The concept of a "diffuse neuroendocrine system" is not a new one. Feyrter developed this
paradigm in 1938, in a philosophical attempt to unify tumors in several anatomic locations which had
potential secretory functions and similar morphologic characteristics. Pearse refined and renamed the
cellular network in question 35 years later, coining the designation of "APUD" system (for Amine
Precursor Uptake & Decarboxylation) to describe its shared biochemical attributes. Inherent in the
latter scheme was the presumption that all "APUD" cells-- and tumors deriving from them (i.e.,
"APUDomas")-- emanated from the remnants of the neural crest.
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
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
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:
As stated earlier, it is a truism that neuroendocrine proliferationss are all potentially
malignant. The only exceptions to this rule in the lung are the pulmonary tumorlet and the
neuroepithelial body, which represent a form of hyperplasia and a normal anatomic structure,
respectively. It is therefore suggested that the following alternative scheme may be more appropriate
because of its relative simplicity and unifying characteristics:
- Minute Pulmonary Lesions
- Neuroendocrine (neuroepithelial) body
- Common Tumors with Light -microscopic Neuroendocrine Appearance
- Carcinoid tumor
- Atypical carcinoid/well-differentiated neuroendocrine carcinoma
- Large cell neuroendocrine carcinoma (intermediate cell neuroendocrine carcinoma)
- Small cell carcinoma
- Pure small cell carcinoma (oat cell and intermediate variants)
- Small cell/large cell neuroendocrine carcinoma
- Combined small cell/non-small cell carcinoma
- Non-small cell carcinoma with neuroendocrine features (neuroendocrine differentiation detected only by immunostaining or electron microscopy)
The following points represent a rationale for this shift in nosology:
- 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])
- 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.
- 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%.
- 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.
- 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.
- 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.
- 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
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
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;"
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
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".
- Feyrter F: Uber Diffuse Endokrine Epitheliale Organe. J.A. Barth,
- Pearse AGE: The APUD cell concept and its implications in pathology. Pathol
Annu 1974; 9: 27-41.
- Lloyd RV: Endocrine Pathology,
Springer-Verlag, New York, 1990.
- Mendelsohn G: Diagnosis and Pathology of Endocrine
Diseases, J.B. Lippincott, Philadelphia, 1988.
- Travis WD, Rush W, Flieder DB, et al.: Survival analysis of 200 pulmonary neuroendocrine tumors with
clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998; 22: 934-944.
- Lequaglie C, Patriarca C, Cataldo I, et al. Prognosis of resected well-differentiated neuroendocrine
carcinoma of the lung. Chest 1991;100:1053-1056.
- Pilotti S, Patriarca C, Lombardi L, et al. Well-differentiated neuroendocrine carcinoma of the lung:
a clinicopathologic and ultrastructural study of 10 cases. Tumori 1992; 78:
- Greenberg SD, Fraire AE, Kinner BNI, Johnson E: Prognosis in carcinoma of the lung: tumor cell type
versus staging. Pathol Annu 1987; 22(2): 387-405.
- Dramer R: Adenomas of the bronchus. Ann Otol Rhinol Laryngol 1930; 39:
- Skinner C, Ewen SWB: Carcinoid lung: difdfuse pulmonary infiltration by a multifocal bronchial
carcinoid. Thorax 1976; 31: 212-219.
- Abdi EA, Goel R, Bishop S, Bain GO: Peripheral carcinoid tumors of the lung: a clinicopathologic
study. J Surg Oncol 1988; 39: 190-196.
- Zarate A, Kovacs K, Flores M, et al.: ACTH and CRF-producing bronchial carcinoid associated with
Cushing's syndrome. Clin Endocrinol 1986; 24: 523-529.
- Ranchod M, Levine GD: Spindle cell carcinoid tumors of the lung: a clinicopathologic study of 35
cases. Am J Surg Pathol 1980; 4: 315-331.
- McCaughan BC, Martini N, Bains MS: Bronchial carcinoids: review of 124 cases. J Thorac Cardiovasc Surg 1985; 89: 8-17.
- McBurney RP, Kirklin JW, Woolner LB. Metastasizing bronchial adenomas. Surg
Gynecol Obstet 1953; 96: 482-492.
- Huang Q, Muzitansky A, Mark EJ: Pulmonary neuroendocrine carcinomas. A review of 234 cases and a
statistical analysis of 50 cases treated at one institution using a simple clinicopathologic
classification. Arch Pathol Lab Med 2002; 126:545-553.
- Arrigoni MG, Woolner LB, Bernatz PE: Atypical carcinoid tumors of the lung. J
Thorac Cardiovasc Surg 1972; 64: 413-421.
- Paladugu RR, Benefield JR, Pak HY, et al.: Bronchopulmonary Kulchitzky cell carcinomas: A new
classification scheme for typical and atypical carcinoids. Cancer 1985; 55:
- Warren WH, Memoli Va, Gould VE. Immunohistochemical and ultrastructural analysis of bronchopulmonary
neuroendocrine neoplasms. II. Well-differentiated neuroendocrine carcinomas. Ultrastruct Pathol 1984; 7: 185-199.
- Warren WH, Memoli VA, Gould VE: Well differentiated and small cell neuroendocrine carcinomas of the
lung: Two related but distinct clinicopathologic entities. Virch Arch B Cell
Pathol 1988; 55: 299-310.
- Warren WH, Memoli VA, Jordan AG, et al.: Re-evaluation of pulmonary neoplasms resected as small cell
carcinomas: Significance of distinguishing between well-differentiated and small cell neuroendocrine
carcinomas. Cancer 1990; 65: 1003-1010.
- Yousem SA. Pulmonary carcinoid tumors and well-differentiated neuroendocrine carcinomas: Is there
room for an atypical carcinoid? Am J Clin Pathol 1991; 95: 763-764.
- Rush W, Zeren H, Griffin JL, et al.: Histologic subtypes of neuroendocrine carcinoma: prognostic
correlations. Lab Invest 1995; 72: 153A.
- Azzopardi JG: Oat cell carcinoma of the bronchus. J Pathol Bacteriol
1959; 78: 513-519.
- Carter D: Small-cell carcinoma of the lung. Am J Surg Pathol 1983; 7:
- Cook RM, Miller YE, Bunn PA Jr: Small cell lung cancer: etiology, biology, clinical features,
staging, and treatment. Curr Probl Cancer 1993; 17: 69-141.
- Yesner R: Small cell tumors of the lung. Am J Surg Pathol 1983; 7:
- Gephardt GN, Grady KJ, Ahmad M, Tubbs RR, Mehta AC, Shepard KV: Peripheral small cell
undifferentiated carcinoma of the lung: Clinicopathologic features of 17 cases.
Cancer 1988; 61: 1002-1008.
- Thomas JS, Lamb D, Ashcroft T, et al.: How reliable is the diagnosis of lung cancer using small
biopsy specimens? Report of a UKCCCR Lung Cancer Working Party. Thorax
- Vollmer RT. The effect of cell size on the pathologic diagnosis of small and large cell carcinomas
of the lung. Cancer 1982; 50: 1380-1383.
- Travis WD, Linnoila RI, Tsokos MG, et al.: Neuroendocrine tumors of the lung with proposed criteria
for large-cell neuroendocrine carcinoma: An ultrastructural, immunohistochemical, and flow cytometric
study of 35 cases. Am J Surg Pathol 1991; 15: 529-553.
- Dresler CM, Ritter JH, Patterson GA, et al.: Clinical-pathologic analysis of 40 patients with large
cell neuroendocrine carcinoma of the lung. Ann Thorac Surg 1997; 63:
- Hirsch FR, Matthews JM, Aisner S, et al.: Histopathologic classification of small cell lung cancer:
changing concepts and terminology. Cancer 1988; 62: 973-977.
- Demirer T, Ravits J, Aboulafia D: Myasthenic (Eaton-Lambert) syndrome associated with pulmonary
large cell neuroendocrine carcinoma. Southern Med J 1994; 87: 1186-1189.
- Stanford MR, Edelsten CE, Hughes JD, et al. Paraneoplastic retinopathy in association with large
cell neuroendocrine bronchial carcinoma. Br J Ophthalmal 1995; 79:
- Jiang SX, Kameya T, Shoji M, Dobashi Y, Shinada J, Yoshimura H: Large cell neuroendocrine carcinoma
of the lung: a histologic and immunohistochemical study of 22 cases. Am J Surg
Pathol1998; 22: 526-537.
- Hamzik J, Vrastyak J, Janik M, et al.: Surgical treatment of small-cell pulmonary carcinoma. Roz V Chirurg 1994; 73: 106-109.
- Mentzer SJ, Reilly JJ, Surgarbaker DJ: Surgical resection in the management of small-cell carcinoma
of the lung. Chest 1993; 103: 349S-351S.
- Smit EF, Croen HJ, Timens W, de Boer WJ, Postmus PE: Surgical resection for small cell carcinoma of
the lung: a retrospective study. Thorax 1994; 49: 20-22.
- MacDowell EM, Wilson TS, Trump BF: Atypical endocrine tumors of the lung. Arch Pathol Lab Med 1981; 105: 20-28.
- Hammond ME, Sause WT: Large cell neuroendocrine tumors of the lung. Cancer 1985; 56: 1624-1629.
- Piehl MR, Gould VE, Warren WH, et al.: Immunohistochemical identification of exocrine and
neuroendocrine subsets of large cell lung carcinomas. Pathol Res Pract
1988; 183: 675-682.
- Wick MR, Berg LC, Hertz M: Large cell carcinoma of the lung with neuroendocrine differentiation: a
comparison with large cell "undifferentiated" pulmonary tumors. Am J Clin
Pathol 1992; 97: 796-805.