoid tumors. (A) the cells of a carcinoid tumor are very uniform, and the nuclei are round with fine chromatin. This panel also shows rose The formation, an architectural feature. (B) Although fine chromatin is seen in the majority of cells, the presence of small chromocenters/nucleoli can be seen in carcinoids; a rose The is also present in this field. (C) the cells in a spindle cell carcinoid are long and narrow with elongated nuclei, but still uniform with fine chromatin. (D) Uniform cells with abundant eosinophilic cytoplasm in an oncocytic carcinoid.
Once neuroendocrine cytology and architecture are confirmed, specific histologic features are required to designate a tumor as typical carcinoid. There should be no necrosis. In addition, the mitotic rate is low; this is less than two mitoses per 2 mm2; this field size represents an attempt to standardize 10 high power field (HPF) across different microscopes.75 Despite the difficulty in determining field size, a more challenging problem in mitotic figure counting is the selection of hot-spot fields. In this regard, the cutoff of less than two mitoses is inclusive of some tumors in which two or three mitoses are identified within one set of fields but not others. This could lead to an atypical carcinoid designation and would be dependent on the numbers of total fields counted per case. This was confirmed by Tsuta et al.76 with atypical carcinoids that were “overcalled” when counting only one set of 10 HPF or 2.0 mm2, which would have been deemed typical using an average or mean approach.
With this in mind, the 2015 WHO/IASLC classification recommended that cases with counts on the cusp of the classification cutoff be analyzed for three sets of 2 mm2 requiring an average number equal to or greater than required for atypical carcinoid. Although a helpful guideline that reduces the “overcalling” of atypical carcinoid, these rules did not define which counts are on the cusp of the classification. For example, do four mitoses in one set of enumerated 2-mm2 fields exclude typical carcinoid, or is this diagnosis still allowed if the average over three sets is still fewer than two? In addition, Tsuta et al. counted many HPFs per case, and perhaps three sets of fields is not a sufficient number to average. With these caveats in mind, from a practical point of view, the counting of at least three sets of fields to achieve an average rate that is two or more addresses the situation in which the very stringent cutoff of two mitoses in 2 mm2 is reached focally within what is otherwise a typical carcinoid.
Margin assessment in carcinoid tumors is critical, but an optimal distance has not been determined. In one series, recurrences were not seen if margins exceeded 1.0 cm, but at less than 2.0 mm, recurrences did occur.77
Figure 14.9 Architectural features of carcinoid tumors. (A) Organoid patterns show solid nests of cells with intervening fine vascularity as seen in this image or in other cases fibrous tissue. (B) Ribbon-like arrangements of cells in a trabecular pattern. (C) Stromal fibrosis with focal calcification is seen.
Special Studies
Although IHC is not required for the diagnosis of typical carcinoid, the difference in biologic behavior between these tumors and what is in their differential diagnosis often warrants additional testing. Neuroendocrine markers may be helpful because these tumors should be positive for one or more neuroendocrine markers and often have diffuse strong reactivity. These markers can include synaptophysin, chromogranin, or CD56/NCAM (neural cell adhesion molecule). Overall, chromogranin is the most specific and least sensitive neuroendocrine marker; synaptophysin has greater sensitivity and reduced specificity, and CD56 has the greatest sensitivity. Of note, CD56 is the least specific, as noted in the chapter introduction.
Given the importance of ASCL1 in neuroendocrine cell development, this target has been proposed as a potential neuroendocrine marker when comparing tumors to squamous cell and adenocarcinoma. ASCL1 staining was seen in all neuroendocrine tumors, independent of grade, but not in other lung carcinomas in their differential diagnosis.78
Cytokeratin can be useful in the diagnosis of carcinoid tumors. However the AE1:AE3 cytokeratin cocktail does not stain a significant proportion of carcinoids (25% to 30% are negative), and low-molecular- weight keratin such as CAM5.2 may be needed to highlight these cases. Thyroid transcription factor 1 (TTF1) may be helpful in the determination of a pulmonary origin for a carcinoid tumor at advanced stage; in addition, TTF1 may be more frequently positive in peripheral carcinoids.79,80 Other markers such as Napsin A, p40, p63, and CK5/6, which may be used in non-small cell carcinoma classification, are negative in carcinoid tumors.81 PAX8, which has been described as a marker of pancreatic and nonileal gastrointestinal endocrine tumors, is negative in pulmonary carcinoids.82
Ki-67 has been proposed as an important adjunct in the classification of carcinoids. In the setting of a small sample, especially one with crush artifact, a low Ki-67 (<10%) may indicate a carcinoid tumor (typical or atypical) rather than a small cell carcinoma, and a high Ki-67 (>50%) may make a carcinoid tumor unlikely.83,84 This may avoid a misclassifica- tion, which could have a direct impact on the treatment strategy for a particular patient. Although broad Ki-67 cutoffs, as noted above, separate the low-grade from the high-grade neuroendocrine tumors, routine use of Ki-67 in the differential diagnosis of typical carcinoid from atypical carcinoid requires further validation of clinically relevant cutoffs. Continued interest in Ki-67 scoring stems from the promise of improvement in interobserver agreement when compared to mitotic counting.85
In one series, although atypical carcinoids had a higher average Ki-67 count, there was overlap with typical carcinoids.86 Using an automated approach to the Ki-67 index, an upper limit cutoff of 7% corresponded to typical carcinoids.87 In a review of prior series, Pelosi et al. describe a lack of uniform methodology toward measuring the Ki-67 index and varied cutoff values for disease categories.88 A proposal for a lung-specific methodology has been published, which will require further validation before it can be adopted into the future classification of carcinoids.89
The role of Ki-67 in the prognostication of pulmonary carcinoids has been investigated. While in univariate analysis a cutoff of 5% has been identified as predictive of survival, this was not independent of histologic classification. There fore evidence of independent use of Ki-67 in lieu of histology was not supported.90
It has been proposed that miRNA profiling could be used to discriminate between types of neuroendocrine tumors; however, a common identified list of these microRNA (miRNA) in a classification schema remains to be developed.91,92
Grading and Staging
In pulmonary carcinoid tumors, the classification system designates typical carcinoids as low grade. In addition, the histologic subtype is of equal if not greater importance than stage.93,94
The majority of typical carcinoids are Stage 1a.72,95 Although nodal disease occurs at a rate of about 10% to 15%, most series show N1 involvement more frequently than N2 involvement. However, increasing use of systematic nodal dissection may increase the rate of N2 detection. In some cases, N2 involvement occurs in the absence of N1 involvement.95 Tumor, node, and metastasis (TNM) staging is associated with survival.96
Variants
Spindle cell carcinoids are more often peripherally located. Although they share the nested patterns with fine vascularity of other carcinoids, the cells themselves are uniform elongated spindle cells. Although they can mimic low-grade smooth muscle tumors, they do not have the interlacing bundles of cells alternating with longitudinal and transverse profiles (eSlide 14.2). Their chromatin is uniform as in other carcinoids. Although in early series they were equated with atypia, the criteria for atypia (mitoses, necrosis) are the same as for classic carcinoids.97 Oncocytic carcinoids are characterized by abundant eosinophilic cytoplasm, which ultrastructurally represent abundant mitochondria.98 It has been suggested that this variant may be especially PET avid.99 There are variants with abundant sclerosis but without amyloid in the stroma; these tumors can be diagnostically challenging because the lesional cells are relatively sparse. This can be especially difficult in small samples; they are otherwise typical carcinoids by biologic behav- ior.100 Some carcinoids can have clear cells, and rarely melanin pigment can be seen. In addition to sclerotic stroma, carcinoids can have amyloid-like stroma and prominent stromal mucin.
Differential Diagnosis
Metastatic carcinoid tumors from other organs (neuroendocrine tumors), such as those from the gastrointestinal tract, can be seen in the lung. In suboptimal specimens with crush artifact, carcinoid tumors can be confused with small cell carcinoma, and Ki-67 can be helpful in this setting.
Because of the uniformity of the cells, tumors of bronchial minor salivary gland origin, such as mucoepidermoid carcinoma with prominent intermediate cells, can be confused with carcinoid tumors. Metastatic breast carcinoma, especially lobular carcinoma and those with a solid growth pattern, can be confused with carcinoids. Plasma cell neoplasms, especially on frozen section (and with amyloid-like stroma), can be quite difficult to distinguish from carcinoid tumors; fortunately this situation is uncommon. Although very rare in the lung, paragangliomas can be very similar histologically to carcinoid tumors. Finally, glomus tumors can have similar monotonous appearance and, given their rarity in lung, can be mistaken for the relatively more common carcinoid tumor.
Genetics
Carcinoid tumors have demonstrated allelic imbalance in 11q13 in the region of the MEN1 gene.101 MEN1 gene mutations and loss of expression are seen.102,103 These 11q deletions are seen in both typical and atypical carcinoids but not in small cell carcinomas or LCNECs. Losses of 10q and 13q are less common in typical than atypical carcinoids.104 Losses in 3p are uncommon in typical carcinoids, and losses of 5q that are common in carcinomas are uncommon in carcinoid tumors.105 ttese findings argue against a transition of low- and intermediate-grade tumors into high-grade tumors.
Mutations and gene expression in carcinoids are distinct from that of small cell carcinoma in that TP53 and RB1 mutation and loss of function are not seen in carcinoid tumors. Specifically, alterations in chromatin remodeling genes and histone methylation are seen in carcinoid tumors.106
Treatment and Prognosis
It is critical to distinguish typical from atypical carcinoids because treatment and prognosis are influenced by this pathologic distinction.
In a large series of typical carcinoids treated by surgical resection, age, male gender, peripheral tumor, prior malignancy, high stage, and poor performance status were predictors of poor outcome. This allows for a predictive nomogram that identifies a subgroup with median 5-year survival of 50%.107
Surgery with negative margins is the treatment for carcinoid tumors. As an indolent tumor, however, 5-year survival without surgical intervention, although inferior to surgery, is reported at 69%.108 For typical carcinoids, in the central location, bronchoplastic surgeries focused on sparing lung parenchyma are a successful approach,109 with negative margin evaluation, often performed at frozen section. This is to avoid the morbidity of pneumonectomy, in an effort to preserve lung function.110112 the presence of an N2 positive lymph node in carcinoid tumor, although an uncommon occurrence overall (3%), does not preclude surgery.44 For peripheral tumors, an anatomic resection is recommended to prevent relapse as sublobar resections are associated with local recurrence;113 this recommendation may be more relevant in atypical carcinoids because in some series sublobar resections have similar outcomes to lobectomy in typical carcinoids.114 Wedge resections are considered inferior to segmental resections in terms of local recurrence, but such considerations are guided by the patient’s residual lung function and tumor location. In some circumstances, a negative margin on limited resection associated with node-negative disease may be sufficient surgical therapy58,95,114 for a typical carcinoid.
In typical carcinoid tumors, the nodal metastatic rate is about 10% to 15%, with the majority of patients having N1 disease.73 Distant metastasis is uncommon, and it occurs in fewer than 3% of patients. Five-year survival is 88%,40 and extension to 10-year survival data shows only a small reduction in that number. However, patients with relapse have a reduction in 5-year survival, and There fore relapse after resection is an adverse parameter for outcome.113
Liver resections of metastatic disease may increase long-term survival, but patient selection warrants avoidance of cases with widely metastatic disease outside the abdomen, or diffuse abdominal disease.115
Bronchoscopic resection is considered an alternative when surgical excision is not possible. In addition, this approach can debulk a tumor that is obstructing an airway. The cure rate by this approach is up to 42% but the initial success rate of effective debulking is variable.116118
Chemotherapy and radiotherapy in the adjuvant setting in typical carcinoids is not generally recommended. In these surgically treated cases, discussions of adjuvant therapy are warranted in patients with incomplete resections with positive margins, and in patients with N2 disease.
Somatostatin analogs may be of use in pulmonary carcinoids in the advanced disease setting, but most studies have focused on abdominal primary tumors.119
Chemotherapeutic options in carcinoid tumors with metastatic disease include regimens of gemcitabine and oxaliplatin and regimens of oxaliplatin, 5-fluorouracil, and leucovorin. These have been associated with partial response or stable disease; these data may apply more to atypical carcinoids than typical ones.120 the response rate to chemotherapy with or without radiation therapy has been reported at 20%; in addition, the response rate does not seem to differ between atypical and typical carcinoids.121 Higher response rates are reported in series in which advanced stage tumors have a greater proportion of atypical carcinoids, and so it remains unclear whether typical carcinoids respond at the same rate.33 Overall, the use of platinum-based chemotherapy in typical carcinoids requires careful consideration of the risk-to-benefit ratio related to drug toxicity.
Streptozotocin-based therapy, which is used in advanced gastrointestinal/pancreatic neuroendocrine tumors, is associated with a lower response rate in pulmonary carcinoids.43,122 A variety of agents including everolimus,123 temozolomide, bevacizumab, and sunitinib have been tried but with lower benefit in pulmonary carcinoids than in neuroendocrine tumors of other organs.113
Control of hormone secretion is critical in advanced carcinoid patients. Somatostatin analogues are used in carcinoid syndrome, although this data is largely derived from patients with gastrointestinal tract primaries because the patients more often experience carcinoid syndrome.124 Patients with Cushing syndrome require control of symptoms as well, with medications such as ketoconazole.
In surgically treated typical carcinoids with advanced disease, median time to recurrence was 6.5 years and median overall survival was 10.2 years.125 In one series of resected carcinoid tumors with review of the literature published in 2015, the overall survival at 5 years was over 90% (88% to 97%), and at 10 years this was just below 90% (82% to 95%)55 for typical carcinoids. The 5-year and 10-year survival in carcinoids is 98% and 94% despite a subset presenting at advanced stage.126
It has been suggested that carcinoids with Cushing syndrome may be associated with adverse prognosis; however, at a minimum, carcinoid tumors associated with Cushing syndrome are more likely to be associated with lymph node metastasis.127,128
Atypical Carcinoid
Definitions and Synonyms
Atypical carcinoids are uncommon neuroendocrine neoplasms of the lung whose biological behavior lies between that of carcinoids and high-grade neuroendocrine carcinomas. It was recognized by Arrigoni and coauthors that these tumors were more likely to harbor mitoses and show necrosis129 than typical carcinoids, with others recognizing a set of distinct clinicopathologic characteristics.130,131
Incidence and Demographics
Atypical carcinoids are rare tumors, representing only 0.05% of lung tumors in the SEER database. The average age of patients with this tumor is 59 to 65 years, with a mean age higher than in typical carcinoids.132 the tumor may be more common in women, at a roughly 2 : 1 ratio, although in some series the gender distribution is balanced.72,131,133 135 Roughly 10% to 20% of pulmonary carcinoid tumors are atypical.55,135,136 Atypical carcinoids are more often associated with former or current smokers than typical carcinoids.47,137,138 Although carcinoid tumors are the most common lung neoplasm in children, atypical carcinoids are rare in this age group. This is evidenced in part by the high 5-year and 10-year survival of carcinoid tumors in children51 and the paucity of published pediatric cases of atypical carcinoids.49
Clinical Manifestations
Atypical carcinoid patients have varied presentations including signs of airway obstruction with pleuritic chest pain, atelectasis, dyspnea, or cough. Hemoptysis can occur, and patients may present with constitutional symptoms. About one-third are asymptomatic.135,138
Cushing syndrome can be a presenting feature of both typical and atypical carcinoids.127,132,139 Carcinoid syndrome may be more common in atypical carcinoids, possibly due to the higher frequency of advanced disease.140 Eaton-Lambert syndrome, which is mainly associated with small cell carcinoma, has been reported in atypical carcinoids.141
Laboratory Findings
Similar to typical carcinoids, evaluation of liver and kidney function, serum chromogranin A, and routine tests such as complete blood count (CBC) and electrolytes have been suggested.54 Specific tests may be needed to evaluate for Cushing syndrome, carcinoid syndrome, or acromegaly.
Radiologic Features
In atypical carcinoids, a larger proportion of tumors are peripheral nodules than in typical carcinoids. The nodules are round or ovoid with a lobulated appearance.142
It has been suggested that FDG avidity on PET scan is higher in atypical carcinoids,143,144 but this has not been universally reproduced.68 For atypical carcinoids, uptake on [68Ga] DOTATOC-PET is lower than typical carcinoids, despite the opposite relationship on FDG-PET.145 Mediastinal nodal status assessment by PET-CT has limited sensitivity overall and should not be relied upon as the sole modality for preoperative staging of carcinoids, including atypical carcinoids.93
Gross Pathology
Although atypical carcinoids are more frequently peripheral than typical carcinoids,132 they are less frequently peripheral than LCNEC.134 the average size of atypical carcinoids is 2.8 to 3.6 cm, which is larger than typical carcinoids.132,138,146,147 the cut surface is also generally tan, but can be more variegated, with evidence of hemorrhage. Necrosis can be seen grossly, although this is often a microscopic feature only (Fig. 14.10A). When central, these tumors can lead to obstruction, with airway dilatation and mucous plugging (Fig. 14.10B).
Microscopic Pathology
The histology of atypical carcinoids is quite varied, similar to that of typical carcinoids. Organoid and trabecular patterns may be accompanied by rosettes, papillary structures, pseudoglandular structures, and patterns of airspace filling. The cells may be more pleomorphic than that seen in typical carcinoids, but this by itself is not a diagnostic criterion for these tumors. In univariate analysis, one series found palisaded nests, papillary patterns, and rosettes to be favorable prognostic patterns; rosettes were favorable prognostically in a multivariate analysis with greater tumor size, and higher mitoses and female gender unfavorable prognostic parameters.137
The mitotic rate range of atypical carcinoids was established by Travis et al., showing that the previously reported cutoff values did not identify the entire spectrum of aggressive behavior in these tumors. Based on this work, the cutoff of 2 mitoses in 2 mm2 (10 HPF) was established at the lower end and 10 mitoses in 2 mm2 (10 HPF) at the upper end (Fig. 14.11A). In addition, necrosis was an independent histologic parameter (Fig. 14.11B).75 Although this has been a useful reappraisal of historical evaluations of atypical carcinoids, there have been some problems with application of these criteria, which were discussed in the carcinoid section. It has been noted that among cases in which interobserver agreement is unanimous for carcinoid as a category, the category of atypical carcinoid remains challenging, with 20% of cases without consensus among observers;148 reappraisal of these cases revealed that recognition of mitoses was observer dependent. Interestingly, a higher mitotic rate within the atypical category is associated with poorer outcome, so that tumors with rates of 6 to 10 per 2 mm2 had poor survival.137
Figure 14.10 Gross pathology of an atypical carcinoid tumor. (A) the cut surface of an atypical carcinoid may be more variegated with visible areas of necrosis. (B) When central, the tumors can obstruct a bronchus resulting in mucous plugging and airway dilatation.
Multicentric neuroendocrine proliferations are seen in association with atypical carcinoids and typical carcinoids.72 In one series, poorer survival was associated with atypical carcinoids when margins were less than 2.0 mm, and the recurrence rate was higher when margins were less than 1.0 cm.77
Special Studies
Atypical carcinoids are positive for cytokeratin (AE1/AE3 and CAM5.2) and neuroendocrine markers such as CD56, chromogranin, and synaptophysin.137,149 IHC for TTF1 is positive in atypical carcinoids, and perhaps at a higher rate in peripherally located tumors and spindle cell variants.79 Extrapulmonary low-grade and intermediate-grade neuroendocrine tumors are TTF1 negative, in contrast to high-grade extrapulmonary neuroendocrine tumors, which can be positive.
The Ki-67 index, although possibly more reproducible than mitotic counts,85 remains to be validated in distinguishing typical from atypical carcinoids. Differences in methodology need to be resolved to establish reasonable cutoff values.88 In a recent study, Rindi et al.89 used a combination of a Ki-67 cutoff of 4% and higher, up to 25%, along with mitotic count and necrosis, to classify atypical carcinoids. Despite consistent results that atypical carcinoids have higher Ki-67 indices than typical carcinoids by well-performed studies, cutoff numbers remain sufficiently varied, hampering a clear classification guideline.87,90,150 However the identifiable mitoses in atypical carcinoids underscores a role for Ki-67 in small samples or crushed samples to eliminate the possibility of a higher-grade tumor.83
Figure 14.11 Microscopic pathology of atypical carcinoids. (A) the morphology of the cells shows crowding and apoptotic debris, with visible mitotic activity and necrosis. Some of these features overlap with small cell carcinoma, but the mitotic rate did not reach the required cutoff. (B) Organoid nests of neuroendocrine cells are seen, but the presence of necrosis is diagnostic of an atypical carcinoid.
Ploidy analysis to distinguish typical and atypical carcinoids has been proposed, and it was found that aneuploidies were associated with atypical histology and prognosis,151 but this approach is not widely used152 because these findings were not sufficiently predictive of biological behavior.153
Analysis of somatostatin receptor tissue distribution may be of interest in determining therapy for somatostatin analogs. Interestingly, IHC detection of these receptors decreased with increasing grade in neuroendocrine tumors; however, the association with therapy has not been conclusively established.154
Grading and Staging
The precise classification of atypical carcinoids is critical to prognosis. In this regard, this group of tumors represents a histologic classification that is an intermediate grade. This is important because treatment decisions are partly stage independent with regard to surgical approaches and adjuvant therapy.93
Atypical carcinoids are usually at a higher stage at presentation than typical carcinoids.73,155 the higher rate of node metastasis and the negative survival impact of nodal involvement (especially N2 nodes) when compared to typical carcinoids makes proper histologic diagnosis critical.94
Variants
Like typical carcinoids, atypical carcinoids with amyloid-like stroma have been reported.156 Rare carcinoids have melanin pigment, including atypical carcinoids.157 Atypical carcinoids with prominent mucinous stroma have been described in the lung,158 with a similar appearance to such tumors from the thymus.
Differential Diagnosis
The main differential diagnoses for atypical carcinoids are other neuroendocrine tumors such as small cell carcinoma and LCNEC. This can be especially difficult in small samples. Given the challenges of mitotic counting, there will be some differences of diagnostic opinion in typical and atypical carcinoid classification. In carcinoid tumors with abundant mucinous stroma, metastatic mucinous carcinomas with uniform cells, as in breast carcinomas, and goblet cell gastrointestinal carcinoids are in the differential diagnosis.158
Genetics
Deletions in 11q are common to both typical and atypical carcinoids when compared to high-grade neuroendocrine carcinomas (small cell and large cell).104 the rate of MEN1 somatic nonsynonymous alterations and MEN1 deletion is higher in atypical than typical carcinoids.102 Overall aneuploidy, 11q22.3-q25 deletions, and 9q 34.11 loss were features of atypical carcinoids.159 Mutations in TP53, which are seen in high-grade neuroendocrine carcinomas, are not commonly seen in atypical carcinoids.160
Treatment and Prognosis
Prognosis is favorable in early-stage disease,161 but outcome is less favorable than typical carcinoids with advanced disease. The recurrence rate is also higher.
The primary treatment for atypical carcinoids is surgical. Although limited resection may be sufficient for typical carcinoids, anatomic resections/lobectomy with nodal dissection have been recommended for atypical carcinoids.133,135,162 This approach may be necessary in part due to higher recurrence rates in atypical carcinoids than typical car- cinoids.73 In the setting of central tumors, a bronchoplastic procedure should be considered over pneumonectomy if disease is limited because consideration of postoperative lung function is important. In advanced disease, resection of liver metastasis may be considered as in typical carcinoids if disease distribution is otherwise favorable (e.g., resectable nodal disease, no abdominal carcinomatosis).163
Unexpected nodal involvement and skip metastasis (N2 involvement without N1 disease) are seen in atypical carcinoids.95 It has also been suggested that after limited resection, the pathologic diagnosis of atypical carcinoid should raise a discussion of completion lobectomy.164
For atypical carcinoids, bronchoscopic resection is not well studied. Given the more aggressive behavior and increased recurrence rate,162 it might be expected that the failure rate of this approach would be high. One series reported curative resection in 5 of 29 patients and a survival of 89% with long-term follow-up.116,161 Among SEER database patients, improved survival is seen among surgically resected patients, whereas radiation therapy is associated with an adverse outcome. This latter finding, however, may be related to stage or patient selection rather than the specific therapy itself.133
Metastatic disease is present in 20% of patients. Localized lung disease is associated with 85% 3-year survival, and survival drops with regional node involvement (69%) and distant metastasis (26%). Age and nodal involvement are poor prognostic characteristics in patients with atypical carcinoids.133 In one series, tumor size and sublobar resection were additional poor prognosis findings.134
Response rate to chemotherapy is about 20% using a variety of agents, but most commonly, a platinum-based agent with etoposide121,125 or with gemcitabine120 is offered to advanced-stage patients. Selection of patients to treat in earlier stages remains controversial. The lower 5-year and 10-year survival when compared to typical carcinoids warrants chemotherapy or chemoradiation therapy in patients with atypical carcinoid55 with an adverse feature. At a minimum, evaluation for multimodality therapy should be considered for patients with N2 disease.52 However, even in relatively large retrospective series, the effect of chemotherapy on survival cannot be determined due to insufficient numbers.135
Median survival in atypical carcinoid is 59 months; in contrast, survival in LCNEC is 28 months.134 Although median survival among advanced disease patients in typical carcinoids is 10.2 years, one series showed a 4-year median survival for atypical carcinoids.125 Among all patients, 5-year survival for atypical carcinoids was 56% to 78% in contrast to 96% in typical carcinoids,165,166 whereas 10-year survival drops to 44% to 46%.147,167
Large Cell Neuroendocrine Carcinoma
Definitions and Synonyms
LCNEC is a non-small cell carcinoma with neuroendocrine architectural patterns with immunohistochemically or ultrastructurally confirmed neuroendocrine differentiation. Large cell carcinoma with neuroendocrine morphology represents a tumor with a neuroendocrine growth pattern, but no evidence of neuroendocrine differentiation by IHC or EM. Large cell carcinoma (or other non-small cell carcinoma) with neuroendocrine differentiation is reserved for tumors that are not morphologically neuroendocrine but have immunoreactivity for neuroendocrine markers.
Incidence and Demographics
LCNEC is a rare tumor, roughly 2% to 3% of lung carcinomas.168-170 ttere is a male predominance, and the majority of patients are cigare The smokers.171,172 the average age of occurrence is between ages 60 and 70, with a wide range beginning about age 35.172,173
Clinical Manifestations
Patients may present with asymptomatic detection of nodules on imaging, but cough, chest pain, dyspnea, or weight loss are among the more common symptomatic presentations.170,171
Patients with LCNEC present at early stage in about 50% of cases.168 Despite this observation, the recurrence rate is high (40% to 50%), the majority of which is loco-regional. These recurrences are often within 1 year.168 Metastatic sites include brain, bone, liver, and lung.171,173 Paraneoplastic syndromes were not reported in one series of 87 patients.168 Although There are reports of myasthenic syndrome (Eaton Lambert), this is rare. Cancer-associated retinopathy, an autoimmune syndrome seen in small cell carcinoma, has been rarely reported in LCNEC.174
It has been noted that LCNEC is clinically more similar to adenocarcinoma and squamous carcinoma in the early stages, but more like small cell carcinoma in advanced stages, based on presentation and distribution of disease.175
Laboratory Findings
Elevations of carcinoembryonic antigen (CEA) are seen in about half of patients with LCNEC.
Figure 14.12 Gross pathology of large cell neuroendocrine carcinoma. (A) This is a centrally located tumor, with lobulation and a fleshy cut surface. Chalky white necrosis is seen. (B) This is a large tumor in a patient with emphysema, showing a yellow tan and hemorrhagic cut surface with extensive areas of necrosis.
Radiologic Features
Tumors on chest CT appear as peripheral nodules more often than central tumors.170 ttey are more often lobulated than spiculated, but irregular margins are also described. Pleural indenting and peripheral location make LCNEC difficult to distinguish from adenocarcinoma.176 Necrosis is often, but not invariably, visualized.177 the tumors can have calcification and be associated with air bronchograms. Mediastinal nodal involvement is a frequent finding. FDG PET showed an average standardized uptake value (SUV)max of 9.178
Gross Pathology
The majority of LCNECs are peripheral tumors; central location is found in about 20%. They are lobulated with a relatively smooth edge, and not umbilicated (Fig. 14.12A). Chalky white areas represent necrosis. In large tumors, the tumor cut surface is yellow-tan to red and can show areas of necrosis; such areas can undergo cystic degeneration (Fig. 14.12B).
Microscopic Pathology
LCNECs were characterized morphologically as having a growth pattern of neuroendocrine tumors—that is, an organoid, trabecular, or rosetteforming tumor with cells that have identifiable cytoplasm and as a result have a lower nuclear-to-cytoplasmic ratio than small cell carcinoma (eSlide 14.3). Necrosis is usually present, and organoid nests with central necrosis can be seen at low magnification (Fig. 14.13A). The organoid nests often have palisading of cells around the periphery (Fig. 14.13B). The cells are of larger size than small cell carcinoma. Nuclear features show generally round shape but with irregular nuclear contours; the chromatin is coarse and can have small to moderate-sized nucleoli (Fig. 14.13C). Macronucleoli in a background of a vesicular chromatin is not a feature of LCNEC. The mitotic rate is often very high, but not less than 10 mitoses in 2 mm2 (10 HPF). In some cases, the organoid and neuroendocrine architecture are less clear, but There remains an absence of keratinization or clear-cut gland formation. However, these cases often have rosette-like structures.179
Morphologic features that are generally present in LCNEC and not in small cell carcinoma include rose The formation, palisading, large tumor cell size, lower nuclear-to-cytoplasmic ratio, and identifiable nucleoli. In contrast, features of small cell carcinoma include finer chromatin and nuclear molding.180
Because this description overlaps with solid type adenocarcinoma and large cell undifferentiated carcinoma,181 There is a requirement to confirm neuroendocrine differentiation using IHC with synaptophysin, chromogranin, or CD56.182
Cytologic features of high-grade neuroendocrine carcinomas have been described. Cellular size, presence of cytoplasm with coarser chromatin pattern, identifiable nucleoli, apoptosis, mitoses, and necrosis are all features seen cytologically.183-185 Additionally larger cell size, naked nuclei, rosettes, and palisading can be appreciated.186 In effusions, LCNEC show small cell cluster patterns, but not large cell clusters. Nuclear features include identifiable nucleoli with apoptosis. Single cell patterns can also be seen. Nuclear molding is usually not prominent.187
Small sample diagnosis, both cytology and small biopsy, are limited in classification of LCNEC. Although malignancy can be identified, precise identification of LCNEC is difficult.188 In a multicenter treatment study, it was noted that more than one-quarter of LCNEC cases were reclassified on rereview, underscoring the difficulty in this diagnosis.189
Special Studies
Because the definition of LCNEC requires immunohistochemical or ultrastructural evidence190 of neuroendocrine differentiation, all tumors in this category have at least one positive marker: CD56, synaptophysin, or chromogranin (Fig. 14.14A). However, when examined, 85% have at least two markers, and 68% have all three positive. Chromogranin A is the least sensitive (although this varies by series) of the three168 and CD56 the most sensitive.171
It has been suggested that higher specificity for LCNEC is achieved with at least two neuroendocrine markers (CD56, chromogranin, synaptophysin);191 this is to address the frequent reactivity of nonneuroendocrine tumors for CD56 and synaptophysin.
Although IHC is positive for KIT,192 platelet derived growth factor receptor A (PDGFRA), and platelet derived growth factor receptor B (PDGFRB) stains, these genes are not mutated in LCNEC. However, to date, targeting these pathways in the absence of mutation has not been effective.171
Staining for cytokeratins has been proposed as helpful in distinguishing LCNEC from small cell carcinoma. Staining intensity is often higher in LCNEC (Fig. 14.14B) and more likely to be membranous and diffuse. Staining in small cell carcinoma is often weaker and has a dot-like staining pattern.193 TTF1 is positive in about half of LCNEC, which is lower than in small cell carcinoma.194
As mentioned in the sections on carcinoids, the Ki-67 index is often high in LCNEC and low in carcinoids. This can be helpful in small specimens when architecture is limited and cellular crush artifact is prominent.
Grading and Staging
LCNEC is a high-grade neuroendocrine carcinoma. Staging follows the protocol for the American Joint Committee on Cancer (AJCC) staging, 7th edition, for lung cancer.
Variants
LCNEC can be pure or can be combined with adenocarcinoma or squamous carcinoma. These combined tumors appear to be biologically similar to LCNEC in terms of outcomes and clinical characteristics.195 the most common histology in combined LCNEC is adenocarcinoma.196,197 the most common reported pattern of adenocarcinoma in combined LCNEC is papillary, followed by acinar. A report of an adenocarcinoma with epidermal growth factor receptor (EGFR) mutation treated with gefitinib with transformation to LCNEC has been reported.198
Figure 14.14 Immunohistochemistry of large cell neuroendocrine carcinoma. (A) Membranous pattern of CD56 immunohistochemistry. (B) Strong membranous cytokeratin immunoreactivity.
Differential Diagnosis
Small cell carcinoma is in the differential diagnosis of LCNEC. The major differences are the morphology of the constituent cells. In small cell carcinoma, high nuclear-to-cytoplasmic ratio, nuclear molding, salt-and-pepper chromatin, and scant cytoplasm contrast with more abundant cytoplasm, absence of nuclear molding, coarser chromatin, and visible nucleoli in LCNEC. However, despite these differences, the frequent combination of LCNEC within small cell carcinoma is a major challenge. There fore on small samples, any evidence of small cell carcinoma warrants a small cell designation because combined tumors are considered small cell carcinoma, combined type. In a study to examine interobserver agreement between small cell carcinoma and LCNEC, the kappa value was 0.4, which is considered fair.199 However, small cell carcinoma, whether pure or combined type (with LCNEC), should be considered small cell carcinoma by classification.195
Because of the combination of morphology and IHC in the diagnosis of LCNEC, there are tumors in which only one or the other criterion is met. There are morphologically neuroendocrine tumors (organoid, rose The forming, trabecular, or palisading) with a high mitotic rate that are not confirmed by IHC for synaptophysin, chromogranin, or CD56; these are named large cell carcinomas with neuroendocrine morphology (Fig. 14.15A). There are also undifferentiated tumors that are not definitively neuroendocrine by morphology but have IHC positive for neuroendocrine markers (Fig. 14.15B and C), which are called large cell carcinoma with neuroendocrine differentiation.200 It may be that tumors with neuroendocrine morphology are clinically similar to LCNEC200,201; however, certain diagnoses, such as basaloid squamous carcinoma and basaloid carcinoma, should be ruled out in that instance. In addition, molecular features of LCNEC and large cell carcinoma with neuroendocrine morphology may differ with regard to retinoblastoma (RB) pathway disruption and cyclin-dependent kinase inhibitor 2A (CDKN2a) (p16) overexpression.202 Tumors that are not neuroendocrine by morphology can be histologically adenocarcinoma or squamous carcinoma (Fig. 14.15D and F) but positive for chromogranin, CD56, or synaptophysin; large cell carcinomas are more challenging morphologically when these markers are positive. It has been reported more often in adenocarcinoma than squamous carcinoma in some series but not others.203,204 It is unclear whether this group is biologically distinct or requires a specific therapeutic approach.
Genetics
LCNEC are associated with TP53 mutations.160 In a series of cases comparing large cell carcinoma with LCNECs, TP53 was seen in both tumor types, but V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were a feature of large cell carcinomas that were adenocarcinoma-like but not LCNEC. In LCNEC, serine/threonine kinase 11 (STK11) and phosphatase and tensin homolog (PTEN) mutations were the next most frequent.205 Oncogenic anaplastic lymphoma kinase (ALK), rearranged during transfection protooncogene (RET), and ROS protooncogene 1 (ROS1) fusions were not identified.
Most LCNEC are negative for EGFR mutations; a single case was reported with an EGFR exon19 mutation206 and response to gefitinib. Other high-grade neuroendocrine tumors with exon19 mutations did not respond to EGFR-targeted therapy.207
A next-generation sequencing study found that among 45 LCNEC cases, some were morphologically and molecularly “small cell-like,” whereas others were more adenocarcinoma-like (some with napsin immunoreactivity). The small cell-like cases were TP53 and RB1 mutated, whereas the adenocarcinoma-like cases were more likely KRAS, STK11, and Kelch-like ECH-associated protein 1 (KEAP1) mutated. The small cell-like LCNEC also had more mitoses and a higher Ki-67 index than the non-small cell lung cancer (NSCLC)-like cases. This observation is of interest because neuroendocrine marker reactivity and an undifferentiated non-small cell appearance may be more in keeping with adenocarcinoma than LCNEC in some tumors that have lower mitotic activity. A third subset, which was rare in this series, was molecularly more like carcinoid tumors, but higher grade and with proliferation of LCNEC morphology.208 In another series of large cell carcinomas with 47 LCNEC, none of the cases of LCNEC had KRAS, EGFR, or ALK alterations, whereas their large cell carcinomas had KRAS mutations as in adenocarcinoma.209 the juxtaposition of these two studies shows that There is some ability to distinguish high-grade LCNECs and solid- type adenocarcinoma/large cell carcinoma using morphology with reasonable correlation with molecular classification, but that use of neuroendocrine markers may cause inclusion of adenocarcinomas with solid growth patterns and immunohistochemical neuroendocrine immunoreactivity as LCNEC. Whether the LCNEC needs two categories—small cell-like and adenocarcinoma-like—is an important consideration,210 given controversies in chemotherapeutic responses (see treatment section). It is possible that a combination of morphology, mitotic activity, mucicarmine reactivity, IHC, and molecular testing may be needed to correctly subclassify this high-grade tumor type.
Copy number alterations and loss of heterozygosity (LOH) have been studied in LCNEC. Loss of 3p, 5q, 11q, 13q, and 5p gain, but these were common to high-grade neuroendocrine carcinoma.211,212 In one series, gain of 3q was seen in small cell carcinoma, but 6p gain and 10q, 16q, and 17p losses were seen in LCNEC;212 in another, frequent 3p14.2 and infrequent 22q13.3 LOH was seen.213 LOH at TP53, 3p14.2, 3p21, 5q11, and 13q14 is seen in LCNEC and small cell carcinoma more frequently than in large cell carcinoma.214 Further analysis suggests tumor suppressor loci on at least four distinct regions of chromosome 5q.215
One report identified neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) and neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) mutations in 31% of LCNEC and suggested that this alteration is related to neuroendocrine differentiation.216 miRNA profiling has been proposed to distinguish low- and high-grade neuroendocrine tumors, but a defined panel has yet to be determined.91,217
Treatment and Prognosis
Despite a resectable tumor, patients with large cell neuroendocrine have a high rate of disease relapse, including metastatic sites in the brain, bone, and liver.169 Stage 1A LCNECs have poorer prognosis than other Stage 1A lung carcinomas.218 As a result of early recurrence, 1-year survival is as low as 27%169,219 with even lower 5-year survival of 13%.173 In a review of multiple series, 5-year survival in all stages ranged from 13% to 57%, with most studies around 30%.171 However, surgery alone for Stage 1 disease is still advocated by some authors220,221 or at a minimum, adjuvant therapy in Stage 1 disease has insufficient data to warrant a clear recommendation.222,223
Treatment response in LCNEC is poor overall with conventional chemotherapy.173 In one series, use of small cell chemotherapy (etoposide/ platinum or irinotecan/platinum) was more effective than non-small cell chemotherapy (platinum plus gemcitabine or taxanes).171 In a small but prospective study, adjuvant therapy with cisplatin and etoposide showed improved survival over surgery alone.224 In retrospective studies, there seems to be some support for adjuvant chemotherapy when compared to surgery alone.172,225-227
The role of thoracic radiotherapy remains unclear, and the role of prophylactic cranial irradiation (PCI) is also unknown.228
In advanced disease, small cell-type therapy of platinum and etoposide seems superior to non-small cell-type therapy.189,229,230 Several studies have shown response rates comparable to small cell carcinoma for etoposide/platinum or some response with irinotecan/platinum,231,232 although platinum/etoposide was more widely used, so this regimen is recommended albeit with limited data.233,234 It may also be the case that series with adenocarcinoma-like LCNEC with high rates of KRAS mutation may demonstrate poorer responses to small cell chemotherapy,210 again warranting future attention to the careful classification of large cell tumors as adenocarcinoma or LCNEC.
Treatment with octreotide has been attempted and may be associated with response.235
Figure 14.15 Differential diagnosis of large cell neuroendocrine carcinoma. (A) Large cell carcinoma with neuroendocrine morphology has the features of large cell neuroendocrine carcinoma but no confirmation by immunohistochemistry (IHC). (B) A nested and gland-forming tumor with areas of cytoplasmic clearing that has some suggestion of neuroendocrine histology but harbors V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations and is thyroid transcription factor 1 and napsin positive, features of adenocarcinoma. However CD56 is positive, as shown in (C). (D) A morphologically squamous cell carcinoma with pavemented appearance, eosinophilic cytoplasm, and intercellular bridges, confirmed by IHC for p40 in (E). In (F), IHC for CD56 is positive in a membranous pattern.
Small Cell Carcinoma
Definitions and Synonyms
Small cell carcinoma is a high-grade neuroendocrine carcinoma characterized by a rapid proliferation rate236 and a tendency for early and widespread metastasis.237,238 the cell of origin is thought to be neuroendocrine cells, although derivation from another pluripotent cell has not been ruled out. Its recognition as an entity dates back to 1926,239 with clearer histopathologic criteria established by Azzopardi in 1959.240
Synonyms include oat cell carcinoma, intermediate cell-type carcinoma, and mixed small cell/large cell carcinoma, but these terms are not currently in use.
Incidence and Demographics
Small cell carcinomas are seen in patients older than 40 years, with a mean age of 68 years.241 Although historically associated with a male predominance, more recent large series of small cell carcinoma show a less dramatic male predominance.241,242 It is strongly associated with current or former smoking with hazard ratios of 50 in current smoking men when compared to never smokers, and 20 in current smoking women. This hazard ratio is closely linked to the number of cigarettes smoked per day but does increase with years of smoking. In men, there is a slight increase in risk based on early age of smoking initiation. After smoking cessation, a marked decrease in risk occurs after 5 years, which becomes markedly reduced after 25 years.243 Overall, the incidence of small cell carcinoma has decreased, mirroring decreases in smoking rates;242,244 rates were as high as 25% in 1975245 and have now reached about 10% to 15% overall. Only a small percentage of small cell carcinomas are diagnosed in never smokers (<3%).241
Other studies have examined potential environmental and occupational risks. Industries with a risk of small cell carcinoma include steel industries and iron foundries, as well as concrete pouring and motor vehicle parts manufacturing.246 Although small cell carcinoma rarely occurs in never smokers, the cause in this subset is unknown. It does not appear to be associated with second-hand smoke.247 Some series suggested residential radon exposure, but this is not uniformly reported. Radiation exposure in uranium miners may lead to a greater proportion of squamous and small cell carcinoma.248 Small cell carcinoma in never smokers is an aggressive disease as in the smoking-related counterpart.249
Clinical Manifestations
Patients with small cell carcinoma have clinical presentations related to central and mediastinal tumor mass effect. This can include chest pain, hemoptysis, and hoarseness, as well as constitutional symptoms of malaise, anorexia, and weight loss. In some instances, compression of the superior vena cava can result in superior vena cava syndrome, with facial edema and reduction of venous drainage of the head and neck. Metastatic disease can present as bone pain or neurologic symptoms from brain metastasis.
In some cases, paraneoplastic syndromes can occur including syndrome of inappropriate antidiuretic hormone (SIADH) secretion,250 Cushing syndrome, cerebellar degeneration, and Eaton-Lambert syn- drome.251 SIADH leading to hyponatremia with a sodium lower than 125 was seen in 11% of patients252 and between 126 and 135 in another 33%. This is an adverse prognostic feature and needs to be corrected during chemotherapy.253 the Eaton-Lambert syndrome is characterized by proximal leg weakness and dry mouth, progressing to proximal arm muscle weakness. Sensory neuropathy and encephalomyelitis are more common in men254 and can be associated with cerebellar symptoms. Rare syndromes, such as opsoclonus-myoclonus syndrome characterized by rapid eye movements and muscle twitching, have also been reported. Cancer-associated retinopathy is a paraneoplastic syndrome in small cell lung cancer (SCLC) with visual field effects and photosensitivity.255 In some cases, paraneoplastic sensory neuronopathy indicates antitumoral immune response with potential favorable outcome and in some cases, rare spontaneous remission.256
Autoantibodies have been associated with a variety of these paraneoplastic syndromes in small cell carcinoma.257 Those that result in Eaton-Lambert syndrome are associated with voltage-gated calcium channel (VGCC) antibodies.258 Sensory neuropathy and limbic encephalitis can be the result of anti-Hu antibodies.259 A subset of paraneoplastic cerebellar degeneration has been associated with anti-Hu antibodies in women and with inflammatory infiltrates; this can include extracerebellar symptoms. However, this can also occur without anti-Hu antibodies. Some cerebellar degeneration patients also have Eaton-Lambert syndrome with high P/Q-type or N-type VGCC.260 Rarer antibodies include anti-SOX2, gamma-aminobutyric acid (GABA) receptor, and rarely, anti-glutamic acid decarboxylase (GAD65), Ri, Yo, amphiphysin, anti-N methyl-D-aspartate receptor,261 and Ma. Although rare, these various paraneoplastic syndromes represent unusual presenting symptoms and disease associations that warrant clinical investigation for malignancy.
Unusual metastatic sites can also be a manifestation of this disease, including involvement of the eye with choroidal and uveal metastasis262 and transplacental transfer.263,264 Bone marrow metastasis is a well- described feature in a proportion of small cell carcinoma patients.265
Laboratory Findings
In small cell carcinoma, CBC with differential, hepatic function, and renal function should be assessed.
Radiologic Features
Because most SCLCs are central, the most common finding is a large central mass within lung parenchyma or in the mediastinum. This can be associated with atelectasis and adenopathy.266 Contrast CT may assist in determining involvement of mediastinal structures. Rarely, SCLC can present as peripheral nodules, either lobulated or spiculated, and in this regard not distinct from other pulmonary neoplasms.267
Although screening with low-dose CT has been shown to decrease mortality in lung cancer, this has not been shown to be effective in reducing small cell carcinoma mortality.268 FDG-PET is a useful adjunct to staging, and because SCLC often have high SUV, PET scanning may be more sensitive a staging tool than CT for thoracic involvement, with the best tool a combination of PET/CT, resulting in upstaging in about 25% of cases.269,270 FDG-PET is not superior in the detection of brain metastasis. Small cell carcinomas are positive by FDG-PET and the SUVmax may relate to survival in limited-stage disease.271
Gross Pathology
SCLC are typically bulky tumors (Fig. 14.16 A and B) with central compression and mediastinal involvement. Invasion of mediastinal structures, compression of the superior vena cava, and bronchopleural fistula formation can be seen. In resected small cell carcinoma, gross features consist of surprising circumscription and some lobulation. The cut surface is described as gritty but usually not overtly cystic or necrotic (Fig. 14.16C). The tumors are usually white or tan, without central umbilication. They are often described as rubbery or firm rather than soft.272 Rare cases of small cell carcinoma can present with diffuse pleural involvement, mimicking mesothelioma.273
Microscopic Pathology
The histologic hallmarks of small cell carcinoma include tumor cells with scant cytoplasm, a high nuclear-to-cytoplasmic ratio, nuclear chromatin that is fine and described as a salt-and-pepper pattern, and generally absent nucleoli (Fig. 14.17A). Nuclei can be round, but fusiform shapes of the tumor cells are often encountered (Fig. 14.17B). Nuclear molding is frequent, and cellular fragility leads to “crush artifact” and streaming of nuclear chromatin described as the Azzopardi effect, named after the pathologist who described these criteria for SCLC (Fig. 14.17C).240 These tumors are commonly said to have a high mitotic count, which is accurate; however, from a practical point of view, small samples with crush artifact can be difficult to assess for mitoses. Apoptotic bodies and nuclear karyorrhexis are more visible on hematoxylin and eosin (H&E) sections. In the absence of mitoses or apoptotic or karyor- rhectic debris, the diagnosis of small cell should be questioned.
Another point that can be difficult to assess is the cell size. Although the name implies that the cells should be small (and defined as less than the diameter of three resting lymphocytes), the cell size does depend on the type of fixation and specimen type. Uncrushed resected small cell carcinoma may be composed of cells that appear larger than three resting lymphocytes, but the other features—high nuclear-to-cytoplasmic ratio and nuclear chromatin pattern—are more diagnostic than cell size alone.274 It is acknowledged that a subset of cells within a small cell carcinoma can have larger nuclei with vesicular nuclei with nucleoli, but if this is in the minority, small cell carcinoma diagnosis should be rendered.272 In a formal analysis of nuclear size, the impression of overlap was confirmed by morphometry.275
In resected small cell carcinomas, patterns associated with neuroendocrine differentiation are more readily appreciated architecturally. Organoid and trabecular patterns are described as are rosettes and solid sheet-like areas (eSlide 14.4). At low magnification, an atypical carcinoid is a consideration. Crush artifact and Azzopardi effect are infrequently encountered in this setting. Apoptosis is always present, and mitotic activity is high, which eliminates an atypical carcinoid as a possibility. Large cell neuroendocrine patterns are frequently encountered, in as many as one-third of cases, but exceeding 10% of the tumor in only 16%.272
Cytologic diagnosis (Fig. 14.18) of small cell carcinoma is an accurate modality.276 the use of endobronchial ultrasound-guided needle biopsy allows for diagnosis and mediastinal node staging.277 ’Hun-prep cytology278 is also feasible, although some features such as crush artifact and nuclear molding are less prominent; cells are more discohesive and small. This can mimic lymphocytes. As a result, use of IHC on cell block sections may be helpful. Despite its utility, the diagnosis of small cell carcinoma by cytology was underutilized (only 20%) in various treatment settings.279
Figure 14.18 Cytology of small cell carcinoma. Crowded, cellular cluster with high nuclear-to-cytoplasmic ratio, apoptosis, and Azzopardi effect.
Combined Type Small Cell Carcinoma
In current classification, small cell carcinoma has only one variant or subcategory, combined small cell carcinoma. Prior terminologies of mixed subtype or intermediate cell type have been abandoned because they were found not to be clinically relevant.280 In the combined subtype, any evidence of non-small cell carcinoma, such as adenocarcinoma or squamous carcinoma, is sufficient for this designation (Fig. 14.19A), but at least 10% of a large cell neuroendocrine component is needed for a combined designation to account for the high frequency of this element at a low percentage in many small cell carcinomas (Fig. 14.19B). As mentioned in the section on LCNEC, cytokeratin staining may be more intense in LCNEC components of small cell carcinoma; in addition, staining for cytokeratin in small cell carcinoma is often focal or dot-like (Fig. 14.19C).
The histology of small cell carcinoma after chemotherapy has been reported to include a larger proportion of non-small cell carcinoma components than on the pretreatment biopsy. Although some of this may be the result of sampling, it may reveal that these non-small cell elements are treatment resistant.281
Special Studies
IHC is often used in the diagnosis of small cell carcinoma. Cytokeratin cocktails of low- and high-molecular-weight keratins are positive in a large percentage of small cell carcinomas, in some series nearly 100%. The staining can be relatively inapparent and dot-like; this can be mistaken for background or artifact (Fig. 14.19C). Epithelial membrane antigen (EMA) and BerEP4 are also positive. CD45 is negative in small cell carcinoma. Neuroendocrine markers may be very focal in SCLC, and the positive rate varies by study. However, a subset of small cell carcinomas will be negative for neuroendocrine markers, and while this could raise a consideration of other diagnoses, it should not prevent the rendering of a small cell carcinoma diagnosis.282 For example, in a large series of resected small cell carcinoma, 58% were positive for chromogranin and 57% positive for synaptophysin, leaving some cases negative for neuroendocrine markers.
IHC for TTF1 is positive in pulmonary small cell carcinoma; however, TTF1 is also frequently positive in extrapulmonary small cell carcinoma.283 Merkel cell carcinoma is TTF1 negative and also has frequent immunoreactivity for CK20, usually negative in pulmonary small cell carcinoma,284 thus allowing for discrimination of Merkel cell carcinoma from small cell carcinoma.
Ki-67 (MIB-1) has been shown to be potentially useful in distinguishing high-grade from low-grade neuroendocrine tumors.285 As discussed in the section on carcinoids, Ki-67 is helpful in small samples, especially those with limited morphologic preservation, to prevent under- and overdiagnosis of small cell carcinoma.84
Although small cell carcinomas show high expression of KIT and its ligand,286 mutations in KIT are not seen, and therapeutic response to imatinib is not demonstrated.287
Grading and Staging
Although practical approaches to staging use the terms limited disease and extensive disease to describe small cell carcinoma extent, the current staging system for SCLC is the same TNM approach used for non-small cell carcinoma. In an examination of staging of SCLC, stratification of T categories and N categories demonstrated statistically significant survival strata, supporting TNM staging.288 However, relatively few of those cases were pathologically staged, and concordance of clinical and pathologic staging in those cases was only 71%, with clinical understaging in 23% of cases.288
Clinical staging should include CT scan of the chest to include the liver and adrenal gland, and CT of the head. Bone scan is recommended. FDG PET scanning is suggested and can replace bone scanning if performed.289 If surgical intervention is considered, mediastinal nodal staging is also critical.289
Variants
The main variant of SCLC is combined SCLC in which SCLC is seen in combination with adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. If in combination with LCNEC, at least 10% of the tumor must be LCNEC. It is very uncommon for SCLC to be seen in combination with spindle cell carcinoma or giant cell carcinoma.
Differential Diagnosis
In the evaluation of small cell carcinoma, several diagnoses can be considered and their likelihood influenced by patient age, smoking history, clinical presentation, and quality of the sample. In small samples, frequent crush artifact leads to limited morphologic assessment. In this regard, it is often useful to consider lymphoma, with examination of concurrent cytology or performance of IHC. Some high-grade carcinomas, such as nonkeratinizing subtypes of squamous carcinoma including basaloid carcinoma, may be a mimicker. As previously discussed, crushed samples of carcinoid and especially atypical carcinoid should be considered, and some advocate Ki-67 in all cases in which morphology is limited. A variety of tumors, such as primitive neuroectodermal tumors (PNETs), desmoplastic small round cell tumors (DSRCTs), variants of synovial sarcoma, and rhabdomyosarcoma may be a consideration; however, morphology, age, nonsmoking history, and clinical presentation are clues that small cell carcinoma is not the correct diagnosis. Extrapulmonary high-grade neuroendocrine tumors, such as Merkel cell carcinoma or thyroid medullary carcinoma, may enter the differential diagnosis as well.
A major differential diagnosis of small cell carcinoma is LCNEC. As described in the LCNEC section, the presence of a small cell component warrants a small cell carcinoma designation. Given the frequency of a large cell neuroendocrine component in small cell carcinoma, this is a frequent problem. However, interobserver agreement in these two tumor types is only fair, and There fore careful adherence to criteria is essential.199 Even with experienced pathologists, this distinction is prone to disagreement.290
Genetics
Small cell carcinomas are characterized by multiple aneuploidies, with deletions in 3p, 4q, 5q, 10q, 13q, and 17p, and gains in 3q and 5p.291,292
Whole exome sequencing identified mutation or copy number loss in TP53 and RB1 in a large proportion of SCLC (62% to >90%).293-295 SCLC genomes have a high mutation rate of 8.62 mutations per million base pairs, with a high percentage of transversion296 that indicates smoking exposure. Other frequently mutated genes include FMN2, NOTCH1, RBL1, RBL2, EP300, TP73, and CREBBP, and some of these mutations were mutually exclusive. Deletions in p16 and FHIT were seen in addition to TP53 and RB1, and gains in MYC, MYCL, MYCN, IRS2, and FGFR1 were encountered.294 Genes involved in chromatin remodeling have been implicated in the pathogenesis of small cell carcinoma, including loss of KAT6B and activation of EZH2.297-299
Mutations in EGFR and translocations in the ALK gene are not typical features of small carcinoma. Rare de novo EGFR mutations are described in small cell carcinoma, in both pure forms and in combined forms with adenocarcinoma. It is unclear based on reported cases whether response to EGFR-TKI occurs in these tumors.300 These patients may be identified based on a light smoking history. Small cell histology also
occurs after EGFR-TKI therapy for adenocarcinoma, and these cases also contribute to the rate of EGFR mutations in small cell histology. However, history of adenocarcinoma with EGFR-TKI therapy helps to identify this group, and this histologic change should not be mistaken for a new primary tumor.301 Adenocarcinoma with ALK translocation can acquire small cell histology after therapy with alectinib and crizotinib and is also a mechanism of treatment resistance.302,303
Treatment and Prognosis
Although prognosis is poor overall in small cell carcinoma, it is stage dependent. Of surgically resected cases, patients with early-stage disease (Stage 1 and Stage 2) have 5-year survival rates that decrease from 56% in Stage 1A and Stage 1B to 40% in Stage 2. Despite these low 5-year survival numbers, this does indicate a potential cure rate in early-stage disease.304 In one series, 5-year survival of surgically resected Stage IIIA and IIIB SCLC falls to 12% and 0% respectively.305 For Stage 4 disease, 2-year survival for SCLC is less than 10%,288 with 5-year survival as low as 3%.306
Therapy for small cell carcinoma incorporates treatment for locore- gional disease and systemic therapy. For early-stage patients, surgical resection may be an option when feasible,289 but surgical therapy alone is not curative.307 As a result, chemotherapy, chemoradiation, or chemotherapy followed by radiation is recommended for successful therapy;308 although not curative, this allows for a more durable initial treatment protocol. In the absence of nodal disease, the combination of chemotherapy and thoracic radiation rather than chemotherapy alone remains debated. PCI is also a consideration and reduces intracranial recurrence.309,310 Concern for loss of cognitive function following cranial irradiation is often offset by treatment benefit, and in prospective studies PCI does not appear to result in progressive cognitive dysfunction in the first 2 years.311 the use of PCI remains an unanswered issue for early-stage patients in whom survival after 2 years is more likely. For advanced-stage patients, chemotherapy or chemoradiation approaches with PCI are considered.289 the standard chemotherapy in small cell carcinoma is etoposide and platinum-based chemotherapy,312 with other agents tried in conjunction with a platinum drug.313,314 Cisplatin and carboplatin seem equivalent, but the addition of a second agent is superior to single-agent therapy.315 Response rates are high (50% to 80%),312,316 but recurrences invariably occur. There does not appear to be a benefit for surgery after chemoradiation in these patients.317 After recurrence, chemotherapy may be reattempted with the initial regimen. In this setting, topotecan has been approved.318 Although survival rates remain low, there is evidence that current regimens have led to significant increases in survival time.319
Combined-type small cell carcinoma appears to be biologically similar to pure small cell carcinoma and treatment approaches are similar.320
Although molecular characterization and identification of pathway activations raise the possibility of future targeted therapies, to date these are largely in preclinical phases and their efficacy remains to be determined.321 Some promising approaches include immune checkpoint inhibition and sunitinib for tyrosine kinase inhibition.322
Primitive Neuroectodermal Tumor
Definitions and Synonyms
PNET is a small, round, blue cell tumor of bone and soft tissue in children and young adults that is histologically and molecularly similar to Ewing sarcoma and belongs in the same family. It occurs in the chest wall but less commonly in lung, and is There fore a rare tumor.323 Its original description was by Arthur Purdy Stout as PNET324 and James Ewing as Ewing sarcoma.325 the description of this tumor in the thorax is attributed to Frederic Askin in 1979.326
Incidence and Demographics
PNET of the thorax is a rare tumor and is very rare as a lung tumor.327-330 It is seen in children and young adults with an overall average age of 29, with an equal male-to-female ratio.331 Because SCLC incidence begins around age 40, most, but not all, PNET cases will not be confused with SCLC.
Clinical Manifestations
A common presentation of PNET is chest pain. However, patients can also present with dyspnea and pleural effusion.
Radiologic Features
CT scans show chest wall infiltration with rib destruction. FDG PET is typically positive in PNET.332
Gross Pathology
Although pulmonary involvement is possible, this is usually a tumor of the chest wall requiring chest wall excision. This is not a tumor of large airways. Pulmonary cases in peripheral lung have been described, albeit rarely.328 ttey are soft, fleshy tumors, with hemorrhage and necrosis.
Microscopic Pathology
The histology of PNET is only vaguely organoid (Fig. 14.20A), with larger sheets of cells with occasional rosette-like structures and little associated stroma (eSlide 14.5). The cells are uniform and round and have little cytoplasm. Often the chromatin is very fine and often described as powdery (Fig. 14.20B); however, like in all neuroendocrine tumors, the characteristic nuclear features will not be present in all cells of the tumor. These are usually mitotically active tumors, but a strict cutoff is not established as it is for other neuroendocrine tumors.
Cytologic assessment of PNET tumors in effusions shows cells with loose cohesive clusters with round to ovoid nuclei and nuclear molding resembling small cell carcinoma.333
Special Studies
The cytoplasmic clearing in PNET is periodic acid-Schiff positive and is diastase sensitive representing glycogen. IHC is of utility in the diagnosis of PNET. Although not entirely specific for this tumor, CD99 with strong membranous staining is typical (Fig. 14.20C). IHC for Fli-1 protooncogene, ETS transcription factor (FLI1) is also of utility, although the specificity of this marker depends on technical issues and specifics of the differential diagnosis (e.g., endothelial tumors). Chromogranin is usually negative in this tumor, but synaptophysin is positive in about one-third of cases. Although cytokeratin is expected to be negative in this tumor, the experience is that at least focal staining can be seen in one-quarter of cases, and in some instances this will be multifocal. Importantly, WT1 should be negative, distinguishing this tumor from a DSRCT and mesothelioma (small cell variant); in addition, desmin should be negative, also in contrast to DSRCT. Calretinin is positive in about 15% of cases, and EMA also can be positive in a few cases. ThF1 is negative in PNET. The combination of positive cytokeratin and TTF1 would be in support of a SCLC. Overall, a panel approach can strongly support the diagnosis, leading to relevant molecular testing confirmation.
Differential Diagnosis
The main histologic differential diagnostic categories of PNET include other tumors that manifest highly cellular proliferations with scant cytoplasm (“small blue cell tumors”). Lymphoma can be mistaken for PNET, but the architecture of PNET and rose The formation should help avoid this confusion, as will IHC, if needed. DSRCT is also in the differential diagnosis, and the desmoplastic stroma and IHC pattern of DSRCT should be helpful in this analysis. Some synovial sarcomas can have a monotonous round cell appearance, but this can also be resolved by a combination of IHC and if needed, cytogenetics or fluorescence in situ hybridization (FISH) testing. SCLC is often not in the differential diagnosis because of younger patient age, but the combination of cytokeratin and TTF1 should be able to resolve difficult cases.
Figure 14.20 Microscopic pathology of primitive neuroectodermal tumor. (A) Low power view shows vaguely organoid architecture with nests of cells without prominent stroma. (B) Cells are uniform, with high nuclear-to-cytoplasm ratio and cytoplasmic clearing. Nuclei show fine chromatin more powdery than "salt and pepper.” (C) Immunohistochemistry for CD99 is strong and membranous when positive in this tumor.
Genetics
PNET tumors have a characteristic chromosomal translocation t[11;22] [q24;q12] involving the Ewing Sarcoma Breakpoint Region 1 (EWSR1) gene resulting in an EWS-FLI1 fusion gene. Although this can be detected by classical cytogenetics,334 the need for fresh cells and the presence of small rearrangements leading to translocations below the resolution of classical cytogenetics leads to the use of other techniques. Break-apart probe FISH testing in the EWS gene is effective at detection in about 90% of PNETs, but this approach does not identify the fusion partner or the specific site of the translocation.335,336 Fusion partners include FLI1, which is the most common, as well as V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog (ERG), ETS variant (ETV), E1AF, and FEV, ETS Transcription Factor (FEV). Although identification of the fusion partner may become more relevant in the future as suggested by some series showing effect on biology,337,338 from the diagnostic point of view, break-apart testing is sufficient. However, EWS break-apart testing will not detect the subset of cases with other translocations (e.g., FUS-ERG fusion).339
Also important is that the family of tumors harboring EWS translocation is growing and includes desmoplastic small round cell tumors, which may be in the differential of PNET. The combination of morphology and IHC should resolve these cases, with some requiring specific fusion detection to resolve the diagnosis.
Treatment and Prognosis
The optimal treatment of PNET of the thorax is resection followed by radiotherapy and chemotherapy.331 In resectable disease, the survival rate at 10 years is 57% to 84%, but this decreases significantly in unresectable disease. In initially resected cases, recurrent unresectable disease is a cause of mortality. Nodal involvement is not typical. Younger patients have a better prognosis overall.340
Other Rare Neuroendocrine Tumors
Primary neuroblastoma of the lung is rare, but has been reported, largely in patients older than 20 years (in contrast to abdominal cases). These rare pulmonary cases have been ganglioneuroblastomas.341 However, pediatric cases have also been reported but are largely extrapulmonary thoracic tumors.342 They are enlarging mass lesions and rarely associated with paraneoplastic syndromes. One reported case was associated with MEN1 syndrome.
The gross appearance of these tumors reflect high cellularity with gray and fleshy areas. The cut surface can grossly exhibit a nodular appearance, and this should be noted and efforts to target these varied areas during sectioning is important. Some cases will have cystic degeneration and calcification.
Histologically, these tumors can be undifferentiated with sheetlike areas of small round cells without stroma or rose The formation. However, demonstration of neuropil, an eosinophilic fibrillary matrix, can be present and is a clue to the diagnosis. Rosettes with a fibrillary center, known as Homer-Wright rosettes, are seen. When ganglion cell differentiation is present, the diagnosis of ganglioneuroblastoma is considered.
Figure 14.21 Microscopic pathology of paraganglioma. Cells with fine nuclear chromatin arranged in organoid architecture with fine surrounding vascularity without other patterns of carcinoid tumor present.
IHC of neuroblastoma is not specific, but given a differential in adults that might include small cell carcinoma, DSRCT, and PNET, relevant negatives could include cytokeratin and CD99. Given the rarity of thoracic neuroblastoma, other tumors, including rhabdomyosarcoma, need to be considered and ruled out with desmin, muscle-specific action, and if needed, myogenin and MyoD1.
For thoracic pediatric tumors, the stage (less than stage 2) and age (younger than 2 years) are more significant than histopathology; patients younger than 2 years had uniformly favorable survival.342,343 Although resection is performed, radical surgery may not be necessary if multimodality therapy is used.344 True pulmonary neuroblastoma is rare, and the paucity of published cases limits a definitive statement regarding prognosis.
Primary pulmonary paraganglioma is a very rare tumor, and its diagnosis requires the application of strict criteria. The reported cases have a mild female predominance,345 and most patients are asymptomatic. The age range is roughly 40 to 70 in the reported cases. Some patients present with cough and pneumonia.346,347 Endobronchial tumors are reported.347
The morphology of these tumors shows an organoid pattern with defined nests of cells with surrounding fine vascularity and sustentacular cells (Fig. 14.21). The tumor cells themselves can be uniform, but in some cases the pleomorphism that is typical of nonpulmonary paragangliomas and pheochromocytomas is seen. The architecture of pulmonary paraganglioma can be less well developed and There fore the sustentacular cells not as well defined. However, patterns typical of carcinoid tumor—trabecular patterns, oncocytic areas, spindle pattern— should support carcinoid tumor over paraganglioma.
By IHC these tumors are frequently chromogranin A and synapto- physin positive. Although There are some conflicting reports, the tumors should be cytokeratin negative. S100-positive sustentacular cells should be present, even if only in some parts of the tumor. The main differential diagnosis is carcinoid tumor, which can have paraganglioma-like features, but are typically cytokeratin positive and lack the S100 sustentacular cells. Because of the potential morphologic overlap between carcinoid tumors and paragangliomas (compare Figs. 14.9A and 14.21), it is important to apply strict morphologic criteria and to emphasize consistent IHC profile before designating a tumor as a pulmonary paraganglioma. In all cases, metastasis from an extrapulmonary paraganglioma must be ruled out.
Minute meningothelial nodules, although historically called chemo- dectomas, are not paragangliomas. By IHC, these are EMA positive and negative for neuroendocrine markers.
Rare tumors are functional with serum norepinephrine elevation. EM can reveal dense core granules with an eccentric clearing typical of norepinephrine containing granules.348
These tumors appear to have a benign clinical course.345
Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.
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1. All of these statements are TRUE of pulmonary paraganglioma EXCEPT:
A. The histology is uniformly organoid with a fine vascularity
B. The cells show typical neuroendocrine chromatin with salt- and-pepper chromatin
C. S100 positive sustentacular cells are present, even if only focally
D. The presence of trabecular or oncocytic patterns does not affect the diagnosis
E. These tumors are cytokeratin negative
ANSWER: D. The presence of growth patterns other than organoid with a fine vascularity should raise the diagnosis of a carcinoid tumor. Paragangliomas are cytokeratin negative and have S100 positive sustentacular cells, even if only focal. The cells can be pleomorphic but have typical neuroendocrine chromatin.
2. Which of the following is TRUE regarding thoracic neuroblastomas?
A. Pulmonary parenchymal neuroblastomas are typically pediatric tumors.
B. Thoracic extrapulmonary neuroblastomas are tumors in older adults.
C. Gangliocytic differentiation is not seen in these tumors.
D. They are focally cytokeratin positive in as many as 25% of cases.
E. Pediatric tumors in patients younger than 2 years have a favorable prognosis.
ANSWER: E. Neuroblastomas of the thorax in patients younger than 2 years have a favorable prognosis. Pulmonary examples have been in adults, whereas extrapulmonary examples are in children. The adult cases have uniformly had gangliocytic differentiation. Primitive neuroectodermal tumors can be keratin positive, but not neuroblastomas.
3. The following are TRUE statements regarding primitive neuroectodermal tumors EXCEPT:
A. A negative fluorescent in situ hybridization break-apart probe assay for Ewing Sarcoma Breakpoint Region 1 gene (EWSR1) rules out the diagnosis of primitive neuroectodermal tumor (PNET).
B. They are bone tumors of the thoracic vertebrae.
C. The tumor cells are synaptophysin but not chromogranin positive.
D. CD99 immunohistochemistry is strongly positive in a cytoplasmic pattern.
E. The tumor produces intracytoplasmic mucin, which is periodic acid-Schiff positive and diastase resistant.
ANSWER: C. PNET tumors are CD99 positive with strong membranous staining and are synaptophysin but not chromogranin positive. About 25% will show cytokeratin reactivity. They are tumors of the chest wall, but not typically of the thoracic spine. The cytoplasmic clearing is glycogen, not mucin and diastase sensitive. Although fluorescence in situ hybridization (FISH) testing using an EWSR1 break-apart probe is a sensitive test, some tumors have translocations involving FUS and will not show EWSR1 break apart by FISH testing.
4. A pathologist is considering a diagnosis of pulmonary small cell carcinoma by hematoxylin and eosin staining. Which of the following should warrant further thought before finalizing the diagnosis?
A. Frequent apoptosis and karyorrhexis but hard to identify mitoses
B. A never smoker under age 30
C. Occasional cells that are larger with visible nucleoli
D. Occasional cells that have visible cytoplasm
E. Absence of crush artifact in a resection specimen
ANSWER: B. Pulmonary small cell carcinoma is very rare in patients younger than 40 years, and moreover is seen in smokers in 97% of cases. In small samples with crush artifact, it can be difficult to identify mitoses, but nuclear debris and apoptosis should be evident. Although nuclei in this tumor are small with salt-and-pepper chromatin, occasional cells can be larger, have small nucleoli, and some cytoplasm. In resection specimens, nuclear molding, Azzopardi effect, and crush artifact are less commonly encountered.
5. Which of these immunohistochemistry (IHC) results should lead to further analysis when considering a diagnosis of small cell carcinoma?
A. The tumor is thyroid transcription factor 1 (TTF1) negative and weakly cytokeratin positive.
B. The tumor is cytokeratin negative but synaptophysin and chromogranin positive.
C. The tumor is cytokeratin positive, positive for WT1 with nuclear staining, and desmin positive.
D. The tumor is cytokeratin positive with a dot like pattern, chromogranin positive, and CD99 focally positive.
E. The tumor is cytokeratin positive but synaptophysin, CD56, and chromogranin negative.
ANSWER: C. In neuroendocrine tumors, reliance on immunohistochemistry alone is difficult and clinical features are of utmost importance. However, based on IHC alone, the tumor in choice C has IHC staining of a desmoplastic small round cell tumor, and this should be considered in this circumstance. Further clinical information (tumor distribution), smoking history, and patient age should all be considered or possibly molecular testing. Small cell carcinoma with classic morphology can be positive for only cytokeratin, and all neuroendocrine markers can be negative. In other cases, a negative cytokeratin with positive neuroendocrine markers can still lead to a diagnosis of small cell carcinoma. Although TTF1 is frequently positive in small cell carcinoma, it is not required for the diagnosis of this tumor.
6. Which of the following is TRUE of the epidemiology of small cell carcinoma?
A. It is a tumor of heavy smokers, with higher risk for smokers with high per-day cigare The consumption.
B. Pack years is the only important consideration, so light smokers for many years are at equal risk as heavy daily smokers for shorter periods.
C. It is a tumor whose increased risk is not affected by smoking cessation due to permanent field change effects.
D. Small cell carcinoma incidence continues to increase due to second-hand smoking exposure.
E. Small cell carcinoma never occurs in lifetime nonsmokers.
ANSWER: A. Although smoking duration and number of cigarettes smoked per day are both risk factors for small cell carcinoma, heavy daily smoking is more relevant. Although risk continues after smoking cessation, decreased risk is seen at 5 years, and markedly reduced risk at 25 years after smoking cessation. Small cell carcinoma rates are decreasing, now down to 10% to 15% from 25% of lung cancers. Although rare, about 3% of small cell carcinomas occur in never smokers.
7. Which of the following is a NOT a clinical feature of small cell carcinoma?
A. Low sodium due to syndrome of inappropriate antidiuretic hormone
B. Glucose elevation due to Cushing syndrome
C. Proximal muscle weakness of legs followed by arm weakness.
D. Muscle twitching and rapid eye movements
E. Parathyroid hormone-like substances leading to hypercalcemia
ANSWER: E. Hypercalcemia due to parathyroid hormone-like substances is a feature of squamous cell carcinoma, not small cell carcinoma. Opsoclonus-myoclonus syndrome, although rare, is seen in small cell carcinoma, as is syndrome of inappropriate antidiuretic hormone, Cushing syndrome, and Eaton-Lambert syndrome.
8. Which of the following is TRUE of organ-localized small cell carcinoma?
A. The gross tumor is typically soft and centrally necrotic.
B. The gross tumor is typically umbilicated, and the edges of the tumor are irregular.
C. The cut surface is often tan-white, gritty, and firm.
D. Cystic degeneration is often present due to rapid growth.
E. The tumors are often pleural based, with spread along the pleural surface.
ANSWER: C. Organ-localized small cell carcinoma are tan-white, gritty, and deceptively circumscribed. Umbilicated tumors with irregular edges are features of adenocarcinoma. Central softening with cystic degeneration are not seen. Although rare examples of small cell carcinoma have mimicked mesothelioma; this is not a frequent finding.
9. A 14-year-old patient has a chronic cough with persistent pneumonia. A computed tomography scan is performed showing an endobronchial mass, which is biopsied. Which of the following is the MOST likely finding on biopsy?
A. A cartilaginous tumor with adipose tissue and epithelial ingrowth
B. A spindle cell tumor with prominent inflammatory infiltrate
C. A myoepithelial tumor with cartilage and epithelial structures
D. Organoid nests, uniform cells with identifiable mitoses, and necrosis
E. Organoid nests, uniform cells without necrosis
ANSWER: E. The most common pediatric endobronchial tumor is a carcinoid tumor, and most cases do not show mitotic activity or necrosis of atypical carcinoids. Hamartomas can be endobronchial as can inflammatory myofibroblastic tumors. However, most hamartomas are not endobronchial, and inflammatory myofibroblastic tumor are not more common than carcinoids. Although tumors of bronchial glands are in the differential diagnosis, mucoepidermoid carcinoma should be considered, and pulmonary mixed tumors are very uncommon.
10. A 50-year-old woman has a cough and dyspnea, with a relatively normal chest x-ray. A computed tomography scan shows mosaic attenuation, and her pulmonary function tests show obstructive physiology. Which of the following is TRUE regarding her disease?
A. Her risk of small cell carcinoma is markedly increased.
B. Small nodules of less than 5.0-mm may be present on tissue biopsy.
C. The disease is typically progressive with multiorgan metastasis.
D. The disease is typically progressive, with the most common outcome of death or organ failure within 5 years.
E. Her airway epithelium will be completely denuded and replaced by neuroendocrine cells.
ANSWER: B. In diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), carcinoid tumorlets are frequently present in association with airways showing neuroendocrine proliferation that undermines normal epithelium and involved airways in a patchy distribution. Most cases are indolent, and even progressive cases are not associated with increased mortality. Some patients do require transplantation. Although DIPNECH is considered a preinvasive neuroendocrine proliferation, it occurs in nonsmokers and does not seem to be associated with increased risk of small cell carcinoma.
11. Which of the following is TRUE of carcinoid epidemiology?
A. It is a tumor of adults older than 40 years.
B. Smoking and second-hand smoke are clear risk factors.
C. It is a tumor of men, with highest rates in Asian and Hispanic men.
D. It is increasing in frequency at a consistent 3% annual rate.
E. Antecedent diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) diagnosis is usually rendered prior to carcinoid diagnosis.
ANSWER: D. Carcinoid tumors are increasing in frequency at a rate of 3% to 6% per annum. It is a tumor of Caucasians and more common in women than men. It is not smoking associated, and although DIPNECH is thought to be a precursor lesion, most carcinoids are diagnosed de novo, without prior DIPNECH.
12. Which of the following clinical presentations is NOT seen with carcinoid tumors?
A. Chronic cough
B. Hemoptysis
C. Recurrent pneumonia
D. Cushing syndrome
E. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion
ANSWER: E. SIADH is seen in small cell carcinoma, not carcinoid tumors. Although carcinoids can be detected in asymptomatic patients by imaging, cough, hemoptysis, recurrent pneumonia, and Cushing syndrome can all be presenting clinical features of carcinoid tumors.
13. A resected tumor has organoid nests and uniform cells with round nuclei and salt-and-pepper chromatin. Which of the following is TRUE regarding pathologic assessment of this tumor?
A. The tumor should be extensively sampled to search for vascular invasion to diagnose atypical carcinoid.
B. The finding of bronchial wall invasion confirms the diagnosis of atypical carcinoid.
C. The finding of one 2.0-mm2 area with two mitoses warrants a designation of atypical carcinoid.
D. A Ki-67 immunohistochemistry is performed and is less than 2%, so the diagnosis is typical carcinoid.
E. Three 2.0-mm2 areas have a total of seven mitoses, and this is diagnostic of atypical carcinoid.
ANSWER: E. For tumors with mitotic counts at the cusp of the diagnostic categories, the average of mitotic counts should exceed two mitoses in 2.0 mm2, but only one such area is not sufficient. Ki-67 cutoffs are not yet established, but the finding of necrosis would change the diagnosis to atypical carcinoid. Invasion of vessels and airway can be seen in both typical and atypical carcinoids.
14. Which of the following is TRUE regarding the molecular changes in neuroendocrine neoplasms?
A. Primitive neuroectodermal tumor (PNET) tumors have characteristic 9 : 22 translocations.
B. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are seen in about 10% of small cell carcinomas.
C. TP53 and RB1 pathways are critical in high-grade neuroendocrine neoplasms.
D. Mutations in Achaete-Scute Family (ASCL1) are seen in most carcinoid tumors.
E. Deletions in 22q affect the NF1 gene resulting in atypical carcinoids.
ANSWER: C. Alterations in TP53 and RB1 pathways are seen in virtually all small cell carcinomas and in a large proportion of large cell neuroendocrine carcinomas (LCNEC). PNETs have EWSR1 translocations, not Philadelphia chromosome. KRAS mutations are not seen in small cell carcinomas or carcinoids; however, a subset of adenocarcinoma-like LCNEC are reported as KRAS mutated. ASCL1 mutations and NF1 loss are not seen in carcinoids, but losses in chromosome 11 where the menin gene is located are seen.
15. The following is correctly defined in the diagnosis of lung carcinomas:
A. Large cell neuroendocrine carcinoma (LCNEC): neuroendocrine morphology, negative neuroendocrine markers
B. Large cell carcinoma with neuroendocrine morphology: prominent nucleoli, prominent crush artifact, nuclear molding
C. Non-small cell carcinoma with neuroendocrine differentiation: no neuroendocrine morphology and positive staining for neuroendocrine markers
D. Large cell carcinoma with neuroendocrine morphology: positive chromogranin and synaptophysin
E. Mitotically active atypical carcinoid: necrosis, with mitotic counts of 12 in 2.0 mm2
ANSWER: C. The diagnosis of LCNEC requires both morphologic neuroendocrine features and immunohistochemistry confirmation. Large cell carcinoma with neuroendocrine morphology does not show features of small cell carcinoma and is negative by immunohistochemistry for neuroendocrine markers. There is no entity of mitotically active atypical carcinoids, although LCNEC at the lower end of the mitotic range may be biologically distinct.
16. ALL of the following are TRUE regarding treatment of carcinoid tumors EXCEPT:
A. Surgical resection is the optimal treatment, if feasible.
B. Lung-sparing bronchoplastic resections should be attempted with negative margins.
C. Atypical carcinoids with mediastinal nodal disease should be considered for adjuvant therapy.
D. Liver metastases can be resected if not associated with diffuse nodal or abdominal disease.
E. Response rates to chemotherapy are as high as 50% using novel agents.
ANSWER: E. Response rates to chemotherapy are relatively low, about 20%. Surgical therapy is optimal, with lung-sparing bronchoplastic techniques for central disease. Liver metastasis can be resected in clinical circumstances in which disease can be controlled in this fashion. Although adjuvant therapy is controversial in lung-limited tumors, with N2 nodes, adjuvant therapy should be offered to patients with atypical carcinoid.
17. The treatment of small cell carcinoma may include all of the following EXCEPT:
A. Chemotherapy with a platinum agent and pemetrexed
B. Cisplatin or carboplatinum with etoposide
C. Prophylactic cranial irradiation for unresectable patients without brain metastasis
D. Surgery for early stage organ-localized tumor
E. Radiation therapy in combination with chemotherapy
ANSWER: A. Chemotherapy with platinum and etoposide is the treatment for small cell carcinoma; pemetrexed is effective in adenocarcinoma. Cranial irradiation decreases the rate of disease recurrence in the brain. Surgery is a reasonable option in early-stage disease, although it is not curative on its own.
18. The following is TRUE regarding combined small cell carcinoma:
A. As a high-grade tumor, spindle cell and giant cell histology is frequently seen.
B. The most common histology in a combined small cell carcinoma is large cell neuroendocrine carcinoma (LCNEC).
C. In combined small cell with adenocarcinoma, epidermal growth factor receptor (EGFR) mutations are never encountered.
D. Adenocarcinoma in combined small cell carcinoma is the most commonly lepidic pattern.
E. Combined small cell carcinoma is treated surgically as if it is a non-small cell carcinoma.
ANSWER: B. The most common non-small cell histology in combined small cell is LCNEC; even requiring 10% presence in a tumor, it represents 16% of all resected small cell cases. EGFR mutations have been described in combined small cell with adenocarcinoma; adenocarcinoma patterns vary but are invasive patterns with abrupt transition not typically lepidic. Combined small cell is treated like small cell carcinoma.
19. Which of the following best describes the use of immunohisto- chemistry (IHC) in neuroendocrine tumors of the lung?
A. Ki-67 is required in all cases because the classification is dependent on Ki-67 cutoff values.
B. All small cell carcinomas require demonstration of neuroendocrine differentiation by IHC.
C. Large cell/non-small cell tumors with neuroendocrine morphology should be sent for IHC for neuroendocrine markers.
D. All adenocarcinomas and squamous carcinomas should be sent for IHC for neuroendocrine markers to search for neuroendocrine differentiation.
E. Carcinoid tumors should be evaluated for synaptophysin and chromogranin because the staining intensity supports typical or atypical histology.
ANSWER: C. Current classification requires confirmation by neuroendocrine markers in high-grade tumors with neuroendocrine morphology that do not have a small cell component.
20. Which of these choices reflects the more reproducible neuroendocrine markers currently available?
A. Synaptophysin, chromogranin A, CD57
B. Synaptophysin, neuron-specific enolase, PGP9.5
C. Chromogranin A, chromogranin B, ASCL1
D. CD56, CD57 and S100
E. Synaptophysin, chromogranin, CD56
ANSWER: E
Case 1
eSlide 14.1
History
The patient is a 48-year-old woman, lifelong nonsmoker, who presented to her internist and pulmonologist with a complaint of dyspnea on exertion and cough. Her pulmonary function tests showed obstructive lung disease. A computed tomography scan was performed that showed mosaic attenuation with lucent areas that remained lucent on expiration. Numerous noncalcified nodules were also detected, the largest of which was 5.0 mm. Emphysema was not seen.
Pathologic Findings
A wedge lung biopsy was performed to evaluate causes of obstructive lung disease. eSlide 14.1 shows two sections, one relatively devoid of airways and the other with four small airways. There is a proliferation of bland, fusiform cells with salt-and-pepper chromatin that undermine the epithelium and cause protrusion into the airway lumen. In one airway they travel along a respiratory bronchiole. There is one nest potentially in an airway wall.
Diagnosis
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome.
Discussion
A subsequent Octreotide scan was negative in the abdomen, chest, and pelvis. The patient had slowly progressive obstructive lung disease over the next decade. She was managed on somatostatin. Although she was evaluated for lung transplantation, the indolent progression has not yet justified transplantation. She has not developed carcinoid tumors or other malignancies during that period.
Case 2
eSlide 14.2
History
The patient is a 71-year-old woman who is status post left lumpectomy for breast carcinoma 10 years prior, who presented for evaluation based on a computed tomography scan finding of a nodule in her left upper lobe, abutting the pleura. She is a 10 pack year former smoker who quit 20 years prior. A mediastinal node dissection was performed and sent for frozen section; it was negative for tumor. A left upper lobectomy was performed.
Pathologic Findings
The tumor was 3.0 cm and was described as tan, firm, and fleshy. It was 1.5 cm from the bronchial margin, and directly subpleural. eSlide
14.2 shows a cellular proliferation of uniform cells with fine chromatin arranged in a vaguely trabecular pattern, but the cells are elongated cells with fusiform nuclei. Area of dense fibrous stroma are seen. Although There is invasion seen, necrosis and mitotic activity are absent. Because this is a 3.0-cm tumor, extensive sampling is needed to rule out necrosis or mitotically active areas.
Diagnosis
Typical carcinoid tumor, spindle cell variant.
Discussion
All margins were negative. The diagnosis of carcinoid tumor was rendered at frozen section, but the location of the tumor requires a lobectomy to achieve a complete resection. Also, frozen section cannot determine typical carcinoid versus atypical carcinoid, and There is some question as to whether wedge type resections are sufficient in atypical carcinoids. However, pathologic evaluation showed a typical carcinoid, spindle cell variant, with negative margins and nodes. The patient is alive and free of disease at 10-year follow-up.
Case 3
eSlide 14.3
History
The patient is a 66-year-old man, former 20 pack year smoker (quit 10 years prior) with complaint of back pain and weight loss. A chest x-ray revealed an 8.0-cm mass, and a biopsy was diagnostic of carcinoma. After negative endobronchial ultrasound nodal sampling, the patient opted for a primary surgical approach over neoadjuvant therapy. With negative mediastinal nodes on frozen section, a right pneumonectomy was performed with excision of a portion of chest wall.
Pathologic Findings
An 11.0-cm tumor was seen that was partially necrotic and hemorrhagic, but areas were seen that were lobulated and fleshy. eSlide 14.3 shows extensive necrosis but also shows a vaguely organoid pattern especially at the periphery of the section. Nests show palisading with central necrosis. Pseudorosettes are seen, but no true rosettes. Cells are relatively large with recognizable cytoplasm. Nuclei are irregular with salt-and- pepper chromatin and cells with identifiable nucleoli. Mitotic rate is high. Immunohistochemistry (IHC) is synaptophysin and CD56 positive and chromogranin negative; thyroid transcription factor 1, p40, and napsin A were also negative. Molecular testing showed TP53 mutation but no mutations in epidermal growth factor receptor or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and negative for anaplastic lymphoma kinase translocation.
Diagnosis
Large cell neuroendocrine carcinoma (LCNEC).
Discussion
The tumor meets the morphology and IHC requirements for LCNEC. The molecular results match the small cell-like molecular profile of this tumor, and this also matches the very high mitotic rate, nuclear features with a mixture of salt-and-pepper chromatin and identifiable nucleoli with lack of adenocarcinoma morphology. The presence of cytoplasm and the larger cells are not in keeping with actual small cell carcinoma. After surgery, the tumor rapidly recurred, and within 5 months a brain metastasis was detected.
Case 4
eSlide 14.4
History
The patient is a 77-year-old woman with a 60 pack year smoking history who was found to have a lung nodule, 1.6 cm, on screening computed tomography (CT) scan. A positron emission tomography (PET)-CT showed a highly avid mass in the lung, but negative mediastinal nodes. Brain magnetic resonance imaging did not show a tumor. A biopsy showed carcinoma. A right upper lobectomy was performed with node dissection.
Pathologic Findings
A 1.7-cm firm, well-circumscribed white mass was seen and entirely sampled. All nodes were negative. eSlide 14.4 reveals a tumor with distinctly organoid morphology. The cells vary in size, but most sections showed a highly cellular population of small cells with scant cytoplasm and a high mitotic rate. Apoptotic bodies and nuclear debris were numerous. Nuclear molding was seen, but Azzopardi effect and crush artifact were not. Some areas of the tumor (best seen on the eSlide) showed nests with larger cells and visible cytoplasm with nuclear morphology and cellularity of large cell neuroendocrine carcinoma (LCNEC). This reaches 10% of the total tumor sections. Both components
were positive for synaptophysin, cytokeratin, and thyroid transcription factor 1 by immunohistochemistry.
Diagnosis
Small cell carcinoma, combined type, with LCNEC.
Discussion
After surgery with negative margins, there was a discussion of adjuvant chemotherapy and the patient successfully completed a platinum/ etoposide-based regimen.
Case 5
eSlide 14.5
History
The patient is a 21-year-old man with a 6.0-cm mass lesion in the chest wall and pleura with compression of the lung parenchyma. A surgical biopsy was performed.
Pathologic Findings
eSlide 14.5 shows a cellular tumor with large organoid nests with little intervening stroma. Apoptotic debris and mitotic activity are seen. The nuclei have a fine chromatin, and in some areas the chromatin is very fine and uniform (“powdery”). Periodic acid-Schiff positive, diastasesensitive material was seen in cytoplasmic clearing. Immunohistochemistry (IHC) with CD99 was strongly membranous, weak synaptophysin, and negative chromogranin. IHC for Fli-1 proto-oncogene, ETS transcription factor is positive.
Diagnosis
Primitive neuroectodermal tumor.
Discussion
The patient was lost to follow-up.