July 16, 2008

Lung Tumors With Neuroendocrine Morphology: Essential Radiologic and Pathologic Features

By Franks, Teri J Galvin, Jeffrey R

* Context.-Tumors with neuroendocrine morphology are a distinct subset of lung neoplasms sharing characteristic histologic, immunohistochemical, ultrastructural, and molecular features. Objective.-To review the current histologic classification and the diagnostic criteria for the major categories of neuroendocrine tumors of the lung.

Data Sources.-Published classification systems from the World Health Organization and pertinent peer-reviewed articles indexed in PubMed (National Library of Medicine) form the basis of this review.

Conclusions.-Accurate classification of the neuroendocrine tumors of the lung requires knowledge of specific criteria separating the major categories, which is essential for determining prognosis and treatment.

(Arch Pathol Lab Med. 2008;132:1055-1061)

Tumors with neuroendocrine morphology are a distinct subset of lung neoplasms that share specific morphologic, immunohistochemical, ultrastructural, and molecular characteristics. The major categories of morphologically identifiable neuroendocrine tumors include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma of the lung (SCLC) (Table 1). Although these tumors share a variety of characteristics, widely varying prognosis and response to therapy necessitated placement in separate categories within the World Health Organization classification.1,2 However, it is easiest to conceptualize this group as a spectrum of malignancy ranging from low-grade TC, to intermediate-grade AC, to the 2 high-grade malignancies, LCNEC and SCLC. These 4 carcinomas are distinguished from nonneuroendocrine lung carcinomas on light microscopy by their display of neuroendocrine morphology including organoid nesting, rosette formation, peripheral palisading of tumor nests, and trabeculae and on immunohistochemistry by reactivity with neuroendocrine markers. Separation within the neuroendocrine tumors rests primarily on mitotic rate and the presence or absence of necrosis, and, in the case of separating LCNEC from SCLC, cell morphology (Table 2).

Although the neuroendocrine tumors of the lung are separated into 4 categories and form a spectrum of malignancy, TC and AC as a group share interesting contrasts to LCNEC and SCLC. Typical carcinoid and AC occur in a younger patient population than LCNEC and SCLC; essentially all patients with LCNEC and SCLC are smokers, whereas approximately one third of TCs and ACs occur in nonsmokers; in contrast to LCNEC and SCLC, TC and AC are frequently associated with neuroendocrine cell hyperplasia with or without tumorlets; and other major histologic subtypes of lung carcinoma occur in combination with LCNEC and SCLC but not with TC and AC.1 Genetic abnormalities in p53,3,4 cyclin D1,5 Bcl-2/Bax,6 and RB loss and loss of heterozygosity at 3p,7,8 occur in a higher percentage of LCNECs and SCLCs than TCs and ACs further distinguishing the 2 high-grade malignancies from the 2 carcinoids.

Staging, treatment, and survival vary widely among the 4 neuroendocrine lung tumors, thus accurate histologic classification is essential. The TNM classification is the most widely used staging system for TC, AC, and LCNEC; however, it is generally not applied to SCLC as it is a poor indicator of survival. Instead, SCLC is staged as limited or extensive disease (Table 3). There is essentially equal distribution of limited and extensive disease at diagnosis.9 Typical carcinoid and AC are treated surgically, most often by lobectomy or pneumonectomy depending on location of the tumor. Whether surgery and/or chemotherapy is the optimal treatment for LCNEC is controversial and has yet to be established. Chemotherapy remains the primary treatment for SCLC. The overall 5- year survival rates for TC, AC, LCNEC, and SCLC after stratification for stage are approximately 90%, 60%, 20%, and 3.5% respectively. 9- 11


Carcinoids comprise 1% to 2% of all lung neoplasms and are the most common lung tumor of childhood.12 In large studies, men and women are affected equally, with a mean age of approximately 45 years.13-15 Symptoms vary with location. Central lesions produce early symptoms including cough, wheezing, dyspnea, and hemoptysis because of airway obstruction, whereas peripheral lesions are frequently discovered incidentally on chest imaging studies in asymptomatic patients.16,17

Eighty-five percent of carcinoids are located centrally within mainstem and lobar bronchi18 and present with evidence of bronchial obstruction as the most common radiologic finding (Figure 1). Carcinoids manifest as welldemarcated, round to oval, hilar or perihilar nodules (less than 3 cm) or masses (3 cm or greater). Airway obstruction is typically complete resulting in volume loss and atelectasis, obstructive pneumonia, or mucoid impaction distal to the tumor. Calcification is common. Tumors often show substantial contrast enhancement because of their rich vascularity. Although AC tends to be larger and have a slightly greater tendency to be peripheral,19 there is substantial overlap and TC and AC are radiographically indistinguishable. 20

Grossly, carcinoids are well-demarcated masses with tan-yellow or red cut surfaces depending on the extent of vascularity. Necrosis and hemorrhage may be present in AC. Size varies from 0.5 cm to 10 cm, with mean diameters of central lesions greater than those in the periphery and AC greater than TC.21 Central lesions tend to have a large endobronchial component, but varying extension outside the bronchial wall can result in the bulk of tumor residing in the surrounding lung parenchyma (Figure 2).

Histologically, carcinoids are composed of uniform polygonal, spindle cells, and/or oxyphilic cells with moderate amounts of cytoplasm, fine nuclear chromatin, and inconspicuous nucleoli. Carcinoids are typically histologically heterogeneous displaying a spectrum of growth patterns. Organoid, rosette, palisading, and trabecular patterns of growth are common, but papillary, sclerosing, follicular, or glandular patterns also occur (Figure 3). Mitotic rate and presence or absence of necrosis distinguish TC from AC; TC has fewer than 2 mitoses per 2 mm2 (10 highpower fields) without necrosis, whereas AC has 2 to 10 mitoses per 2 mm2 (10 high-power fields) and/or necrosis. Pleomorphism and nuclear atypia can be prominent but are unreliable features for separating the 2 carcinoids.11 The majority of carcinoids are immunoreactive with pancytokeratin, and neuroendocrine differentiation can be confirmed with the neuroendocrine markers chromogranin, synaptophysin, and CD56 (N-CAM).

There are several pitfalls in this setting. Size alone distinguishes tumorlets from the carcinoids, the former are arbitrarily defined as less than 0.5 cm and the latter 0.5 cm or greater, so that on limited material this distinction cannot necessarily be made. On small specimens, such as transbronchial or endobronchial biopsies or needle biopsies, separation of TC from AC is possible if necrosis or a sufficient number of mitoses are present; however, a resected specimen is typically required to make this determination. Because carcinoids often present a significant endobronchial component, surface erosions are common and the endobronchial portion is readily accessible to the bronchoscopists' forceps and needles. Care must be taken not to misinterpret necrosis from erosion and biopsy sites as tumor necrosis; if present, necrosis changes the diagnosis of TC to AC and a worse prognosis. Necrosis in AC is described as punctate, usually occurring in the center of tumor nests (Figure 4), rather than diffuse along the surface as in erosion or linear from instrumentation. Because the nuclear morphology of carcinoid is similar to small cell carcinoma- fine chromatin with inconspicuous nucleoli-care must also be taken in small biopsies to evaluate the volume of cytoplasm and number of mitoses to avoid misdiagnosis. Even in small biopsies, the scant volume of cytoplasm and high mitotic rate of small cell carcinoma are usually evident.


Large cell neuroendocrine carcinoma accounts for approximately 3% of lung cancers,22 and patients are typically male cigarette smokers in the sixth decade of life.23 Symptoms produced by the primary tumor are similar to other non-small cell lung carcinomas and vary with location.

The radiologic findings in LCNEC are also indistinguishable from those of other non-small cell lung carcinomas. Approximately 80% of LCNECs appear as peripheral nodules or masses; the remainder form central masses frequently contiguous with the mediastinum.24,25 Tumors are well-defined and lobulated with an increasingly heterogeneous pattern of enhancement in larger examples (Figure 5).

Large cell neuroendocrine carcinoma is similar to other non- small cell carcinomas on gross examination. Histologically, LCNEC is composed of cytologically malignant large cells demonstrating neuroendocrine morphology, most commonly rosette formation and peripheral palisading of tumor nests. However, these features are often subtle, making distinction from non-small cell lung carcinoma difficult. In some cases, rosettes are the only histologic marker of neuroendocrine differentiation. Tumor cells show cytologic features of non-small cell lung carcinoma including large cell size, low nuclear-cytoplasmic ratio, vesicular or fine chromatin, and frequent nucleoli. Large cell neuroendocrine carcinoma may have fine nuclear chromatin and lack nucleoli but qualify because of large cell size and abundant cytoplasm.1 Mitotic counts are defined as greater than 10/2 mm2 (10 high-power fields); however, the median count is 70/2 mm2.1 Necrosis is usually present, often in large zones. Cell size, cytoplasmic volume, and presence of nucleoli facilitate separation from SCLC (Figure 6). The histologic diagnosis of LCNEC requires fulfillment of 2 criteria: demonstration of neuroendocrine morphology by light microscopy and positive immunohistochemical staining for 1 or more neuroendocrine markers (other than neuron- specific enolase).1,2 Chromogranin, synaptophysin, and CD56 (N-CAM) are the most sensitive and specific neuroendocrine markers. One positive marker is sufficient for diagnosis if the staining is clear cut2; however, most often several markers will be reactive. Ten percent to 20% of non-small cell lung cancers (squamous cell, adenocarcinoma, and large cell carcinoma) demonstrate neuroendocrine differentiation by immunohistochemistry but not morphologically and should be classified by conventional subtype with neuroendocrine differentiation noted.1 Whether these tumors have better or worse survival or are more or less responsive to chemotherapy than non- small cell lung cancers without neuroendocrine differentiation is controversial; studies report better, worse, and no difference in prognosis and response to chemotherapy.2


Approximately 20% of lung cancers are SCLCs.26 Similar to LCNEC, most patients with SCLC are older male smokers. The central location of most tumors gives rise to the common clinical manifestations of cough, dyspnea, and hemoptysis. Invasion of mediastinal structures may result in dysphagia, hoarseness, and superior vena cava syndrome.

Small cell carcinoma is relatively distinctive on imaging. Approximately 95% of tumors are central and related to proximal airways, particularly lobar and main bronchi; less than 5% arise in the peripheral lung without obvious airway association.27 Central tumors are poorly demarcated. Metastases to hilar lymph nodes and mediastinal involvement secondary to metastases to mediastinal lymph nodes and/or direct invasion from a contiguous mass are almost invariably present (Figure 7). Peripheral SCLC is radiologically indistinguishable from other lung neoplasms.

Grossly, SCLC characteristically spreads along airway submucosa and peribronchovascular connective tissue. Subsequent extension into the lung parenchyma results in an expanding mass that obliterates airways and vessels by external compression rather than intraluminal growth. In contrast to squamous cell carcinoma, endobronchial growth is uncommon in SCLC.

Histologically, SCLCs are composed of small cells, defined as less than the size of three small resting lymphocytes, with scant cytoplasm, fine nuclear chromatin, and inconspicuous or absent nucleoli.1 Although SCLC can display organoid nesting, rosettes, peripheral palisading of tumor nests, and trabeculae, sheetlike growth with rosettes or absent neuroendocrine morphology are more common. Cell borders are indistinct, spindle morphology may be striking, and molding of tumor cells may be present. The mitotic rate is high with a median of 80/2 mm2.1 Good quality hematoxylin- eosin-stained sections are essential for evaluation. In suboptimal histologic sections, bubble artifact gives cell nuclei the appearance of having vesicular chromatin, which can lead to an erroneous diagnosis of non-small cell carcinoma (Figure 8).

Small cell carcinoma is immunoreactive with pancytokeratin, cytokeratin 7, chromogranin, synaptophysin, CD56, and thyroid transcription factor 1 in most cases; however, up to 10% of tumors are negative for all neuroendocrine markers.28 In small biopsies, especially those with extensive crush artifact, separation of SCLC from lymphoma on hematoxylin-eosin staining alone can be difficult; pancytokeratin and/or CD45RB (leukocyte common antigen) stains will usually resolve the problem.Merkel cell carcinoma, in cervical lymph node biopsies, and primitive neuroectodermal tumors are also pitfalls in diagnosis because of their histologic similarity to SCLC. In contrast to SCLC, Merkel cell carcinoma is cytokeratin 20 positive, and cytokeratin 7 and thyroid transcription factor 1 negative, whereas primitive neuroectodermal tumor is CD99 positive, is less mitotically active, and the majority are pancytokeratin negative.

In conclusion, the identification of neuroendocrine tumors of the lung is a step-wise process. First, tumors must be recognized as neuroendocrine by the presence on light microscopy of neuroendocrine morphology including organoid nesting, rosette formation, peripheral palisading of tumor nests, and trabeculae. Once a tumor is considered to be neuroendocrine, separation into the 4 major neuroendocrine categories is achieved using mitotic rate and the presence or absence of necrosis, and in the instance of separating LCNEC from SCLC, cell morphology. The diagnosis of LCNEC requires the presence of both neuroendocrine morphology by light microscopy and demonstration of neuroendocrine differentiation by immunohistochemistry. Tumors of the lung with neuroendocrine differentiation have widely varying prognosis and response to therapy; thus, accurate histologic classification is essential.

Table 1. Spectrum of Neuroendocrine Proliferations and Neoplasms of the Lung*

Neuroendocrine cell hyperplasia and tumorlets

Neuroendocrine cell hyperplasia

associated with fibrosis and/or inflammation

adjacent to carcinoid tumors

diffuse idiopathic neuroendocrine cell hyperplasia with or without airway fibrosis/obstruction


Tumors with neuroendocrine morphology

Typical carcinoid

Atypical carcinoid

Large cell neuroendocrine carcinoma

Small cell carcinoma

Non-small cell carcinomas with neuroendocrine differentiation

Other tumors with neuroendocrine properties

Pulmonary blastoma

Primitive neuroectodermal tumor

Desmoplastic round cell tumor

Carcinomas with rhabdoid phenotype


* Reprinted from Travis et al,1 with permission from theWorld Health Organization.

Table 2. Criteria for the Histologic Diagnosis of Neuroendocrine Tumors

Typical carcinoid

Carcinoid morphology

Less than 2 mitoses per 2 mm2 (10 HPFs)*

No necrosis

0.5 cm or larger

Atypical carcinoid

Carcinoid morphology

2-10 mitoses per 2 mm2 (10 HPFs) OR

Necrosis (often punctuate)

Large cell neuroendocrine carcinoma

Neuroendocrine morphology:

organoid nesting, rosettes, palisading, trabeculae

High mitotic rate:

11 or greater per 2 mm2 (10 HPFs), median of 70 per 2 mm2 (10 HPFs)

Necrosis (often large zones)

Cytologic features of non-small cell carcinoma (NSCLC):

large cell size

low nuclear to cytoplasmic ratio

vesicular, coarse or fine chromatin, and/or frequent nucleoli (some tumors have fine nuclear chromatin and lack nucleoli, but qualify as NSCLC because of large cell size and abundant cytoplasm)

Positive immunohistochemical staining for one or more neuroendocrine markers (other than neuron specific enolase) and/or neuroendocrine granules by electron microscopy

Small cell carcinoma

Small cell size (less than the diameter of 3 small resting lymphocytes)

High nuclear to cytoplasmic ratio

Finely granular nuclear chromatin, absent/inconspicuous nucleoli

High mitotic rate:

11 or greater per 2 mm2 (10 HPFs), median of 80 per 2 mm2 (10 HPFs)

Frequent necrosis (often large zones)

* On some microscopes 2 mm2 does not equate to 10 high-power fields (HPFs); explanation of HPF area and mitosis counting is given in Travis et al.1(p10) Reprinted with permission from the World Health Organization.

Table 3. Staging of Small Cell Lung Cancer*

Limited disease (equivalent to TNM stage I-III)

Disease restricted to one hemithorax with regional lymph node metastases:

Hilar ipsilateral and contralateral

Mediastinal ipsilateral and contralateral

Supraclavicular ipsilateral and contralateral

Ipsilateral pleural effusion

Extensive disease (equivalent to TNM stage IV)

Sites of disease beyond that of limited disease

* Reprinted from Travis et al,2 with permission from theWorld Health Organization.


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Teri J. Franks, MD; Jeffrey R. Galvin, MD

Accepted for publication December 17, 2007.

From the Departments of Pulmonary and Mediastinal Pathology (Dr Franks) and Radiologic Pathology (Dr Galvin), Armed Forces Institute of Pathology, Washington, DC; and the Departments of Diagnostic Radiology and Internal Medicine, Division of Pulmonary/Critical Care Medicine, University of Maryland School of Medicine, Baltimore (Dr Galvin).

The authors have no relevant financial interest in the products or companies described in this article.

The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army or Defense. This is a US Government work, and as such, is in the public domain in the United States of America.

Reprints: Teri J. Franks, MD, Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, 6825 16th St NW, Bldg 54, Room 2071, Washington, DC 20306 (e-mail: [email protected] afip.osd.mil).

Copyright College of American Pathologists Jul 2008

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