Continuing nosological revisionism over the past ten years has pushed pathologists away from such traditional diagnostic terms as "carcinoid" and "islet cell tumor" (of the pancreas) in describing certain potentially-malignant but low-grade epithelial neoplasms of the neuroendocrine system. Similarly, the classification of poorly-differentiated lesions has changed somewhat as well. This section will attempt to outline the current foundations of existing classification schemes for neuroendocrine tumors, and will, hopefully, allow the reader to come away with a simplified-- and therefore practical-- understanding of this confusing area of oncology.

There is, perhaps, no other single aspect of neuroendocrine pulmonary neoplasia that is as exasperating as the pathological terminology that has been used to describe it. Such terms as "bronchial adenoma," "carcinoid," "atypical carcinoid," "Kulchitsky cell carcinoma," "argentaffinoma," "APUDoma," "atypical endocrine carcinoma," "oat cell carcinoma," "small cell carcinoma," "large-cell neuroendocrine carcinoma," and "large-cell carcinoma with neuroendocrine features" have all been employed in the past in this context.

When all is said and done, the diverse lexicon of the past can be simplified to yield a basic division of neuroendocrine tumors into two broad categories-- epithelial (group 1) and neural (group 2). With that piece of information in hand, one can then go on to structure a much more "user-friendly" and straightforward classification scheme, which , in fact, has made significant in-roads in the pathology literature. Another crucial concept in understanding the categorization and clinical behavior of neuroendocrine neoplasms is that all of them are at least potentially malignanttumors. Therefore, it follows logically that the modifier "benign" should not ever be applied in conjunction with any of the above-cited diagnostic terms. For example, in reference to classical bronchial "carcinoids"-- generally regarded as defining the "low" end of the spectrum of biological behavior in this context-- there are many well-documented examples of metastasizing lesions that can be found in the literature on these tumors.

Current terminological recommendations are, therefore, different from those that might have pertained even 10 years ago, or from those with which some practitioners may feel comfortable. The designation of neuroendocrine carcinoma has been proposed as a replacement for various group 1 terms, with modifiers of "well-differentiated" (grade I/III); "moderately-differentiated" (grade II/III); and "poorly-differentiated" (grade III/III) being appended as appropriate. In contrast, most of the traditional rubric has been retained in reference to group 2 tumors (e.g., pheochromocytomas, paragangliomas, etc., which will not be considered further in this discussion). In his or her report on a biopsy or resection specimen, the pathologist can then work within this framework--using further descriptive comments and summaries of the aggregate literature on each tumor-- to provide the clinician with an outline of expected behavior for each neoplasm based on its individual nuances.

Up to this point, we have focused on "pure" neuroendocrine neoplasms. Increasingly in recent years, however, it has been recognized that human malignancies much more often show mixed or "divergent" differentiation than was ever appreciated in the past. Accordingly, surgeons and oncologists are now faced with such diagnoses as "adenocarcinoma/squamous carcinoma with neuroendocrine features" or, more simply, "mixed adenocarcinoma-small cell neuroendocrine carcinoma." In this scenario, the pathologist is attempting to convey the concept that the tumor at hand looks like conventional squamous carcinoma or adenocarcinoma, admixed with small cell (neuroendocrine) carcinoma in a routine hematoxylin and eosin stain. It would be expected that the responses to therapy and behavior of such mixed lesions would also be a hybrid of those attending each component (i.e., adenocarcinoma or small cell carcinoma) in pure form. Nonetheless, optimal therapeutic approaches for each of these "amalgam" tumors have yet to be delineated.

In specific reference to the nosology of pulmonary neuroendocrine tumors, the World Health Organization has summarized the "traditional" or "standard" classification scheme that has been in use for several years:

1. Minute Pulmonary Lesions
   1. Tumorlet
   2. Neuroendocrine (neuroepithelial) body
2. Common Tumors with Light -microscopic Neuroendocrine Appearance
   1. Carcinoid tumor
   2. Atypical carcinoid/well-differentiated neuroendocrine carcinoma
   3. Large cell neuroendocrine carcinoma (intermediate cell neuroendocrine carcinoma)
   4. Small cell carcinoma
      1. Pure small cell carcinoma (oat cell and intermediate variants)
      2. Small cell/large cell neuroendocrine carcinoma
      3. Combined small cell/non-small cell carcinoma
3. Non-small cell carcinoma with neuroendocrine features (neuroendocrine differentiation detected only by immunostaining or electron microscopy)

• Neuroendocrine Hyperplasias/Anatomic Variants:
  • tumorlet, neuropeithelial body
• Type I Lesions:
  • Neuroendocrine carcinomas
    • Grade I ( old category of "classic carcinoid")
    • Grade II (old category of "atypical carcinoid"/"well differentiated neuroendocrine carcinoma")
    • Grade III (further characterized by cell size as small-cell neuroendocrine carcinoma or large-cell neuroendocrine carcinoma or mixed small-cell/large-cell neuroendocrine carcinoma) (old categories of "oat cell carcinoma;" "endocrine large-cell undifferentiated carcinoma;" and "mixed small-cell/large-cell undifferentiated carcinoma")
    • Mixed neuroendocrine/non-neuroendocrine carcinoma
    • Large cell carcinoma with occult neuroendocrine differentiation
• Type II Lesions:
  • (Paraganglioma; primitive neuroectodermal tumor, etc. [exceedingly rare in the lung])

1. Anywhere from 5 to 15% of classic bronchial carcinoids may involve regional lymph nodes; at least 2-3% may be fatal. While these tumors are thus have low malignant potential, and can usually be cured by complete resection, that potential is not nil.
2. There is nothing "atypical" or "well differentiated" about type 1, grade II lesions. They are full-blown cancers, with a five year mortality that averages 35-50%.
3. The term "atypical carcinoid" has taken on a wastebasket-like quality among many pathologists. Some use the term for any lesion that is not, dichotomously, a central classic carcinoid or a small cell carcinoma. Hence, such widely disparate lesions as peripheral spindle cell carcinoid and large cell neuroendocrine carcinoma have been included erroneously in this category.
4. Type 1 large cell neuroendocrine tumors are high-grade, both in regard to their behavior and their histologic and cytologic features, as detailed below. To refer to these lesions as "intermediate," appears to underestimate their biologic potential.
5. It is time to examine the entire small-cell/non-small-cell carcinoma distinction. Should T1/N0 peripheral small cell neuroendocrine carcinomas not be resected, simply because of their histology? Most surgeons currently think not. Can one accurately distinguish between grade II and III neuroendocrine carcinomas by cytologic sampling alone? This is often not possible. Can grade III small-cell and grade III large-cell neuroendocrine carcinomas always be distinguished from one another on cytologic samples? (Again, the answer is thought to be no.) These are important points, given the fact that small-cell neuroendocrine carcinoma is almost never excised in many centers, once that diagnosis is made by cytologic means or limited biopsy (a decision that is probably ill-advised for stage I tumors). On the other hand, grade II neuroendocrine carcinomas and grade III large-cell neuroendocrine carcinomas undeniably should be handled surgically, at least in part.
6. The above-cited terminology can be applied to virtually all organs, not only the lung, without the need to master a bewildering bevy of idiosyncratic terms for each site.

At this time, a tenable approach is to use the designation of "neuroendocrine carcinoma," followed by a grade, for all type I neuroendocrine tumors of the lung. In parenthesis, or in a comment, the "standard" terminology is provided as well, for educational purposes. At some point in the future, it should be possible (and desirable) to drop the latter nosology altogether.

Specific Neuroendocrine Carcinoma Morphotypes

Grade I Neuroendocrine Carcinoma ("Classical Carcinoid")
Pulmonary carcinoids were initially labeled as an "adenoma" of the bronchus, a term which unfortunately persists, to some extent, in current clinical usage. Their similarity to gastrointestinal carcinoids, so named as "carcinoma-like tumors," was noted many decades ago. While the majority of classic carcinoids are centrally located, approximately 10-20% are found in the periphery of the lung. The criterion commonly used to distinguish these two locations is the relationship of the lesion to a cartilaginous airway; tumors which are so associated are considered central, while those without such a relationship to a tubular airway are considered peripheral.

Central grade I neuroendocrine carcinomas (NECs) ("carcinoids with classic histology") are rarely a diagnostic dilemma. They typically grow as polypoid intraluminal masses, with an intact overlying epithelium, or one demonstrating squamous metaplasia. This pattern explains the usual clinical presentation, which is largely that of localized obstruction, manifested by wheezing, cough, or pneumonia. These patients almost never present with the carcinoid syndrome; rare patients have had associated Cushing's syndrome or other endocrinopathies. Localized obstruction also dominates the radiographic picture as well, with evidence of localized pneumonia, or atelectasis. Rarely, a central mass growing with a "dumb-bell" like configuration will be seen on plain films, and CT scans will usually demonstrate a lesion within and adjacent to a large airway. Men and women are approximately equally affected, and young to middle-aged adults account for the majority of cases. The lesions are thus usually seen in patients who are substantially younger than those with ordinary bronchogenic carcinomas.

Gross features include a lesional size of 2 to 4 cm. Grade I NECs are usually tan to dark red, and should lack obvious necrosis or hemorrhage. Both central and peripheral tumors display a wide variety of growth patterns, including trabecular, ribbon-like, nested, or in solid sheets. The cytoplasm is relatively abundant, and may be strikingly oncocytic. Spindle cell change is rarely noted in central lesions and is more usual in peripheral grade I NECs; it should be emphasized that fusiform cells are not, in and of themselves, evidence of more aggressive biologic potential. Mitotic activity is very limited, and necrosis is absent.

The behavior of central and peripheral grade I NEC of the lung is generally good. Complete excision is the treatment of choice, which may necessitate lobectomy or a more complicated sleeve resection. Endobronchial excisions are associated with an unacceptable rate of local recurrence. Metastatic rates vary from 1 to 20%; a figure of ~5-10% is probably closest to the true incidence, and, when present, secondary deposits are usually seen in adjacent peribronchial or hilar lymph nodes. It is this observation that leads to the conclusion that these lesions are undeniable carcinomas. Moreover, distant metastases of prototypical grade I pulmonary NECs have been well-documented, although they are rare. These show a tendency for involvement of the skin, bones, liver, or brain. Overall, survival is in excess of 90 to 95% at 5 years.

Grade II Neuroendocrine Carcinoma ("Atypical Carcinoid")
Very few areas of pathology arouse the combination of angst, confusion, and controversy as the discussion surrounding the proper labeling of "atypical carcinoids." That term was first used by Arrigoni and colleagues in 1972. They reviewed 216 pulmonary "carcinoids" and found 23 with unusual features, including pleomorphism, increased mitotic activity, hyperchromatic nuclei, high nucleocytoplasmic ratios, and evidence of spontaneous necrosis or hemorrhage. In this original series, 70% of the lesions metastasized, and 7 individuals (30%) died of their tumors. Since the seminal report, a number of other terms have been advanced as successors for "atypical carcinoid," including "Kulchitzky cell carcinoma" (127) and "well-differentiated neuroendocrine carcinoma".

The term "grade II NEC" is preferred for this neoplasm, and the following criteria can be used to define it: a mitotic rate of 5 or more per 10 high power-fields; at least moderate nuclear pleomorphism; spontaneous necrosis; and at least a focal loss of an the organoid growth pattern associated with low-grade neuroendocrine carcinomas of the lung. As indicated by Yousem, a requirement for two or more of these criteria is a reasonable one before the designation of "grade II NEC" is used, to avoid over-grading.

Grade II NECs are slightly larger than their grade I relatives, often being greater than 3 cm. in diameter. Lymph node metastases are present at diagnosis in 30 to 50% of cases, and roughly 25% will have remote metastatic disease. Mortality from this neoplasm is in the range 30 to 50% at 2 years; Rush et al. have reported respective 5 and 10 year survivals of 60% and 40%. Early case studies indicated that there was a survival benefit to postoperative adjuvant chemotherapy with or without radiation therapy, but later studies have failed to demonstrate such results. In fact, some evidence suggests that grade II lesions are not as likely to respond to the type of chemotherapy employed for grade III small-cell neuroendocrine carcinoma. Nonetheless, until there are additional prospective trials of adjuvant agents are carried out, this will continue to be a topic that is controversial.

Grade III Neuroendocrine Carcinoma, Small-Cell Type ("Oat-Cell Carcinoma;" "Small-Cell Carcinoma")
High grade small-cell neuroendocrine carcinoma is probably the best-recognized neoplasm in the family of neuroendocrine lung tumors, accounting for about 20% of all pulmonary carcinomas. The classic morphologic appearance of this lesion features small, hyperchromatic, molded cells; almost no visible cytoplasm; inconspicuous or absent nucleoli; single-cell necrosis; and a relative absence of stromal desmoplasia. En-masse (coagulative) necrosis is not uncommon, and the tumor cells of small-cell NEC may be focally pleomorphic as well.

A difficulty that may be encountered is the identification of cells that have the appearance of small cell carcinoma in a fine needle aspirate of an apparently solitary peripheral lung nodule. Although 90% of small cell neuroendocrine carcinomas are central, peripheral lesions of this type account for the other 10% of cases. It is believed that sufficient data are now available to suggest that the latter neoplasms should be resected. This step provides adequate tissue to accurately grade the lesion, and may prove to be the therapy of choice in stage I or II peripheral small-cell neuroendocrine carcinomas. Another problem relating to small-cell NEC is that although they are definable as high-grade NECs, their small-cell nature may not be obvious in limited biopsy material. A tenable approach for the pathologist in such circumstances is to use the more generic term of "high-grade neuroendocrine carcinoma" (with no specification of small-cell or large-cell subtype) and let the clinical staging dictate the therapy.

Grade III Neuroendocrine Carcinoma, Large-Cell Type ("Large Cell Neuroendocrine Carcinoma")
The diagnosis of "large cell neuroendocrine carcinoma" is synonymous with grade III neuroendocrine carcinoma, large-cell type (LCNEC), and is a relatively new entry to the nomenclature of pulmonary carcinomas. Travis et al. proposed that this term should be used for tumors which have obvious features of neuroendocrine differentiation by light microscopy, but that do not fit into the diagnostic categories of "carcinoid," "atypical carcinoid," or "small cell carcinoma". The histologic attributes in question include a cell size at least three times that of small-cell NEC; the presence of an organoid growth pattern; cellular palisading or rosette-like areas; geographic necrosis; a high mitotic rate (approximating that of small-cell NEC); and a variably granular chromatin pattern. As so defined, LCNEC resembles the cases previously called "intermediately-differentiated neuroendocrine carcinoma" by Warren and co-workers. It is felt that the latter term has two deficiencies, the first of which is its possible confusion with an old designation for a variant of small-cell carcinoma; namely, "intermediate variant small cell carcinoma". The second problem is that LCNEC is quite clearly a high-grade tumor biologically, and the term "intermediate" would instead suggest placement in the grade II category.

The clinical features of LCNECs are distinctive. In reports by Travis et al. and others, these lesions almost always occur in heavy smokers, as does small cell NEC. Although a few cases present as central masses, most tend to be located in the more peripheral lung parenchyma.. Many examples of LCNEC are T1 or T2 tumors pathologically, and yet, the aggressive potential of these lesions cannot be overstated. Only 10% of the patients reported by Warren et al. were alive at 2 years, despite the fact that they all had stage I tumors. All patients in series published by Travis & coworkers were dead of disease or had distant metastases at two years' followup. Another report on LCNEC by Rush et al. documented 5 and 10 year survival rates of 33% and 11%, respectively. The speaker has studied a series of 47 LCNECs from 2 institutions. The survival for stage I cases in that experience was 18% at 40 months. Thus, the behavior of LCNEC is significantly worse than that of poorly-differentiated adenocarcinoma or squamous carcinoma, or large-cell "undifferentiated" carcinoma. Surprisingly, the survival of patients with resected, low-stage small cell NECs is better than that of individuals with LCNEC.

The optimal therapy for LCNECs is still unsettled. Because these tumors tend to present as low stage lesions, most will be surgically resected. As is true of grade II NECs, there are, as yet, no large randomized trials to address the value of post-operative chemotherapy or radiation for LCNEC. Patients who die of their tumors develop distant metastases or intrathoracic recurrences; thus, adjunctive treatment modalities would appear to have some intuitive merit.

Large Cell Carcinoma with "Occult" Neuroendocrine Differentiation
Several authors have described tumors in the lung that were variably designated as "atypical endocrine carcinomas," "endocrine large-cell carcinomas," or "large cell carcinomas with neuroendocrine differentiation". The tumor cells in such lesions are at least three times as large as those of small cell carcinomas, and they approximate the cell size of poorly-differentiated adenocarcinomas or squamous cell carcinomas. The lesions furthermore have rather monomorphic nuclei with dispersed or vesicular chromatin and prominent nucleoli. The presence of neuroendocrine differentiation is inapparent on light microscopy, because the usual "organoid" qualities of growth and cytologic attributes of neuroendocrine cells are not obvious. However, when such tumors are examined by electron microscopy or immunohistology (for such neuroendocrine markers as chromogranin-A, synaptophysin, CD57, neural cell adhesion molecule, or specific neuropeptides), "occult" evidence of neuroendocrine differentiation is indeed revealed. Of the reported large-cell carcinomas with neuroendocrine features, roughly 50% were dead and another 20% were alive with recurrent disease at 3 years' followup, as compared with a disease-free survival of 47% for stage-matched, truly undifferentiated large-cell carcinomas at the same time point. Thus, it appears that the behavior of those large-cell pulmonary carcinomas with occult neuroendocrine differentiation may be more aggressive.

While some observers have suggested that large cell carcinoma with occult neuroendocrine differentiation should be grouped together with LCNEC, they should probably be kept as separate categories. The reasons for doing this are twofold. First, it should be stressed that large-cell carcinomas with "occult" neuroendocrine differentiation lack the usual morphologic features that define the spectrum of overt neuroendocrine carcinomas. They can only be recognized with special techniques, and, as such, are outside the spectrum of neuroendocrine neoplasms that have been presented thus far. The second is related to therapeutic considerations; the optimal therapy for such lesions is open to question, and may prove to be different from that used for LCNEC.

As mentioned above, there may be prognostic value in the recognition of "occult" neuroendocrine differentiation in large-cell carcinomas of the lung that otherwise look like other large-cell carcinomas on conventional microscopic examination. Sufficient evidence exists to suggest that it is justifiable for the pathologist to adjunctively assess (by electron microscopy or immunohistochemistry) the possible presence of neuroendocrine differentiation before calling a large cell carcinoma as "undifferentiated".

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