Well-Differentiated Neuroendocrine Carcinomas: The Spectrum of Histologic Subtypes and Various Clinical Behaviors

https://doi.org/10.1053/j.semtcvs.2006.08.008Get rights and content

The term “well-differentiated neuroendocrine carcinoma” was coined to describe a variety of demonstrably neuroendocrine tumors which were more aggressive (both with respect to their histologic appearance and their clinical course) than (typical) bronchial carcinoids but were also clearly distinguishable from small cell neuroendocrine carcinomas. This umbrella term encompasses a variety of tumors previously described by a variety of terms including “atypical” carcinoids, “malignant tumorlets,” peripheral stage I small-cell carcinoma, as well as neoplasms described simply as “undifferentiated carcinoma” (prior to the recognition of their neuroendocrine properties). As such, this term is a broad term and is not simply synonymous with “atypical carcinoid.” Over time, at least 3 subtypes have been identified based upon their histologic appearance and mitotic index, with correspondingly aggressive clinical courses.

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.

References (59)

  • W.A. Cooper et al.

    The surgical spectrum of pulmonary neuroendocrine neoplasms

    Chest

    (2001)
  • M. Musi et al.

    Bronchial carcinoid tumors: a study of clinicopathologic features and the role of octreotide scintigraphy

    Lung Cancer

    (1998)
  • C.F. Thomas et al.

    Typical and atypical pulmonary carcinoidsOutcome in patients presenting with regional lymph node involvement

    Chest

    (2001)
  • V.W. Rusch et al.

    Molecular markers help characterize neuroendocrine lung tumors

    Ann Thorac Surg

    (1996)
  • V. Costes et al.

    Typical and atypical bronchopulmonary carcinoid tumors: a clinicopathologic and Ki-67-labelling study

    Hum Pathol

    (1995)
  • Z.K. Arbiser et al.

    Neuroendocrine lung tumors: grade correlates with proliferation but not angiogenesis

    Mod Pathol

    (2001)
  • A. Santinelli et al.

    Ploidy, proliferative activity, p53, and bcl-2 expression in bronchopulmonary carcinoids: relationship with prognosis

    Pathol Res Pract

    (1999)
  • S. Petzmann et al.

    Loss of heterozygosity on chromosome arm 11q in lung carcinoids

    Hum Pathol

    (2001)
  • A.K. Walch et al.

    Typical and atypical carcinoid tumors of the lung are characterized by 11q deletions as detected by comparative genomic hybridization

    Am J Pathol

    (1998)
  • R. Ullmann et al.

    Unbalanced chromosomal aberrations in neuroendocrine lung tumors as detected by comparative genomic hybridization

    Hum Pathol

    (1998)
  • S. Oberndorfer

    Karzinoide Tumoren des Dunndarms

    Frankf Z Pathol

    (1907)
  • H. Hamperl

    Ueber gutartige Bronchialtumoren (Cylindrome und Carcinoide)

    Virchows Arch (Pathol Anat)

    (1937)
  • V.E. Gould et al.

    Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms

    Lab Invest

    (1983)
  • E.J. Mark et al.

    Peripheral small cell carcinoma of the lung resembling carcinoid tumor: a clinical and pathologic study of 14 cases

    Arch Pathol Lab Med

    (1985)
  • I.D. Craig et al.

    Spindle-cell carcinoid of the lungCytologic, histologic, and ultrastructural features

    Acta Cytol

    (1982)
  • W.H. Warren et al.

    Differential diagnosis of small cell neuroendocrine carcinoma of the lung

    Chest Surg Clin N Am

    (1997)
  • W.H. Warren et al.

    Reevaluation of pulmonary neoplasms resected as small cell carcinomasSignificance of distinguishing between well-differentiated and small cell neuroendocrine carcinomas

    Cancer

    (1990)
  • W.H. Warren et al.

    Well-differentiated and small cell neuroendocrine carcinomas of the lungTwo related but distinct clinicopathologic entities

    Virchows Arch

    (1988)
  • S.A. Youssem

    Pulmonary carcinoid tumors and well-differentiated neuroendocrine carcinomasIs there room for an atypical carcinoid?

    Am J Clin Pathol

    (1991)
  • Cited by (10)

    • The puzzle of gynecologic neuroendocrine carcinomas: State of the art and future directions

      2021, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      According to the 2014 World Health Organization (WHO) new classification, NETs can be divided in two biologically and clinically different groups: well differentiated NETs (WDNETs), or carcinoids, and poorly differentiated NETs (PDNETs), or NE carcinomas (NECs), which in turn incorporate large cell (LCNECs) and small cell NECs (SCNECs), the latter representing the vast majority (Kurman, 2014; Rindi et al., 2018; van Meerbeeck et al., 2011; Remick and Ruckdeschel, 1992; Haider et al., 2006; Wong et al., 2009) (Fig. 2). NECs are exceedingly aggressive and characterized by high mitotic rate (>10 mitotic figures/10 HPF), high histologic grade (grade 3), pleomorphism, extensive necrosis, frequent lymph vascular space involvement (LVSI), advanced stage, worse prognosis and higher likelihood of recurrence (Gardner et al., 2011; DeLellis, 2001; Dikmen et al., 2004; Warren et al., 2006). These tumors are often mixed with small foci of more traditional histologic subtypes, which are usually less than 5–10 % of the total volume of the tumor (Patibandla et al., 2018; Gibbs et al., 2019; Salvo et al., 2019).

    • Surgical treatment of bronchial carcinoid tumors: A single-center experience

      2010, Lung Cancer
      Citation Excerpt :

      Atypical carcinoids (ACs) have a more aggressive behavior, with higher rates of metastasis and lower overall survival. ACs are usually located more peripherally and therefore are less symptomatic [4]. Surgery remains the mainstay for the treatment of such tumors and strategy may vary according to histology.

    View all citing articles on Scopus
    View full text