Well-Differentiated Neuroendocrine Carcinomas: The Spectrum of Histologic Subtypes and Various Clinical Behaviors
Section snippets
Histologic Features of Well-Differentiated Neuroendocrine Carcinoma
In view of the above, the term “well-differentiated neuroendocrine carcinoma” (WDNC) was proposed as an umbrella term to describe demonstrably neuroendocrine neoplasms that essentially had some degree of preservation of an organoid architecture, displaying moderate but unquestionable pleomorphism. In these neoplasms, the mitotic activity, degree of lymphatic/vascular invasion, and pattern of necrosis was intermediate between typical bronchial carcinoid (TC) and classic SCNC.
These tumors
Cytologic Features
Morphologically, WDNCs consist of cohesive nests of monomorphic, polygonal to fusiform cells with abundant eosinophilic cytoplasm and pleomorphic nuclei, inconspicuous nucleoli, occasional mitotic figure focal necrosis, and rosette-like structures. The latter features can be misinterpreted as acini, leading to the frequent misdiagnosis of adenocarcinoma. The features of focal necrosis and mitotic activity serve as useful features to distinguish it from TC. The absence of widespread necrosis and
Ultrastructural Features
Ultrastructurally, WDNCs display features by which they can be distinguished from TCs. The relatively large cells are loosely packed, linked by numerous, if rudimentary, junctions. The complement of cytoplasmic organelles is variable but inconspicuous. The cytoplasmic matrix is of low density. Tangles of cytoplasmic processes are often present within which are often located neurosecretory granules. These granules are generally not as plentiful as seen in TCs and tend to be smaller in size.
Molecular Marker Studies
Immunohistochemically, the majority of WDNCs display immunoreactivity to the pan-neuroendocrine markers (neuron specific enolase (NSE), synaptophysin, and chromogranin). There is also immunoreactivity to serotonin and a wide array of neuropeptides, often with two or more hormones present. According to our experience, the most frequently expressed are immunoreactivity to ACTH followed by bombesin, leu-enkephalin, vasoactive intestinal polypeptide (VIP), and calcitonin. As was the case in TCs,
Clinical Features
In our studies, 50% of patients with WDNC were smokers, whereas almost all patients with SCNC were smokers, and the majority of patients with TCs were nonsmokers.
In contrast to TCs (which are typically polypoid and endobronchial but initially limited to the bronchial wall), more than 50% of WDNCs arise peripherally, invariably invading the parenchyma. Typically, patients with TC present with a persistent cough, hemoptysis, recurring pneumonias, and wheeze, whereas patients with WDNC tend to be
Flow Cytometry Profile, Proliferation Index Studies, and Apoptosis-Related Factors (p53, bcl-2)
Flow cytometry has been used to estimate the ploidy status to distinguish TC from WDNC. TCs were found to be diploid in 90% of cases (10% aneuploid, 10% tetraploid). In contrast, WDNCs were found to have only 17% diploid (43% aneuploid, 13% tetraploid). SCNC has been shown to be aneuploid in 85% of cases.42
Ki67 is a nuclear antigen present throughout the G1,S, G2,M phases of cell cycle, but absent in the resting cell (G0). As such, it is a very reliable marker of cellular proliferation and is
Molecular Cytogenetic Analysis
In general, TC and WDNC can be distinguished from LCNC and SCNC by the frequency and the site of chromosomal aberrations. TC and WDNC have fewer chromosomal aberrations and the better prognosis than LCNC/SCNC where chromosomal aberrations are frequent, and the prognosis is correspondingly poor. WDNC can be distinguished from LCNC/SCNC on this basis. However, the genetic alterations are not so specific as to serve as a basis of classification of these tumors, nor has the genetic profile been
Genomic Alterations
Gene sequence analysis of Ki-ras-2 and c-raf-1 has failed to show any evidence of point mutation among pulmonary neuroendocrine tumors.43, 48, 59 Although genomic studies are in their infancy, oncogenes distinguishing neuroendocrine from nonneuroendocrine neoplasms, or oncogenes that help subclassify pulmonary neuroendocrine tumors, have not been identified.
Conclusions
Over the last 25 years, we have become increasingly aware of the spectrum of neuroendocrine pulmonary neoplasms, their range of behaviors, and features by which they can be distinguished. The identification of well-differentiated neuroendocrine carcinomas (as distinct from bronchial carcinoids and small-cell carcinomas) is becoming increasingly clarified with the use of tumor markers and special studies. Although the role of surgery is well defined, the response to radiotherapy and chemotherapy
Acknowledgment
The authors wish to thank Martin Derom for continued secretarial services and encouragement provided.
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