Neuroendocrine carcinomas constitute an important group of primary neoplasms in the lung. Although the gamut of primary lung tumors that may show neuroendocrine differentiation is rather complex, involving tumors not only of epithelial but also of mesenchymal or neural origin, this chapter focuses mainly on epithelial tumors.
Neuroendocrine tumors are ubiquitous neoplasms that have been the subject of investigation for over a century. Although these low-grade tumors initially were described as neoplasms with a better prognosis than that for conventional carcinoma (carcinoid tumor), in time, different studies have conceptualized them as a family of neoplasms that may expand from an indolent and insignificant small lesion (so-called tumorlet), most often encountered by chance, to low-, intermediate-, and high-grade malignancies. To provide a better understanding of these tumors in terms of clinical course, behavior, and possible histogenesis, different studies including morphologic, immunohistochemical, and, more recently, molecular investigations, have attempted to classify this family of neoplasms; however, universal agreement is still lacking. Some reviews on the subject either precede the most recent classification of lung tumors by the World Health Organization (WHO) or have separated these tumors in the conventional three-way category system. Although other studies have followed the WHO classification, those studies have stated the difficulty inherent in making these diagnoses using surgical biopsy specimens.
The problem deepens owing to the fact that the designation given to some of these tumors may depend largely on the anatomic site in which they may appear. As an example, in the WHO classification for tumors of the pleura, lung, thymus, and heart, tumors in the thymus are separated into low- and high-grade malignancy, whereas those in the lung are separated into a four-way category system.
HISTORICAL ASPECTS
Siegfried Oberndorfer is credited for coining the term carcinoid tumor in 1907. In 1904, Bunting from Johns Hopkins reported a case under the designation “multiple primary carcinomata” and made reference to other possible descriptions that dated back to the 18th century. Thus, it appears that this tumor may have been recognized well over a century ago. In 1914, Gossett and Masson described similar tumors in the appendix and made an analogy with the previous description by Oberndorfer. At the same time these tumors were being studied in the gastrointestinal tract, similar tumors in the respiratory tract, especially those occurring in the bronchial wall, were being reported as bronchial adenomas. Gmelich and colleagues identified the presence of Kulschitzky cells (K cells) in bronchioles and established the relationship of these cells and the occurrence of these neoplasms in the lung. Of interest, Hausman and Weimann described a case with lymph node metastasis from a “pulmonary tumorlet.” These investigators noted that such tumors have a low malignant potential. The so-called tumorlet measured 1.5 cm in greatest dimension and had spindle cell morphology, with lymph node metastasis, as noted. Azzopardi, in a study of 100 cases of what he called “oat cell carcinoma,” comprising 16 surgical cases and 84 cases from autopsy material, described positive structural features characteristic of this tumor that included streams, ribbons, rosettes, and ductules. As suggested by this definition and at least one of the illustrations presented in his review, some of the cases presented in this study may not represent oat cell carcinoma as it is defined today, corresponding instead to low- or intermediate-grade neuroendocrine carcinomas. A similar conclusion may be drawn from consideration of the 138 cases of oat cell carcinoma described by Yukato and associates, in which some of those tumors, although neuroendocrine in nature, may not necessarily be of the oat cell type as it is defined today.
HISTOGENESIS, DIFFERENTIATION, MULTIDIRECTIONAL DIFFERENTIATION, DIVERGENT DIFFERENTIATION
Gould and colleagues introduced the term multidirectional differentiation after observing the presence of neuroendocrine, mucosubstance-producing, and squamous cells in pulmonary carcinomas. These investigators also noted that certain tumors may share similar patterns of differentiation. Further observations of interest in some cases included predominant features of squamous differentiation seen at electron microscopy. Accordingly, the investigators designated those tumors as “neuroendocrine carcinomas with squamous differentiation.” They also noted that some squamous and adenocarcinomas of the lung may show bound membrane and dense core granules at electron microscopy. Nevertheless, Gould also warned about the possibility of cell populations that demonstrate similar or identical patterns of differentiation but which may not necessarily share identical or even closely related embryogenesis.
Earlier workers had documented the presence of non–small cell neoplasms that, histologically, looked like squamous cell carcinomas or adenocarcinomas and showed the presence of neurosecretory granules on ultrastructural studies. These neoplasms had been classified as atypical endocrine tumors. Such descriptions have raised concerns about the true significance of the many classification systems available for neuroendocrine tumors To complicate matters further, some small cell carcinomas do not demonstrate immunohistochemical differentiation for neuroendocrine markers, nor are neurosecretory granules detected on ultrastructural studies; however, they do show the ultrastructural features of epithelial tumors. Regardless of the histologic subtype, all lung tumors have the potential to show neuroendocrine differentiation by immunohistochemistry or electron microscopy.
More recently, some investigators have argued that the current revised classification of tumors by the WHO in fact clearly defines each one of the neuroendocrine tumors of the lung. These workers have introduced the term divergent differentiation , stating that this concept applies to a subset of non–small cell carcinomas that are not considered morphologically neuroendocrine but that express neuroendocrine differentiation with neuroendocrine markers (so-called non–small cell carcinoma with neuroendocrine differentiation). In addition, Brambilla and colleagues state that the so-called tumorlets do not differ in cellular components from the so-called typical carcinoid, and that these tumorlets also display divergent differentiation. Early reports of “metastatic tumorlets” are incorrect; such lesions represent the current so-called typical carcinoid.
CLASSIFICATIONS
Neuroendocrine lung neoplasms have been a subject of numerous classification systems. Many of them, although logical, fail to provide a practical approach; others, although practical, fail to properly define this complex group of tumors. This section reviews the most important past and present classification systems and evaluates their practical significance. The most important classification schema and diagnostic criteria are presented in Tables 5-1 and 5-2 .
| Authors | Tumor Designation | Equivalent (Conventional Classification) |
|---|---|---|
| Gould et al. | Bronchopulmonary carcinoid | Conventional carcinoid |
| Well-differentiated neuroendocrine carcinoma | Atypical carcinoid | |
| Neuroendocrine carcinoma of intermediate-size cells | Variant of small cell carcinoma | |
| Neuroendocrine carcinoma of small cell type | Small cell carcinoma | |
| Paladugu et al. | Kulchitzky cell carcinoma type I | Conventional carcinoid |
| Kulchitzky cell carcinoma type II | Atypical carcinoid | |
| Kulchitzky cell carcinoma type III | Small cell carcinoma | |
| Capella et al. | Benign or low-grade malignant nonfunctioning well-differentiated tumor | Conventional carcinoid |
| Low-grade malignant nonfunctioning well-differentiated carcinoma | Atypical carcinoid | |
| High-grade malignant functioning or nonfunctioning poorly differentiated carcinoma | Small, large, and intermediate cell | |
| Travis et al. | Typical carcinoid | Conventional carcinoid |
| Atypical carcinoid | Atypical carcinoid | |
| Small cell carcinoma | Small cell carcinoma | |
| Large cell neuroendocrine carcinoma | ||
| Huang et al. | Well-differentiated neuroendocrine carcinoma | Conventional carcinoid |
| Moderately differentiated neuroendocrine carcinoma | Atypical carcinoid | |
| Poorly differentiated neuroendocrine carcinoma | Atypical carcinoid with more mitosis | |
| Undifferentiated large cell neuroendocrine carcinoma | Large cell neuroendocrine carcinoma | |
| Undifferentiated small cell carcinoma | Small cell carcinoma | |
| Moran and Suster | Well-differentiated neuroendocrine carcinoma | Conventional carcinoid |
| Moderately differentiated neuroendocrine carcinoma | Atypical carcinoid | |
| Poorly differentiated neuroendocrine carcinoma | Large cell and small cell neuroendocrine carcinoma |
| Tumor | Size | Mitotic Activity | Necrosis |
|---|---|---|---|
| Carcinoid tumorlet | <0.5 cm | None | None |
| Well-differentiated neuroendocrine carcinoma | >0.5 cm | <3 mitotic figures per 10 hpf | Minimal and focal |
| Moderately differentiated neuroendocrine carcinoma | >0.5 cm | >3 mitotic figures per 10 hpf | Comedo-like |
| Poorly differentiated neuroendocrine carcinoma | |||
| Small cell carcinoma * | >10 mitotic figures per 10 hpf | Marked | |
| Large cell neuroendocrine carcinoma † | >10 mitotic figures per 10 hpf | Marked | |
* On resected specimens. Criteria do not apply to biopsy specimens.
† On resected specimens. Diagnosis also requires positive histologic findings and immunohistochemical neuroendocrine markers.
In 1977, Gould introduced the terms neuroendocrinoma and neuroendocrine carcinoma by drawing an analogy between these tumors and the APUD (amine precursor uptake and decarboxylation) cell system neoplasms with respect to their aberrant secretory activities. Gould emphasized the numerous neoplasms that may belong to this APUD system, which is not limited to the respiratory tract or to a particular group of tumors—for example, carcinoid tumor. This investigator also elaborated on abandoning traditional terms such as bronchial adenoma , a term that does not convey the true nature of these neoplasms and yet is used to encompass a diverse group of tumoral conditions. This study highlights three important issues: First, the term bronchopulmonary neuroendocrine tumor is preferable to bronchopulmonary carcinoid ; second, it is argued that “oat cell carcinomas” represent the malignant counterpart of carcinoid tumor; and third, the term undifferentiated oat cell carcinoma is in widespread use. In 1983, Gould and colleagues presented a new classification system for neuroendocrine pulmonary neoplasms that included four categories instead of the conventional three. Their schema is as follows:
Bronchopulmonary carcinoid : Typical histologic features, locally invasive, potential for recurrence, and distant metastasis. Bronchopulmonary carcinoid is separated from neuroendocrine carcinoma (see further on). The cases presented showed penetration of the bronchial wall and mediastinal soft tissue. In addition, six cases showed direct invasion into lymph nodes at the time of initial presentation.
Well-differentiated neuroendocrine carcinoma : Even though Gould and colleagues recognized that this designation may not be entirely satisfactory, this category is for tumors that retain a clearly organoid pattern, moderate cellular pleomorphism, mitosis, and “true” lymph node metastasis.
Neuroendocrine carcinoma of intermediate-size cells : This tumor type represents a variant of small cell neuroendocrine carcinoma; the cells are twice the size of “small cell” counterparts with prominent nucleoli and abundant mitotic figures. Of interest, the investigators noted that 7 of the 11 cases presented showed features of glandular or squamous differentiation.
Neuroendocrine carcinoma of small cell type : Typical “oat” cell carcinoma, abundant mitoses and inconspicuous nucleoli. The authors comment that not all tumors in this category are neuroendocrine and recommend the systematic use of immunohistochemistry to separate those tumors that are neuroendocrine from those which are not neuroendocrine.
In 1985, Warren and associates presented a study of 81 cases of pulmonary neuroendocrine neoplasms assessing Gould’s classification systems and determined their usefulness for the proper identification and treatment of patients with those neoplasms. Paladugu and colleagues presented a new classification system for these neuroendocrine neoplasms, which they designated bronchopulmonary Kulchitzky cell carcinomas (KCCs), that reverted to a three-category schema. These investigators used the designations KCC-I, KCC-II, and KCC-III for typical carcinoid, atypical carcinoid, and small cell carcinoma, respectively. Of interest, they reported mortality rates of 1.7% for KCC-I and 27% for KCC-II. Histologically, the KCC-II tumors showed a mitotic activity level of 1 mitotic figure per high-power field. These workers concluded that their nomenclature is preferable to that of the Gould classification both because they consider the K cell to be the origin of these tumors and because it is simpler and less confusing. In 1972, however, Arrigoni and coworkers had introduced the concept of “atypical carcinoid” by separating those tumors based on cellular atypia and mitotic activity with an average of 1 mitotic figure per 1 or 2 high-power fields, leaving a possibility of 5 to 10 mitotic figures per 10 high-power fields.
A point of interest is that in the Arrigoni, Gould, and Paladugu classification systems, the number of mitotic figures per 10 high-power fields is subject to interpretation. On a background of that state of confusion, in 1982, Mills and associates presented a study of 17 cases of atypical carcinoid tumors of the lung in which the mitotic count in those tumors ranged from 2 to 28 mitotic figures (mean, 14; median, 13) per 10 high-power fields. Also, Valli and colleagues presented a study of 33 cases of atypical carcinoid tumors of the lung in which the mitotic activity ranged from 4 to 80 figures per 1.52 mm 2 . Other reports use the criterion of increased mitotic activity level with more than 1 mitotic figure per 1 or 2 high-power fields.
At that point, it was evident that the criterion used to separate carcinoid from atypical carcinoid by mitotic activity was less than ideal. In 1995, Capella and associates revised the classification of neuroendocrine tumors of the lung, pancreas, and gut. Their reclassification follows:
Benign or low-grade malignant nonfunctioning well-differentiated tumor as the equivalent for conventional carcinoid
Low-grade malignant nonfunctioning well-differentiated carcinoma as the equivalent for atypical carcinoid
High-grade malignant functioning or nonfunctioning poorly differentiated carcinoma as the equivalent for the large cell type and the small or intermediate cell type
The criterion separating typical from atypical carcinoid was established at no more than 3 mitotic figures per 10 high-power fields. These investigators added that if metastasis or gross invasion is present, tumors should be called “low-grade neuroendocrine carcinoma.”
In 1991, Travis and coworkers had presented a study of 35 cases of neuroendocrine carcinomas of the lung in which a proposed criteria was presented for large cell neuroendocrine carcinoma. In this study, previous criteria for other neuroendocrine carcinomas were followed, and the large cell carcinoma was presented as a tumor with a “neuroendocrine pattern,” high mitotic activity with an average of 66 figures per 10 high-power fields, and prominent nucleoli. These workers suggested that the prognosis for large cell neuroendocrine carcinoma is between those of atypical carcinoid and small cell carcinoma. However, in 1998, Travis’ group presented a new study of neuroendocrine neoplasms in which their goals were to provide clear definitions for the four neuroendocrine tumors, and to modify the criteria for the diagnosis of carcinoid and atypical carcinoid. The “new” classification system placed large cell neuroendocrine carcinoma in the high-grade category of tumors, contrary to the investigators’ previous study. This new approach is as follows:
Conventional carcinoid tumor : Restricted to no more than 1 mitotic figure per 10 high-power fields
Atypical carcinoid : More than 2 but fewer than 10 mitotic figures per 10 high-power fields, or necrosis (often punctate)
Large cell neuroendocrine carcinoma : Tumors with “neuroendocrine morphology,” mitotic activity of more than 11 figures per 10 high-power fields, cytologic features of large cell carcinoma, and positive immunohistochemical staining for neuroendocrine markers
Small cell carcinoma : Tumors with the cytology of small cell tumor cells (absent nucleoli), mitotic activity of more than 11 figures per 10 high-power fields, and frequent necrosis
This system is essentially repeated in the most recent version of the WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. Of note, however, it represents a classification for resected specimens. In a separate study on the reproducibility of the proposed classification of neuroendocrine lung tumors conducted by Travis and coworkers, in which five experienced pulmonary pathologists participated in the evaluation of 40 surgically resected neuroendocrine tumors, unanimous agreement on classification was reached in only 55% of the cases. The most common disagreements were between large cell neuroendocrine carcinoma and small cell carcinoma. Finally, in 2002, Huang and associates presented the most recent attempt to classify neuroendocrine tumors of the lung. These workers studied 234 cases, classified into five different categories. Their system essentially follows the Travis criteria for the separation of carcinoid and atypical carcinoid (well- and moderately differentiated neuroendocrine carcinoma): The categories of large cell neuroendocrine carcinoma and small cell carcinoma are retained, with the prefix of “undifferentiated,” with mitotic counts of more than 30 per 10 high-power fields. A new category is what the authors call “poorly differentiated neuroendocrine carcinoma,” which is conceptualized as an atypical carcinoid with an increased mitotic count of more than 10 per 10 high-power fields.
GENERAL CLINICAL FEATURES
Neuroendocrine carcinomas of the lung may be associated with paraneoplastic syndromes including Cushing’s syndrome, inappropriate secretion of antidiuretic hormone, and carcinoid syndrome. The last-named condition may be present in approximately 10% of patients whose tumor demonstrates a well-differentiated histologic pattern. In addition, depending on the location of the tumor, patients with carcinomas in the central location also may experience symptoms of pulmonary obstruction, dyspnea, cough, or chest pain. Patients with tumors in the periphery of the lung may be asymptomatic until the tumor reaches a larger size. Although neuroendocrine carcinomas may occur at any age, the tumors are more commonly encountered in the fifth to seventh decades of life. No gender predilection has been noted.
GENERAL MACROSCOPIC FEATURES
Those tumors occurring in the central location may manifest as polypoid tumors obstructing the lumen of the airway ( Figs. 5-1 and 5-2 ). Tumor size may range from 1 cm to larger than 10 cm in diameter. These tumors are light brown, and the cut surface is tan and homogeneous in appearance. The presence of areas of necrosis or hemorrhage should alert the pathologist to the possibility of a higher grade ( Fig. 5-3 ). In high-grade neuroendocrine carcinomas, it is common to encounter invasion into mediastinal structures at the time of diagnosis.
TUMORLET
The histopathologic features present in the so-called tumorlet are essentially the same as those in otherwise well-differentiated neuroendocrine carcinomas. As a matter of fact, the tumorlet may represent the true carcinoid tumor of the lung. However, the diagnosis of tumorlets is restricted to lesions no more than 0.5 cm in greatest dimension. Although this lesion more often is found incidentally in lung biopsy specimens, with the use of more sophisticated radiologic techniques, the diagnosis of tumorlet is becoming more common ( Figs. 5-4 and 5-5 ).
WELL- AND MODERATELY DIFFERENTIATED NEUROENDOCRINE CARCINOMAS (CARCINOID AND ATYPICAL CARCINOID)
The current designation provided by the WHO defines well- and moderately differentiated neuroendocrine carcinomas as having neuroendocrine morphology: organoid, trabecular, insular, palisading, ribbon, and rosette-like features. The difference between well- and moderately differentiated neuroendocrine carcinomas is that the former has fewer than 2 mitotic figures per 10 high-power fields, whereas the latter has 2 to 10 mitotic figures per 10 high-power fields. Clinically, both tumors may be associated with carcinoid syndrome and show a spectrum of cell differentiation that includes spindle cells, oncocytic, and melanocytic features, among others. Although the WHO still maintains the nomenclature of carcinoid and atypical carcinoid, some investigators believe that the most accurate designation for these neoplasms is that of neuroendocrine carcinoma, which conveys the true nature of these tumors. This is the designation that is used in this section.
At low magnification, the tumor displays an organized growth pattern, which may show a nesting, solid, pseudoglandular, or trabecular arrangement composed of a rather homogeneous cellular proliferation characterized by small to medium-sized cells with moderate amounts of occasional cytoplasm, round to oval nuclei, and sometimes nucleoli ( Figs. 5-6 to 5-10 ). Rosette formation may be readily identifiable ( Fig. 5-11 ). The presence of necrosis in the form of comedo-like necrotic areas or hemorrhage, coupled with the presence of 2 or more mitotic figures per 10 high-power fields, is the criterion for classification as a moderately differentiated neuroendocrine carcinoma ( Figs. 5-12 to 5-14 ).
Several histologic variants have been described for both well- and moderately differentiated neuroendocrine carcinomas.
Spindle cell neuroendocrine carcinoma : In this variant, although an organoid pattern may be present, the cell morphology is that of fusiform cells with inconspicuous nucleoli and finely dispersed chromatin ( Fig. 5-15 ). In some cases the spindle cell proliferation may be associated with dilated blood vessels, imparting a hemangiopericytic pattern. However, this variant also may display nuclear atypia and increased mitotic activity ( Figs. 5-16 and 5-17 ).
Figure 5-15
Well-differentiated neuroendocrine carcinoma with prominent spindle cell growth.
Figure 5-16
Moderately differentiated neuroendocrine carcinoma with prominent spindle cell growth and nuclear atypia.
Figure 5-17
Moderately differentiated neuroendocrine carcinoma with spindle cell growth and increased mitotic activity.
Oncocytic neuroendocrine carcinoma : The growth pattern of this neoplasm is essentially similar to that of the conventional cell type. The tumors may display a diffuse growth pattern or have a glandular appearance ( Figs. 5-18 and 5-19 ). Cytologically, the cells are of medium size, with ample eosinophilic cytoplasm, round to oval nuclei, and sometimes prominent nucleoli. Clusters of oncocytic cells may be present among tumor cells ( Figs. 5-20 and 5-21 ). This variant also may display features of moderately differentiated carcinoma, including increased mitotic activity ( Fig. 5-22 ). Caution is in order, however, in assessing mitotic activity, because oncocytic tumors may display areas of nuclear atypia without mitotic activity.
Figure 5-18
Well-differentiated neuroendocrine carcinoma with glandular and oncocytic features.
Figure 5-19
Well-differentiated neuroendocrine carcinoma with solid and oncocytic growth pattern.
Figure 5-20
Well-differentiated neuroendocrine carcinoma with oncocytic growth pattern and clusters of so-called oncoblasts.
Figure 5-21
Moderately differentiated neuroendocrine carcinoma with disorganized oncocytic growth pattern.
Figure 5-22
Moderately differentiated neuroendocrine carcinoma with oncocytic features. Note the presence of several mitotic figures.
Mucinous neuroendocrine carcinoma : This is a rare variant among primary neuroendocrine carcinomas of the lung. The presence of mucous material may be limited to the intraluminal component in some cases of glandular arrangement, or more rarely, the mucinous component may be intermixed with the neoplastic cellular proliferation ( Fig. 5-23 ).
