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[Pathology] Atlas of Well-Differentiated Neuroendocrine Carcinoma (“Thymic Carcinoid”)

Well-Differentiated Neuroendocrine Carcinoma, Thymic Carcinoid, [Pathology] Atlas of Well-Differentiated Neuroendocrine Carcinoma (“Thymic Carcinoid”), Neuroendocrine Neoplasms of the Thymus



Neoplastic neuroendocrine proliferations of the mediastinum can originate from neuroendocrine cells that are native to the thymus, or they may arise from extra-adrenal paraganglia ectopically located in the mediastinum (i.e., paragangliomas).
Neuroendocrine carcinomas originating in the thymus are most common in middle-aged adults, with a male predilection, and can encompass the entire spectrum from welldifferentiated tumors that are similar to their counterpart in other organs (i.e., carcinoid tumors) to poorly differentiated, highly malignant neoplasms (such as small cell neuroendocrine carcinomas). The term “carcinoid tumor,” which has been used in the past, is best replaced by “well-differentiated neuroendocrine carcinoma” or “low-grade neuroendocrine carcinoma,” given that the malignant potential of these lesions has now been amply established. In up to one-third of patients, these tumors can be associated with paraneoplastic syndromes, including Cushing’s syndrome, syndrome of inappropriate secretion of antidiuretic hormone, and the Eaton-Lambert syndrome. Up to one-third of cases also occur in association with the multiple endocrine neoplasia (MEN) types I and II syndromes.

The classification of neuroendocrine carcinomas in the mediastinum has remained controversial. Although the current World Health Organization (WHO) classification retains the terms “carcinoid” and “atypical carcinoid” for some of these tumors, the current trend is to use the term “well- differentiated neuroendocrine carcinoma” for “carcinoid” and to use “moderately differentiated neuroendocrinecarcinoma” for “atypical carcinoid.” The new terms more accurately and realistically denote the actual biologic behavior of these tumors, whereas the WHO schema lumps typical carcinoid and atypical carcinoid under the category of welldifferentiated neuroendocrine carcinoma, implying that they share a similar biologic behavior. The most recent large study (Moran and Suster, Am J Clin Pathol; 2000), however, has demonstrated that there is a stepwise progression in malignant behavior that is directly related to prognosis for these tumors as they progress from well-differentiated to moderately differentiated to poorly differentiated types.
Thus, separation of well-differentiated tumors from moderately or poorly differentiated tumors is warranted. 

Table 3.1 presents the criteria for histologic diagnosis of primary neuroendocrine carcinomas of the thymus. In general, increasing grade of malignancy in these tumors translates into increased cytologic atypia and loss of architectural, organotypical features of neuroendocrine differentiation.
The morphologic spectrum displayed by these tumors can be quite variable, and numerous unusual morphologic variants have been described. Correct diagnosis in such instances requires awareness of these variants, which must be considered in the differential diagnosis so that an appropriate immunohistochemical workup can be initiated.


Well-Differentiated Neuroendocrine Carcinoma (“Thymic Carcinoid”)

The growth patterns and cytologic characteristics of neuroendocrine carcinomas of the thymus (Figs. 3.1, 3.2, 3.3, 3.4, 3.5, and 3.6, Table 3.2) can be quite varied.
 
Fig. 3.1 Gross appearance of well-differentiated neuroendocrine 
carcinoma of the thymus (thymic carcinoid) shows a well-circumscribed,
fleshy, tan-white mass with foci of hemorrhage and a vaguely lobulated
cut surface

Fig. 3.2 Scanning magnification of well-differentiated neuroendocrine 
carcinoma of the thymus (thymic carcinoid) shows well- developed
“organoid” (neuroendocrine) architecture, with discrete nests of tumor
cells separated by fibrovascular stroma  


Fig. 3.3 Higher magnification of well-differentiated neuroendocrine
carcinoma of the thymus with “organoid” (neuroendocrine) growth 
pattern shows well-defi ned small nests of cells containing a monotonous,
round cell population with abundant cytoplasm and small, round to oval
nuclei with stippled (“salt-and-pepper”) chromatin pattern

Fig. 3.4 High power of well-differentiated neuroendocrine carcinoma
of the thymus shows round cells with round to oval nuclei showing a
stippled chromatin pattern with an ample rim of eosinophilic
cytoplasm  


Fig. 3.5 Another example of the organoid, nested (“tzellballen”)
growth pattern in thymic neuroendocrine carcinoma shows larger nests
of monotonous tumor cells separated by thin and compressed fibrovascular septa  


Fig. 3.6 Higher magnification of Fig. 3.5, showing well-differentiated
neuroendocrine carcinoma of the thymus with a monotonous population of 
small, round cells surrounded by abundant eosinophilic cytoplasm. A few 
isolated tumor cells show a small nucleolus, but there is
no evidence of necrosis, nuclear pleomorphism, or mitotic activity

Table 3.2 Growth patterns and cytologic variants of thymic neuroendocrine carcinomas  



Suggested Reading

Cardillo G, Rea F, Lucci M, Paul MA, Margoritora S, Carleo F, et al. Primary neuroendocrine tumors of the thymus: a multicenter experience of 35 patients. Ann Thorac Surg. 2012;94:241–5.

Chetty R, Batitang S, Govender D. Large cell neuroendocrine carcinoma of the thymus. Histopathology. 1997;11:274–6.

Crona J, Bjorklund P, Welin S, Kozlovacki G, Oberg K, Granberg D. Treatment, prognostic markers and survival in thymic neuroendocrine tumors. A study from a single tertiary referral centre. Lung Cancer. 2013;79:289–93.

Economopoulus GC, Lewis Jr JW, Lee MW, Silverman NA. Carcinoid tumors of the thymus. Ann Thorac Surg. 1990;50:58–61. 

Floros D, Dosios T, Tsourdis A, Yiatromanolakis N. Carcinoid tumor of the thymus with multiple endocrine adenomatosis. Pathol Res Pract. 1982;175:404–9.

Gal AA, Kornstein MJ, Cohen C, Duarte IG, Miller JI, Mansour KA. Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study. Ann Thorac Surg. 2001;72:1179–82.

Klemm KM, Moran CA, Suster S. Pigmented thymic carcinoids. A clinicopathological and immunohistochemical study of 2 cases. Mod Pathol. 1999;12:946–8.

Montpreville VT, Machiarini P, Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of 14 cases. J Thorac Cardiovasc Surg. 1996;111:134–41.

Moran CA, Suster S. Angiomatous neuroendocrine carcinoma of the thymus: report of a distinctive morphological variant of neuroendocrine tumor of the thymus resembling a vascular neoplasm. Hum
Pathol. 1999a;30:635–9.

Moran CA, Suster S. Spindle cell neuroendocrine carcinomas of the thymus (spindle cell thymic carcinoid): a clinicopathologic and immunohistochemical study of seven cases. Mod Pathol. 1999b;12:587–91.

Moran CA, Suster S. Neuroendocrine carcinoma (carcinoid) of the thymus: A clinicopathologic analysis of 80 cases. Am J Clin Pathol. 2000a;114:100–10.

Moran CA, Suster S. Primary neuroendocrine carcinoma (carcinoid) of the thymus with prominent oncocytic features: clinicopathologic study of 22 cases. Mod Pathol. 2000b;13:489–94. 

Moran CA, Suster S. Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma: a clinicopathologic and immunohistochemical study of 11 cases. Am J Clin Pathol. 2000c;113:345–50.

Moran CA, Suster S. Cystic well-differentiated neuroendocrine carcinoma (carcinoid tumor). A clinicopathologic and immunohistochemical study of two cases. Am J Clin Pathol. 2006a;126:377–80. 

Moran CA, Suster S. Spectrum of pathologic features in neuroendocrine neoplasms of the mediastinum. Pathol Case Rev. 2006b;11:199–205.

Moran CA, Suster S, Fishback N, Koss MN. Mediastinal paragangliomas: a clinicopathologic and immunohistochemical study of 16 cases. Cancer. 1993;72:2358–64.

Olson JL, Salyer WR. Mediastinal paragangliomas (aortic body tumor): A report of four cases and a review of the literature. Cancer. 1978;41:2405–12.

Rosai J, Levine G, Weber WR, Higa E. Carcinoid tumors and oat cell carcinomas of the thymus. Pathol Annu. 1977;2:33–62.

Saito T, Kimoto M, Nakai S, Ikoma A, Toyoshima H, Kawakami M, et al. Ectopic ACTH syndrome associated with large cell neuroendocrine carcinoma of the thymus. Intern Med. 2011;50:1471–5.

Suster S, Moran CA. Thymic carcinoid with prominent mucinous stroma: report of a distinctive morphologic variant of thymic neuroendocrine neoplasm. Am J Surg Pathol. 1995;19:1277–85.

Suster S, Moran CA. Neuroendocrine neoplasms of the mediastinum. Am J Clin Pathol. 2001;115(S):17–27.

Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer. 1991;67:1025–32.

Tiffet O, Nicholson AG, Ladas G, Sheppard MN, Goldstraw P. A clinicopathologic study of 12 cases of neuroendocrine tumors arising in the thymus. Chest. 2003;124:141–6.

Valli M, Fabris GA, Dewar A, Chikte S, Fisher C, Corrin B, Sheppard MN. Atypical carcinoid tumor of the thymus: a study of eight cases. Histopathology. 1994;24:371–5.

Wick MR, Carney JA, Bernatz PE, Brown LR. Primary mediastinal carcinoid tumors. Am J Surg Pathol. 1982;6:195–205.

Wick MR, Scheithauer BW. Oat cell carcinoma of the thymus. Cancer. 1982;49:1652–7.
 

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Free Medical Atlas: [Pathology] Atlas of Well-Differentiated Neuroendocrine Carcinoma (“Thymic Carcinoid”)
[Pathology] Atlas of Well-Differentiated Neuroendocrine Carcinoma (“Thymic Carcinoid”)
Well-Differentiated Neuroendocrine Carcinoma, Thymic Carcinoid, [Pathology] Atlas of Well-Differentiated Neuroendocrine Carcinoma (“Thymic Carcinoid”), Neuroendocrine Neoplasms of the Thymus
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