P U L M O N A RY NEUROENDOCRINE TUMORS Leslie A. Litzky, MDa,b,* KEYWORDS  Neuroendocrine tumors  Nonneuroendocrine cell carcinomas  Carcinoid tumor  Atypical carcinoid tumor  Small cell carcinoma  Large cell neuroendocrine carcinoma  Neuroendocrine cell hyperplasia

ABSTRACT

OVERVIEW The current 2004 World Health Organization (WHO) classification system divides the pulmonary neuroendocrine tumors into 4 separate entities: typical carcinoid tumor, atypical carcinoid tumor, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC).1 The WHO classification provides for stratification in risk assessment and incorporates the outcome-based differences in neuroendocrine tumors that have alternatively been conceptualized as lowgrade, intermediate-grade, and high-grade

Key Points NEUROENDOCRINE TUMORS OF

THE

LUNG

1. The current 2004 WHO classification recognizes 4 distinct tumors: typical carcinoid tumor, atypical carcinoid tumor, SCLC and LCNEC. There are major epidemiologic, clinical, morphologic, and molecular differences between the carcinoid tumors and the highgrade neuroendocrine carcinomas (SCLC and LCNEC). The current WHO classification is not without controversy and practical difficulties. 2. The diagnosis of pulmonary neuroendocrine tumors is primarily based on light microscopy. A good-quality, thinly cut, and well-stained hematoxylin-eosin section is an essential starting point for accurate diagnosis. 3. Small biopsies are particularly challenging for the reliable separation of these tumors. Comparison with concurrent cytology specimens, if available, may improve morphologic characterization. Immunohistochemical stains are also useful in specific circumstances. 4. There is morphologic and immunophenotypic overlap, particularly between the high-grade neuroendocrine tumors and when compared with other non–SCLCs. Although morphologic separation is occasionally difficult, the distinction may not be therapeutically or prognostically significant.

a Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 6 Founders Building, 3400 Spruce Street, Philadelphia, PA 19104, USA b Section of Medical Pathology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104, USA * Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 6 Founders Building, 3400 Spruce Street, Philadelphia, PA 19104. E-mail address: [email protected]

Surgical Pathology 3 (2010) 27–59 doi:10.1016/j.path.2010.03.007 1875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

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ulmonary neuroendocrine tumors are frequently encountered as small biopsy and resection specimens. Although the World Health Organization (WHO) classification is used as a diagnostic framework globally and in daily practice, it is not without controversy and practical difficulties. The WHO criteria for pulmonary neuroendocrine tumors are reviewed with the recognition that the definitions are based on resected specimens, which are often not the usual clinical circumstances. A practical approach is emphasized, and the differential diagnosis is discussed with particular attention to the context in which diagnostic difficulties are most frequently encountered, such as small biopsies and frozen sections.

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Litzky neuroendocrine carcinomas.2,3 Although the WHO classification is used as a diagnostic framework globally and in daily practice, it is not without controversy and practical difficulties. A detailed history and critical analysis of the classification of neuroendocrine carcinomas of the lung has been published, and some of the issues discussed in the publication are also addressed in this article.3 Despite some significant differences in epidemiology and clinical presentation as well as prognosis and molecular characteristics, neuroendocrine tumors of the lung are typically approached as a distinct group from a pathologic perspective. Historically, this approach evolved from the pathologist’s initial recognition of neuroendocrine morphology by light microscopy—both in terms of histologic patterns as well as cytologic features. In addition to neuroendocrine morphology, the pulmonary neuroendocrine tumors have been further separated out on the basis of mitotic rate, the presence of necrosis, and other cellular characteristics. The use of ancillary tests such as immunohistochemical stains plays a specific but limited role in the diagnosis of neuroendocrine tumors, but immunohistochemical tests have utility in the broader differential diagnosis of other tumors involving the lung. In the subsequent sections, a clinical overview as well as the gross and microscopic features of each pulmonary neuroendocrine tumor is provided. The WHO criteria are reviewed with the recognition that the definitions are based on resected specimens, which are often not the usual clinical circumstances. The differential diagnosis is discussed with particular attention to the context in which diagnostic difficulties are most frequently encountered, such as small biopsies and frozen sections. Although there is an increasing amount of literature on the molecular characteristics of pulmonary neuroendocrine tumors that might be used to distinguish the tumors, guide therapy, or refine prognosis, this is not reviewed and a practical approach is emphasized.

CARCINOID TUMORS: TYPICAL AND ATYPICAL OVERVIEW The general clinical context in which carcinoid tumors are likely to occur is of some utility—both in terms of formulating an appropriate differential diagnosis and in avoiding diagnostic misinterpretations with significant clinical consequences. Typical carcinoid tumors account for only 1% to 2% of all pulmonary tumors but are frequently encountered in surgical pathology as resection

specimens, given that more than 70% present as stage I disease.4–6 Atypical carcinoid tumors are also seen as resection specimens with about 40% to 60% presenting with stage I disease.5,6 The mean age range at presentation for patients with typical carcinoid and atypical carcinoid tumors is 45 to 55 years, and this differs from patients with SCLC and LCNEC who, on average, tend to present in the seventh decade of their lives. Typical carcinoid tumors occur in all age groups and are common in the pediatric population.7 The male/female ratio is 1:1 in both types of carcinoid tumors. The percentage of patients with a smoking history and atypical carcinoids (at least 60%) differs from those with typical carcinoids in whom there is no association with smoking.5 About 50% of all patients with typical carcinoid tumors are asymptomatic. The remaining half of patients present with the common pulmonary symptoms that suggest an endobronchial mass such as hemoptysis, recurrent or postobstructive pneumonia, dyspnea, and asthmalike symptoms. The clinical presentation of atypical carcinoids is essentially identical to that of typical carcinoid tumors. A substantial proportion of patients with atypical carcinoid tumors are asymptomatic at the time of identification, whereas the remainder have the usual symptoms of cough, hemoptysis, or evidence of bronchial obstruction.8 Typical and atypical carcinoid tumors occur both centrally and peripherally, but as the diagnostic criteria for these entities have been further refined, the incidence of peripherally based tumors is higher in atypical carcinoid tumors.9 The association of bronchopulmonary carcinoid tumors with carcinoid syndrome is unusual and most often occurs in the presence of hepatic metastases. However, there is a documented association with Cushing syndrome, which does not appear to be as aggressive a variant as previously reported.10 Acromegaly has also been reported.11 Bronchopulmonary carcinoids occur in about 5% of patients with multiple endocrine neoplasia type 1, although most occur as nonfamilial (ie, sporadic) isolated tumors.11 The International Association for the Study of Lung Cancer (IASLC) proposals for the seventh edition of TNM are useful in predicting prognosis for bronchopulmonary carcinoid tumors. The IASLC staging project has recommended the adoption of TNM staging system. The 2009 common altering protocol (CAP) for the examination of resected pulmonary specimens has been extended to carcinoid tumors.11,12 The prospective collection of data through an International Registry of Pulmonary Neuroendocrine Tumors that is being planned by the IASLC will hopefully

Pulmonary Neuroendocrine Tumors provide for further detailed analysis and better understanding of these tumors.13 Although typical carcinoid tumors have an excellent prognosis with reported 5-year survival rates of 87% to 100%, it is critical to understand that typical carcinoids are low-grade but malignant tumors.4,8,14–16 The 5year survival rate for atypical carcinoid tumors is significantly lower, and about 40% of atypical carcinoid tumors present at stage II or greater. To date, one of the largest series of 106 atypical carcinoid tumors, using the WHO criteria, reported a 5-year survival rate of 71% for stage I tumors, 46% for stage II, and 37% for stages III/IV.9

GROSS FEATURES Carcinoid tumors can be divided into central and peripheral variants. About 75% of typical carcinoids and 60% of atypical carcinoids present as central tumors. Central carcinoid tumors grossly appear as polypoid endobronchial masses. The tumor usually has a significant exophytic component, but because of the extensive submucosal growth it often has a smooth surface. Indeed, the bronchoscopist is occasionally perplexed when superficial mucosal biopsies fail to document Fig. 1. Carcinoid tumor (typical). Cut section demonstrates a large endobronchial tumor with distal bronchiectasis and mucous plugging.

a mass that can be clearly visualized (or the pathologist is vexed when confronted with a few atypical cells at the base of the biopsy). Some central carcinoid tumors give rise to a mass that has been described as an ‘‘iceberg’’ in which there is more extensive airway and parenchymal extension than can be appreciated from the endobronchial lesion.17 It is not uncommon to see distal bronchiectasis and mucous plugging behind such tumors (Fig. 1). The gross polypoid configuration can present a problem in accurately defining the margin of resection (Fig. 2). Meticulous dissection of the airway often demonstrates that the point of bronchial wall attachment is more distal than it grossly appears, and care should be taken to avoid creating a false-positive proximal bronchial margin (Fig. 3). Peripheral carcinoid tumors appear as well-defined parenchymal nodules without any anatomic connection to a bronchus (Fig. 4). On a cut surface, carcinoid tumors are usually circumscribed and can be white to gray, tan, pink, or red brown in color (Figs. 5 and 6). The consistency varies from soft or rubbery to more firm. The cut surface is usually more homogenous in appearance than in SCLC, LCNEC, and other non-SCLCs. A minority of atypical carcinoid tumors have obvious necrosis or hemorrhage and

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Litzky Fig. 2. Carcinoid tumor (typical). Lobectomy specimen showing the typical smooth surface of an endobronchial carcinoid tumor that appears to be projecting beyond the bronchial margin of resection.

grossly appear similar to typical carcinoid tumors (Fig. 7).9

MICROSCOPIC FEATURES OF CARCINOID TUMORS AND DIFFUSE IDIOPATHIC PULMONARY NEUROENDOCRINE CELL HYPERPLASIA Carcinoid tumors have the diverse growth patterns that are characteristic of neuroendocrine differentiation. The tumor cells form organoid nests, trabeculae, insular islands, and ribbon or rosettelike arrangements (Fig. 8). Carcinoid tumors can also

have papillary, sclerosing, follicular, or pseudoglandular patterns. Carcinoid tumors are usually associated with a delicate, highly vascularized stroma (Fig. 9). Occasional cases are associated with a hyalinized stroma that may have cartilage or bone formation, as well as amyloid deposition (Figs. 10 and 11). The tumor cells are generally uniform in appearance and have a low nuclear/ cytoplasmic ratio with round to oval nuclei and moderate amounts of eosinophilic cytoplasm. Some carcinoid tumors have either focal or prominent spindle cell features with fusiform cells that have less cytoplasm (Fig. 12). The nuclear

Fig. 3. Carcinoid tumor (typical). Same tumor as in Fig. 2 that is carefully sectioned to show that the point of attachment of the tumor is much further away from the bronchial margin of resection.

Pulmonary Neuroendocrine Tumors Fig. 4. Peripheral carcinoid tumor (typical). The tumor is well circumscribed and intraparenchymal without a connection to an airway.

Fig. 5. Carcinoid tumor (typical). Cut surface demonstrates a variegated tan-red surface.

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Litzky Fig. 6. Carcinoid tumor (typical). Cut surface demonstrates a variegated gray-red surface.

chromatin can vary between finely granular and somewhat more coarse with absent or inconspicuous nucleoli (Figs. 13 and 14). The 2004 WHO criteria for the diagnosis of typical carcinoid tumor require less than 2 mitoses per 2 mm2 and no necrosis.1 The 2004 WHO classification defines an atypical carcinoid tumor as a tumor with a low-power appearance of carcinoid tumor but that has 2 to 10 mitoses per 2 mm2 and/or a foci of necrosis (Figs. 15–17). The necrosis is typically punctate but can be more conspicuous

(Figs. 18 and 19). These features can be focal, and therefore, from a practical point of view, it is difficult to make the distinction between a typical and atypical carcinoid tumor on the basis of a cytology specimen, small biopsy, frozen section, or grossly at the time of resection. It is also important to note any clinical history of a prior procedure, such as fine needle biopsy, to avoid overinterpreting procedurerelated necrosis. Other features such as cytologic atypia and vascular invasion may be noted,

Fig. 7. Carcinoid tumor (atypical). The cut surface is homogenous in appearance and not grossly distinctive from other typical carcinoid tumors.

Pulmonary Neuroendocrine Tumors Fig. 8. Carcinoid tumor (typical). The tumor cells are arranged in a characteristic pattern of nests and trabeculae. The nuclei are more ovoid in appearance (hematoxylin-eosin, original magnification 100).

but these features are not the basis for the separation of typical from atypical carcinoid tumors in the WHO classification. Sections of the background lung in resected carcinoid tumors may show neuroendocrine cell hyperplasia (NEH). Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) was

Fig. 9. Carcinoid tumor (typical). The tumor cells are arranged in nests within a delicate fibrovascular stroma. The tumor nuclei are more rounded in appearance (hematoxylin-eosin, original magnification 200).

formally recognized as a preinvasive lesion, beginning with the 1999 WHO revision, although the significance of DIPNECH and its neoplastic potential have yet to be fully elucidated.1,2 DIPNECH is defined as a generalized proliferation of scattered single cells, small nodules (neuroendocrine bodies) or linear proliferations of pulmonary

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Litzky Fig. 10. Carcinoid tumor (typical). Carcinoid with hyalinized stroma (hematoxylin-eosin, original magnification 400).

neuroendocrine cells that may be confined to the bronchial and bronchiolar epithelium, including local extraluminal proliferation in the form of tumorlets (by WHO definition, 95%) that the diagnosis should be carefully considered when outside of this usual clinical context. In contrast to SCLC, a substantial proportion (60%) present as peripheral tumors and there are significant differences in stage at presentation. In contrast to SCLC, in which less than 10% present at stage I, 45% of LCNECs present at stage I and 55% at stage II or greater. Nevertheless, despite the initial differences in stage at presentation, the survival rates for SCLC and LCNEC, whether for surgery in earlystage disease or for those patients with advanced disease, are essentially identical. The practical implication of all these data suggests that there may be limited value in making the histologic distinction between SCLC and LCNEC in these circumstances, although that is often difficult for some clinicians to accept. It is difficult to know how much clinical utility is there in documenting neuroendocrine differentiation in patients with early-stage or advanced-stage disease, with an

otherwise poorly differentiated non–SCLC. The reassuring news in this regard is that the initial surgical management remains the same, and perhaps the current focus on the molecular characterization of these tumors may have implications for future diagnosis, therapy, and prognosis.

GROSS FEATURES LCNECs are more frequently encountered as large peripheral tumors with an average size of 3 to 4 cm.4 These tumors are often circumscribed, but, in contrast to most carcinoid tumors, the cut surface is often grossly described as necrotic. There are no other features that grossly distinguish LCNEC from other non-SCLCs or from the rare presentation of a peripheral SCLC.

MICROSCOPIC FEATURES According to the 2004 WHO classification, there are 4 requirements for the diagnosis of LCNEC.1 The first criterion is the appearance of neuroendocrine morphology with organoid nesting, palisading, trabeculae, or rosettelike structures. The second criterion is a high mitotic rate, which is greater than 10 mitoses per 2 mm2. In actual practice, the mitotic counts are usually much higher and average in the range of 75 per 10 high-power fields. Ki-67 staining can also be used to evaluate the proliferation rate, which may be especially helpful in smaller samples. Typical percentages of Ki-67 staining are in the range of 50% to 100%.4 Large areas of necrosis are also common. The third criterion is that neuroendocrine differentiation must be demonstrated by immunohistochemistry or electron microscopy. Acceptable antibodies include chromogranin, synaptophysin, and CD56 but not neuron-specific enolase. The fourth criterion is the identification of non–small cell cytologic features. These criteria include large cell size, low nuclear/ cytoplasmic ratio, prominent nucleoli, and coarse vesicular chromatin (Figs. 36–39).

DIFFERENTIAL DIAGNOSIS In a generous and well-preserved sample, separation from carcinoid tumors can be made on the basis of mitotic rate, the extent of necrosis, and higher-grade cytologic features. Even with a larger sample, the separation from SCLC (primarily by cytologic distinctions) or from other non–SCLCs (by neuroendocrine morphology and neuroendocrine differentiation by immunohistochemistry) can be more problematic. Most pathologists conceptualize their idea of ‘‘small’’ on the basis of far more frequent

Pulmonary Neuroendocrine Tumors Fig. 36. LCNEC. Appearance of neuroendocrine morphology under lowpower field with nests of tumor cells (hematoxylin-eosin, original magnification 100).

endobronchial biopsies and do not often have the opportunity to see the spectrum of cell size that can be seen in SCLC. Nevertheless, there is a significant overlap in cell size in LCNEC and SCLC.37 Nuclear/cytoplasmic ratio can be easier to recognize and is used to separate LCNEC from SCLC. Prominent nucleoli and vesicular chromatin are similarly easier to recognize, but there is often some inherent variability in the tumors themselves as well as histologic artifacts such as thickly cut sections make evaluation difficult. For tumors Fig. 37. LCNEC. Tumor cells confirmed to be positive by neuroendocrine immunohistochemical stains. The cells have a variable nuclear chromatin pattern with some more prominently nucleolated (hematoxylineosin, original magnification 400).

that have clear-cut areas of both small cell and large cell carcinoma, the diagnosis of combined small cell and large cell carcinoma can be applied (Figs. 40–45). LCNECs with components of adenocarcinoma, squamous cell carcinoma, giant cell carcinoma, and/or spindle cell carcinoma can be classified as combined LCNEC.1 At the other end of the spectrum, separation from non– SCLCs, which may appear to have histologic features that suggest neuroendocrine differentiation and may or may not have evidence of

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Litzky Fig. 38. LCNEC. Tumor cells confirmed to be positive by neuroendocrine immunohistochemical stains. These cells have more cytoplasm and obvious nucleolation (hematoxylin-eosin, original magnification 400).

neuroendocrine differentiation by immunohistochemistry, must be considered (Figs. 46 and 47). The basaloid variant of squamous cell carcinoma shows prominent peripheral palisading, but careful scrutinization for small keratinizing foci as well as a panel of immunohistochemical stains that include neuroendocrine markers and TTF-1, CK903, and p63 may be helpful. A subset of pulmonary blastomas also show focal neuroendocrine differentiation and may not be separable on a small biopsy, but a larger resection specimen should show the characteristic biphasic appearance with fetal-type glands and embryonic stroma (Figs. 48 and 49).

PITFALLS IN SMALL BIOPSY DIAGNOSIS As previously discussed, a significant issue with the current WHO classification of pulmonary neuroendocrine tumors is that 3 of the 4 entities (typical carcinoid tumor, atypical carcinoid tumor, and LCNEC) cannot be definitively diagnosed on a cytology or small-biopsy specimen, given that the current criteria are based on a thorough histologic examination of the resected specimen.3 Moreover, some of the criteria for SCLC are more difficult to apply in a small specimen. In a patient who is an operative candidate, this has little immediate consequence for the initially recommended surgical Fig. 39. LCNEC. Tumor cells confirmed to be positive by neuroendocrine immunohistochemical stains. These cells have more cytoplasm but no obvious nucleolation (hematoxylin-eosin, original magnification 200).

Pulmonary Neuroendocrine Tumors Fig. 40. Combined small cell and large cell carcinoma. Low-power field showing sheets of tumor cells and extensive necrosis (hematoxylineosin, original magnification 50).

management but may be a more significant issue if the patient has more advanced disease or is inoperable for other reasons. SCLC of the lung is most frequently encountered as a bronchoscopic biopsy or fine-needle biopsy specimen. Patients tend to present with advanced disease that classically includes a large hilar mass and bulky mediastinal adenopathy; there is often evidence of distant

Fig. 41. Combined small cell and large cell carcinoma (positive CD56 immunohistochemical stain, original magnification 100).

metastases. As was emphasized in the section on small carcinoma, the diagnosis of SCLC should be seriously reevaluated in the absence of a significant smoking history. It is only in the complete absence of clinical history and radiographic correlation that the pathologist is likely to misinterpret a low-grade neuroendocrine carcinoma, such as a carcinoid tumor, for SCLC. Nevertheless, such instances do

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Litzky Fig. 42. Combined small cell and large cell carcinoma (positive chromogranin immunohistochemical stain, original magnification 200).

occur and in retrospect, these errors are usually attributable to scant cellularity, poor cellular preservation, or crush artifact (Fig. 50). If there is sufficient tissue, additional immunohistochemical stains may help to confirm the diagnosis of carcinoma with neuroendocrine differentiation but usually do not help in separating low-grade from high-grade neuroendocrine carcinomas, a distinction that must be primarily based on careful morphologic

evaluation of hematoxylin-eosin stained sections. In a retrospective study that included 7 patients with carcinoid tumors, which were overdiagnosed on bronchoscopic biopsies, the Ki-67 labeling index proved to be the most useful ancillary technique with a high Ki-67 labeling index (>50%) supporting a diagnosis of SCLC.31 As a nuclear marker, Ki-67 positivity was more easily assessed in areas with extensive crush artifacts. Other contrasting features

Fig. 43. Combined small cell and large cell carcinoma. Two areas side by side showing increased amounts of cytoplasm in one area and a higher nuclear/cytoplasmic ratio in the other (hematoxylineosin, original magnification 100).

Pulmonary Neuroendocrine Tumors Fig. 44. Combined small cell and large cell carcinoma. An interesting result with TTF-1 showing strong staining on one side and negative staining in another area (TTF-1 immunohistochemical stain, original magnification 100).

included a tumor stroma containing thin-walled vessels (favoring carcinoid tumor) versus a stroma with thick-walled blood vessels showing a glomeruloid configuration (favoring SCLC) and higher levels of neuroendocrine marker immunoreactivity in carcinoid tumors. Differences in nuclear chromatin were also noted—granular and sometimes coarse (favoring carcinoid tumor) versus finely and evenly dispersed (favoring SCLC). In many circumstances,

Fig. 45. Combined small cell and large cell carcinoma. Classic focus of SCLC (hematoxylin-eosin, original magnification 400).

a concurrent cytology specimen is obtained with these types of biopsy specimens and morphologic comparison with cytologic preparations can be extremely useful. PAX-5 has been reported to be useful in fine-needle aspiration biopsies in a similar way to Ki-67, but the 2 ancillary tests have not been directly compared.38 On the opposite end of the spectrum, it is occasionally difficult to exclude a non–SCLC with or without neuroendocrine

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Litzky Fig. 46. Large cell carcinoma. The appearance under low-power field might suggest neuroendocrine morphology (hematoxylin-eosin, original magnification 200).

differentiation and a LCNEC. Extensive necrosis within the sample as well as delayed fixation or improper processing can obscure cytologic details. Occasionally, a negative TTF-1 stain combined with negative neuroendocrine markers along with a positive p63 and CK903 may be helpful in supporting a diagnosis of a poorly differentiated squamous cell carcinoma, if there are some suggestive cytohistologic features in a scant sample. However, in general, if there are no viable and well-preserved

areas of the tumor available for evaluation, it is better to acknowledge that fact and avoid misclassification in circumstances when the clinician insists that the distinction is clinically relevant.

PITFALLS IN FROZEN SECTION DIAGNOSIS The interoperative diagnosis of pulmonary neuroendocrine tumors can be challenging and there had been a relative paucity of literature on this Fig. 47. Large cell carcinoma. Neuroendocrine markers were tested negative despite the neuroendocrine appearance (hematoxylin-eosin, original magnification 400).

Pulmonary Neuroendocrine Tumors Fig. 48. Pulmonary blastoma. Primitive stroma mimics a neuroendocrine tumor and may be focally positive with neuroendocrine markers, and this might be a pitfall in a smaller biopsy (hematoxylin-eosin, original magnification 200).

issue until the publication by Gupta and colleagues,39 which used an evidence-based approach to determine what specific pathologic features might be most helpful at the time of frozen section diagnosis. As these investigators emphasized, although it is generally assumed that the pathologic features that allow for a diagnosis of carcinoid tumors on a permanent section are easily appreciable on a frozen section, this is not

Fig. 49. Pulmonary blastoma. In a larger resection specimen, the characteristic fetal glands can be identified (hematoxylineosin, original magnification 400).

necessarily the case. In particular, the presence of an organoid pattern, ‘‘salt and pepper’’ chromatin, and nuclear pleomorphism, as well as other cytohistologic features can be difficult to evaluate due to frozen section artifacts (Figs. 51 and 52). The deferral and error rates for carcinoid tumors were reported to be 4.13% and 7.5%, respectively, which exceeds the CAP-reported general frozen section error rate of 1.36% and is

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Litzky Fig. 50. Carcinoid tumor with crush artifact. This tumor was initially biopsied and was reported as SCLC. However, the tumor was subsequently resected and was demonstrated to be a carcinoid tumor (hematoxylin-eosin, original magnification 400).

sufficiently high enough to encourage one’s clinical colleagues to pursue a preoperative diagnosis whenever technically feasible and clinically indicated. Nevertheless, for a variety of reasons, surgical pathologists do encounter a pulmonary nodule for frozen section diagnosis, and a general knowledge of the most common errors is useful. Tumors more likely to be confused with either typical or atypical carcinoid tumors include lymphoma, squamous cell carcinoma, and metastatic breast carcinoma. Carcinoid tumors with more spindle cells are also occasionally mistaken

for other mesenchymal spindle cell lesions, such as a smooth muscle tumor. Some of these intraoperative deferrals/errors are of little clinical consequence in that the immediate surgical management may not differ, but in other instances, these misdiagnoses result in unnecessary lobectomies or redo thoracotomies. Of the multiple pathologic features analyzed in the frozen section study, stromal hyalinization, organoid pattern, and the presence of spindle cells provided the strongest evidence for the frozen section diagnosis of carcinoid tumors. Although in this study, examination Fig. 51. Carcinoid tumor. Frozen artifact makes it difficult to discern a characteristic nesting pattern, and the tumor appears somewhat more spindled (hematoxylin-eosin, original magnification 200).

Pulmonary Neuroendocrine Tumors Fig. 52. Carcinoid tumor. Frozen artifact makes it difficult to appreciate the finely granular chromatin pattern (hematoxylin-eosin, originalmagnification400).

of touch preparations provided only limited assistance, cytologic evaluation by touch preparation is still a complementary procedure that should be readily used in difficult cases. A similar type of comprehensive study on the intraoperative evaluation of the higher-grade neuroendocrine carcinomas has not been done, but it would be reasonable to assume that because the rates of interobserver agreements for LCNEC are low on permanent sections, the intraoperative discrepancy rate is significant. In this instance, it is of some comfort to note the recent literature that

Pitfalls NEUROENDOCRINE TUMORS OF THE LUNG ! Overdiagnosis of typical and atypical pulmonary carcinoid tumors as SCLC on biopsy specimens. ! Intraoperative misinterpretations of pulmonary neuroendocrine tumors, resulting in either unnecessary lobectomies or second thoracotomies. ! Failure to specimens.

thoroughly

sample

resected

! Insufficient attention to the clinical and radiographic context while considering the differential diagnosis and before rendering a final diagnosis.

supports the identical surgical management and staging for pulmonary neuroendocrine tumors as for other types of non–SCLC.27,40,41

SUMMARY Pulmonary neuroendocrine tumors should be evaluated using appropriately fixed and good-quality hematoxylin-eosin stained sections. When these tumors are approached in a methodical way with as careful morphologic evaluation as the quality of the specimen permits, an accurate and specific diagnosis is often possible. In situations when a specific classification is not possible, a precise diagnosis may not be clinically necessary for management decisions. Immunohistochemical stains have the most utility in cases in which there is a broader differential diagnosis.

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Litzky 5. Flieder DB. Neuroendocrine tumors of the lung: recent developments in histopathology. Curr Opin Pulm Med 2002;8:275–80. 6. Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006;24:70–6. 7. Dishop ML, Kuruvilla S. Primary and metastatic lung tumors in the pediatric population: a review and 25year experience at a large children’s hospital. Arch Pathol Lab Med 2008;132(7):1079–103. 8. Fink G, Krelbaum T, Yellin A, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001;119:1647–51. 9. Beasley MB, Thunnissen FB, Brambilla E, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000;31:1255–65. 10. Deb SJ, Nichols FC, Allen MS, et al. Pulmonary carcinoid tumors with Cushing’s syndrome: an aggressive variant or not? Ann Thorac Surg 2005;79(4):1132–6. 11. Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary neuroendocrine tumors. Cancer 2008; 113(1):5–21. 12. Matoso A, Singh K, Jacob R, et al. Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors. Appl Immunohistochem Mol Morphol 2010;18(2):142–9. 13. Lim E, Goldstraw P, Nicholson AG, et al. Proceedings of the IASLC international workshop on advances in pulmonary neuroendocrine tumors. J Thorac Oncol 2007;3(10):1194–201. 14. Thomas CF Jr, Tazelaar HD, Jett JR. Typical and atypical pulmonary carcinoids: outcome in patients presenting with regional lymph node involvement. Chest 2001;119(4):1143–50. 15. Garcia-Yuste M, Matilla JM, Cueto A, et al. Typical and atypical carcinoid tumours: analysis of the experience of the Spanish multi-centric study of neuroendocrine tumours of the lung. Eur J Cardiothorac Surg 2007;31(2):192–7. 16. Travis WD, Rush W, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid tumor and its separation from typical carcinoid. Am J Surg Pathol 1998;22:934–44. 17. Ishida T, Yokoyama H, Sugio K, et al. Carcinoid tumor of the lung: clinicopathological and immunohistochemical studies. Eur J Surg Oncol 1992;18: 180–7. 18. Miller RR, Muller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol 1995;19:653–8. 19. Rizvi SM, Goodwill J, Lim E, et al. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and

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