BRIEF REPORT
Adrenocorticotropic Hormone-Producing Thymic Neuroendocrine Carcinoma With Oncocytic Features: A Case Report and Review of Literature Nadja K. Falk, M.D.,1* Annikka Weissferdt, M.D., F.R.C.Path,1 Mouhammed A. Habra, M.D.,2 and Sinchita Roy-Chowdhuri, M.D.,
Thymic neuroendocrine carcinomas are the most common mediastinal neuroendocrine tumor. These malignancies are not often diagnosed by fine-needle aspiration (FNA), as they are more commonly diagnosed by biopsy or excision. We describe a case of a FNA of a paratracheal mass from a 38-year-old man who presented with Cushing syndrome. A low-grade neuroendocrine carcinoma with oncocytic features was diagnosed, which was later confirmed by excision of the thymus, anterior mediastinal and paratracheal soft tissue, and lymph nodes. Oncocytic features in these tumors are a rare finding and bring metastatic medullary thyroid carcinomas as well as other metastases into the differential diagnosis. The prognosis of neuroendocrine carcinomas in this location is worse than neuroendocrine carcinomas in other areas, and close follow-up is recommended. Diagn. Cytopathol. 2014;00:000–000. VC 2014 Wiley Periodicals, Inc. Key Words: oncocytic neuroendocrine carcinoma; fine-needle aspiration; thymus; cytology
Primary mediastinal neuroendocrine neoplasms encompass less than 5% of mediastinal tumors, the most common being thymic neuroendocrine carcinoma (TNC). These tumors are found predominantly in the anterosupe1 Cytopathology Section, Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 2 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. *Correspondence to: Nadja Falk, M.D., Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Unit # 53, Houston, TX 77030, USA. E-mail: [email protected] Received 22 April 2014; Revised 17 July 2014; Accepted 6 October 2014 DOI: 10.1002/dc.23209 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
C 2014 WILEY PERIODICALS, INC. V
1 Ph.D.
rior mediastinum and are more commonly seen in males in their 50s. Approximately, 25% of TNCs are functionally active and can be part of familial endocrine neoplasia syndrome type I. Adrenocorticotropic hormone (ACTH) secretion is associated with approximately one-third of these tumors and leads to Cushing syndrome.1–4
Case Findings A 38-year-old male presented with Cushing syndrome and was referred to our institution. He had a recent development of hypertension, type 2 diabetes mellitus and 70 pound weight gain with easy bruising and skin ulcers. On physical examination, abdominal striae, neck soft tissue swelling, severe bilateral lower extremity edema, and significant proximal muscle weakness were noted. He had elevated ACTH and 24-hour urinary free cortisol levels of 123 pg/mL (reference range < 46 pg/mL) and 112 microgram/24 hours (reference range 0–50 microgram/24 hours), respectively, with normal thyroid stimulating hormone and free T4 thyroxine levels. A pituitary MRI revealed no masses. An Indium 111 Octreotide whole body scan with SPECT/CT scan of the neck, chest, abdomen, and pelvis revealed a lobulated upper mediastinal mass with enlarged paratracheal and prevascular lymph nodes and no thyroid abnormailties. Metyrapone, a cortisol lowering therapy, was prescribed.
Materials and Methods and Results Cytology A fine-needle aspiration (FNA) of paratracheal soft tissue was performed by interventional radiology. On-site Diagnostic Cytopathology, Vol. 00, No 00
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immediate assessment was performed. Alcohol- fixed and air-dried smears were prepared and stained using Papanicolaou (Pap) and Diff-Quik (DQ) stains, respectively. Examination of aspirate material from the paratracheal soft tissue revealed highly cellular smears. The small to intermediate sized monotonous cells were arranged in loosely cohesive clusters and as single cells (Fig. 1A). The nuclei were round or oval, eccentrically placed, with finely granular “salt-and-pepper” chromatin, occasional prominent nucleoli, and abundant slightly granular cytoplasm (Fig. 1B). A cell block was made, and sections were stained with hematoxylin and eosin (H&E). Tumor cells with round or oval somewhat eccentrically placed nuclei, finely granular chromatin, occasional prominent nucleoli, and abundant oncocytic cytoplasm were seen (Fig. 1C). Immunohistochemical stains were performed on cell block sections, which showed tumor cells to be diffusely positive for CAM 5.2 (Fig. 2A), synaptophysin (Fig. 2B), chromogranin (Fig. 2C), and focally positive for ACTH (Fig. 2D). The proliferation index was 7% of tumor cells (Fig. 2E). Five months later and after three cycles of etoposide and cisplatin, the thymus was removed.
Histology The thymic mass measured 6.5 cm 3 4.5 cm 3 3.5 cm and had a pale pink homogeneous cut surface. At low magnification, the thymic tumor infiltrated into the surrounding adipose tissue. It was composed of nests of tumor cells surrounded by fibrovascular septa (Fig. 3A). The neoplastic cells were predominantly round with abundant cytoplasm and eccentrically placed round nuclei with finely granular chromatin and occasional nucleoli (Fig. 3B). The cytologic and histologic findings in this case were those of a well-differentiated TNC with oncocytic features as exhibited by the neuroendocrine nuclear features, absent mitoses, low proliferation index, and no surrounding necrosis.
Discussion Grossly, TNCs are an average diameter of 10 cm with a tan and homogeneous surface.3,5 Well differentiated TNC, which is the rarest type,5 histologically has an organoid architecture surrounded by thick fibrovascular septa. The cytologic smears are highly cellular and the small to medium sized monotonous cells are in groups or as single cells. The sometimes eccentric nuclei are uniformly round to oval with finely granular “salt and pepper” chromatin and indistinct nucleoli, however rare macronucleoli may be observed. There is a moderate amount of finely granular eosinophilic cytoplasm with well-defined cell borders.1–3,5–10 Rosettes, cytoplasmic inclusion-like paranuclear structures, spindle 2
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Fig. 1. Paratracheal fine-needle aspirate smear demonstrates loosely cohesive clusters and as single cells (Papanicolaou, 1003) (A) and cells with eccentric round to oval nuclei, granular chromatin, prominent nucleoli, and abundant cytoplasm (Papanicolaou, 4003) (B). Cell block section showing tumor cells with round or oval somewhat eccentrically placed nuclei, finely granular chromatin, occasional prominent nucleoli, and abundant oncocytic cytoplasm (H&E, 4003) (C). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
cells, and prominent capillaries have been reported, but were not appreciated in this case.5,7,8,11 Moderately-differentiated TNC is the most commonly seen sub-type. The smears show larger intact cells
Diagnostic Cytopathology DOI 10.1002/dc
ONCOCYTIC THYMIC NEUROENDOCRINE CARCINOMA
Fig. 2. Paratracheal fine-needle aspirate showing immunohistochemical positivity in tumor cells for CAM 5.2 (1003) (A), synaptophysin (1003) (B), chromogranin (1003) (C), ACTH (1003) (D), and a low Ki-67 proliferation index of approximately 7% of tumor cells (1003) (E). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
with smaller apoptotic cells. The nuclei have occasionally prominent nucleoli with more scant cytoplasm. Poorly-differentiated TNC has a loss of the organoid pattern histologically. Cytologically, small cell neuroendocrine carcinoma has small- to medium-sized cells with “molding” of nuclei and crush artifact. The nucleoli are inconspicuous. Large cell neuroendocrine carcinoma cells may have slightly more cytoplasm and prominent nucleoli. Additional features that may occasionally be seen include spindle cell features,
melanin pigment deposition, an angiectatic growth pattern, cystic features, extracellular mucin deposition, cytoplasmic lipid vacuoles, and oncocytic features.1–3,5,6,9,10,12 Histologic sections, or cell blocks, are used for mitotic counts as mitotic counts are not validated on cytologic smears.5 Similar to lung primaries, less than two, less than ten, and greater than ten mitoses per ten high power fields are seen in well-, moderately-, and poorly-differentiated neuroendocrine carcinomas, respectively. Increasing Diagnostic Cytopathology, Vol. 00, No 00
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Fig. 3. Histologic section of the thymic mass showing nests of tumor cells surrounded by fibrovascular septa (H&E, 403) (A) and tumor cells with eccentrically placed round nuclei with finely granular chromatin, occasional nucleoli, and abundant cytoplasm (H&E, 2003) (B). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
amounts of necrosis are also seen with moderately- and poorly-differentiated neuroendocrine carcinoma.1,2,5,10,13,14 Primary TNCs are usually positive for CAM5.2 lowmolecular weight cytokeratin. Approximately 60% of cases are positive for both synaptophysin and chromogranin. Neuron-specific enolase positivity may also be appreciated.1,3,15,16 Immature cell junctions and dense-core neurosecretory granules are seen ultrastructurally.17 The differential diagnosis of oncocytic TNC includes medullary thyroid carcinoma,1,14,16,18 thymoma,5,7,8,10,19 metastatic neuroendocrine neoplasms,20 metastatic carcinomas particularly kidney,21 breast,22 and hepatocellular carcinoma fibrolamellar variant,23,24 metastatic malignant melanoma,14,23 malignant mesothelioma,1,14,16,25 paraganglioma,14,23 parathyroid adenoma,14 and thyroid H€urthle cell neoplasms (Table I). The neoplastic cells of TNC may rarely be embedded in an eosinophilic amyloid-like stroma as in medullary thyroid carcinoma.2–4 The incidence of ectopic thyroid in the anterior mediastinum is 3–20% and a case of mediastinal medullary thyroid carcinoma presenting with ectopic adrenocorticotropic syndrome has been reported.26 Oncocytic neuroendocrine neoplasms are rare and could include thyroid, lung, larynx, stomach, parathyroid, pituitary, and pancreatic primaries, which can also be hormonally active.20 Oncocytic renal neoplasms include oncocytoma, chromophobe renal cell carcinoma, and clear cell renal cell carcinoma.21 Metastatic oncocytic breast carcinomas include lobular and apocrine carcinomas.22 Thirty percent of TNCs are associated with endocrinopathies.27–29 In their study of 22 cases of primary TNCs
Table I. Comparison of Clinical Presentation, Cytologic Findings, and Positively Staining Immunohistochemical Profile of Thymic Neuroendocrine Carcinoma and the Differential Diagnosis Neoplasm Thymic Neuroendocrine Carcinoma Medullary Thyroid Carcinoma
Thymoma Metastatic Hepatocellular Carcinoma, Fibrolamellar Variant Metastatic Malignant Melanoma Malignant Mesothelioma Paraganglioma
Parathyroid Adenoma
4
Distinguishing clinical and cytologic findings
Positive immunohistochemical stains
Male > female; 6th decade Monotonous cell groups or single cells, eccentric nucleoli, “salt and pepper” chromatin, eosinophilic cytoplasm Sporadic (average age 50 years) or hereditary (younger, autosomal dominant) Oncocytic epithelioid or spindle cells, red cytoplasmic granules, amyloid Lymphocytes and epithelial cells (varying amounts and morphology depending on type) Young patients without cirrhosis Large eosinophilic polygonal cells with prominent nucleoli, cytoplasmic “pale bodies” and bile pigment; hyalinized fibrous tissue bands Dyshesive cells with eccentric nuclei with occasional intranuclear inclusions, prominent nucleoli, multinucleation and melanin pigment Female > male; 6th–7th decade Epithelioid, spindle or biphasic cells; cell clusters with “knobby” edges; “windows” between cells Epithelioid, spindle and ganglion cells with “salt and pepper” chromatin and cytoplasmic hyaline globules; loose cell clusters (Zellballen) surrounded by sustentacular cells Round nuclei, coarsely granular chromatin, moderately abundant granular cytoplasm
Cytokeratin CAM 5.2, synaptophysin, chromogranin, neuron specific enolase
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Cyokeratin, calcitonin, carcinoembryonic antigen, chromogranin, thyroid transcription factor-1 Cytokeratin 5/6 and p63 (epithelial cells) Arginase-1, glypican-3, hep-par 1
S-100, HMB-45, mart-1, melan-A CD 5/6, calretinin, wilms tumor 1, thrombomodulin, podoplanin, D2–40 Chromogranin, synaptophysin, S-100 (sustentacular cells) Parathyroid hormone
Diagnostic Cytopathology DOI 10.1002/dc
ONCOCYTIC THYMIC NEUROENDOCRINE CARCINOMA
with oncocytic features, Moran and Suster found one case to be associated with Cushing syndrome. Most of the cases were well-differentiated, and the association with Cushing syndrome did not alter the tumor behavior.16 Patients with TNC associated with paraneoplastic syndromes have a 65% 5-year mortality rate as opposed to 35% in non-syndromic patients.4 Serum hormone levels and immunohistochemical findings may not always correlate.30 When TNC is associated with Cushing syndrome, medical management should be attempted before bilateral adrenalectomy is performed.17,28,31 The initial treatment for TNC is thymectomy with mediastinal lymph node sampling. A median sternotomy may be indicated for aggressive local resection. The use of and timing of radiation and chemotherapy is controversial.17,28,31 This patient received neoadjuvant chemotherapy with etoposide and cisplatin, which ended two months prior to his tumor resection. The primary mass grew slightly, however, the morphology of the tumor was unchanged without increased mitoses or necrosis. His postoperative course was complicated by aspiration pneumonia and the development of a seroma in the soft tissue of his neck. Eventually his steroids were weaned, and he was discharged one month post-operatively. The prognosis of TNC is worse than similar tumors in other locations. Intermediate and poorly differentiated TNCs have a progressively worse prognosis than the welldifferentiated tumors, and the poorly differentiated TNCs have a 65% 10-year mortality rate.8 Approximately 90% of patients with poorly differentiated TNCs die from the disease, and the median survival is 15 months with or without treatment. Metastases have been seen most frequently in lymph nodes, lungs, and bone.2–4,17,29 TNCs rarely cause metastatic effusions where similar features to FNA are seen.29 Close follow-up with metastatic workup every 6–12 months is recommended for up to 10 years.2–4,17,29 This case is unique in that the cytopathologist made the initial diagnosis of this patient’s well-differentiated TNC as the first tissue diagnosis is commonly made from CT-guided core needle biopsies instead.5 Interesting findings in this case included the presentation with Cushing syndrome and prominent oncocytic cytologic features. The pathologist must consider various primary and metastatic neoplasms. Recognizing TNC is paramount, due to the poor prognosis when compared to other sites of primary neuroendocrine carcinoma, particularly when the tumor is associated with paraneoplastic syndromes.
References 1. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000;114:100–110. 2. Suster S, Moran CA. Neuroendocrine neoplasms of the mediastinum. Am J Clin Pathol 2001;115 (Suppl):S17–S27.
3. Moran CA. Primary neuroendocrine carcinomas of the mediastinum: Review of current criteria for histopathologic diagnosis and classification. Semin Diagn Pathol 2005;22:223–229. 4. Ruffini E, Oliaro A, Novero D, Campisi P, Filosso PL. Neuroendocrine tumors of the thymus. Thorac Surg Clin 2011;21:13–23. 5. Wakely PE, Jr. Fine needle aspiration in the diagnosis of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008;22:433– 442. 6. Kalhor N, Moran CA. Mediastinal neuroendocrine tumours. Diagn Histopathol 2010;16:237–242. 7. Wang DY, Kui SH, Chang DB, et al. Fine needle aspiration cytology of thymic carcinoid tumor. Acta Cytol 1995:434–427. 8. Nichols GL, Jr, Hopkins MB, III, Geisinger KR. Thymic carcinoid. Reports of a case with diagnosis by fine needle aspiration biopsy. Acta Cytol 1997;41:1839–1844. 9. Wakely PE, Jr. Cytopathology–histopathology of the mediastinum II. Mesenchymal, neural, and neuroendocrine neoplasms. Ann Diagn Pathol 2005;9:24–32. 10. Wakely PE, Jr. Cytopathology of thymic epithelial neoplasms. Semin Diagn Pathol 2005;22:213–222. 11. Gherardi G, Marveggio C, Placidi A. Neuroendocrine carcinoma of the thymus: Aspiration biopsy, immunocytochemistry, and clinicopathologic correlates. Diagn Cytopathol 1995;12:158–164. 12. Smith NL, Finley JL. Lipid-rich carcinoid tumor of the thymus gland: Diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 2001;25:130–133. 13. DeMay RM. Mediastinum. In: The art and science of cytopathology. 2nd ed. Chicago: American Society for Clinical Pathology; 2012. p 1218–1248. 14. Cibas ES, Ducatman BS. Cytology diagnostic principles and clinical correlates. 3rd edition. Philadelphia: Saunders Elsevier; 2009. 537 p. 15. Hallmann RS, Schneeweiss LG, Correa E, Zamora J. Fine needle aspiration biopsy of thymic carcinoid tumor: A case with immunocytochemical correlation. Acta Cytol 1998;42:1042–1043. 16. Moran CA, Suster S. Primary neuroendocrine carcinoma (thymic carcinoid) of the thymus with prominent oncocytic features: A clinicopathologic study of 22 cases. Mod Pathol 2000;13:489–494. 17. Chaer R, Massad MG, Evans A, Snow NJ, Geha AS. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg 2002;74:1733– 1740. 18. Pusztaszeri MP, Bongiovanni M, Faquin WC. Update on the cytologic and molecular features of medullary thyroid carcinoma. Adv Anat Pathol 2014;21:26–35. 19. Renshaw AA, Haja JC, Neal MH, Wilbur DC, Cytopathology Resource Committee CoAP. Distinguishing carcinoid tumor of the mediastinum from thymoma: Correlating cytologic features and performance in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. Arch Pathol Lab Med 2006;130:1612–1615. 20. Volante M, La Rosa S, Castellano I, Finzi G, Capella C, Bussolati G. Clinico-pathological features of a series of 11 oncocytic endocrine tumours of the pancreas. Virchows Arch 2006;448:545–551. 21. Abrahams NA, Tamboli P. Oncocytic renal neoplasms: Diagnostic considerations. Clin Lab Med 2005;25:317–339, vi. 22. Damiani S, Dina R, Eusebi V. Eosinophilic and granular cell tumors of the breast. Semin Diagn Pathol 1999;16:117–125. 23. Sarode VR, Castellani R, Post A. Fine-needle aspiration cytology and differential diagnoses of fibrolamellar hepatocellular carcinoma metastatic to the mediastinum: Case report. Diagn Cytopathol 2002; 26:95–98. 24. Crowe A, Knight CS, Jhala D, Bynon SJ, Jhala NC. Diagnosis of metastatic fibrolamellar hepatocellular carcinoma by endoscopic ultrasound-guided fine needle aspiration. Cytojournal 2011;8:2. Diagnostic Cytopathology, Vol. 00, No 00
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FALK ET AL. 25. Suster S, Moran CA. Applications and limitations of immunohistochemistry in the diagnosis of malignant mesothelioma. Adv Anat Pathol 2006;13:316–329. 26. Wang X, Mu Y, Dou J, et al. Medullar thyroid carcinoma in mediastinum initially presenting as ectopic ACTH syndrome. Neuroendocrinol Lett 2011;32:421–424. 27. de Perrot M, Spiliopoulos A, Fischer S, Totsch M, Keshavjee S. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome. Ann Thorac Surg 2002;73:675–681. 28. Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus—Experience with 12 patients over 25 years. J Clin Endocrinol Metab 2012;97:2223–2230.
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29. Cameron SE, Alsharif M, McKeon D, Pambuccian SE. Cytology of metastatic thymic well-differentiated neuroendocrine carcinoma (thymic carcinoid) in pleural fluid: Report of a case. Diagn Cytopathol 2008;36:333–337. 30. Shahani S, Nudelman RJ, Nalini R, Kim H, Samson SL. Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: A case report and review of the literature. Diagn Pathol 2010;5:56. 31. Morris LF, Harris RS, Milton DR, et al. Impact and timing of bilateral adrenalectomy for refractory adrenocorticotropic hormonedependent Cushing’s syndrome. Surgery 2013;156:1174–1183;discussion 83–84.
Adrenocorticotropic Hormone-Producing Thymic Neuroendocrine Carcinoma With Oncocytic Features: A Case Report and Review of Literature Nadja K. Falk, M.D.,1* Annikka Weissferdt, M.D., F.R.C.Path,1 Mouhammed A. Habra, M.D.,2 and Sinchita Roy-Chowdhuri, M.D.,
Thymic neuroendocrine carcinomas are the most common mediastinal neuroendocrine tumor. These malignancies are not often diagnosed by fine-needle aspiration (FNA), as they are more commonly diagnosed by biopsy or excision. We describe a case of a FNA of a paratracheal mass from a 38-year-old man who presented with Cushing syndrome. A low-grade neuroendocrine carcinoma with oncocytic features was diagnosed, which was later confirmed by excision of the thymus, anterior mediastinal and paratracheal soft tissue, and lymph nodes. Oncocytic features in these tumors are a rare finding and bring metastatic medullary thyroid carcinomas as well as other metastases into the differential diagnosis. The prognosis of neuroendocrine carcinomas in this location is worse than neuroendocrine carcinomas in other areas, and close follow-up is recommended. Diagn. Cytopathol. 2014;00:000–000. VC 2014 Wiley Periodicals, Inc. Key Words: oncocytic neuroendocrine carcinoma; fine-needle aspiration; thymus; cytology
Primary mediastinal neuroendocrine neoplasms encompass less than 5% of mediastinal tumors, the most common being thymic neuroendocrine carcinoma (TNC). These tumors are found predominantly in the anterosupe1 Cytopathology Section, Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 2 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. *Correspondence to: Nadja Falk, M.D., Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Unit # 53, Houston, TX 77030, USA. E-mail: [email protected] Received 22 April 2014; Revised 17 July 2014; Accepted 6 October 2014 DOI: 10.1002/dc.23209 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
C 2014 WILEY PERIODICALS, INC. V
1 Ph.D.
rior mediastinum and are more commonly seen in males in their 50s. Approximately, 25% of TNCs are functionally active and can be part of familial endocrine neoplasia syndrome type I. Adrenocorticotropic hormone (ACTH) secretion is associated with approximately one-third of these tumors and leads to Cushing syndrome.1–4
Case Findings A 38-year-old male presented with Cushing syndrome and was referred to our institution. He had a recent development of hypertension, type 2 diabetes mellitus and 70 pound weight gain with easy bruising and skin ulcers. On physical examination, abdominal striae, neck soft tissue swelling, severe bilateral lower extremity edema, and significant proximal muscle weakness were noted. He had elevated ACTH and 24-hour urinary free cortisol levels of 123 pg/mL (reference range < 46 pg/mL) and 112 microgram/24 hours (reference range 0–50 microgram/24 hours), respectively, with normal thyroid stimulating hormone and free T4 thyroxine levels. A pituitary MRI revealed no masses. An Indium 111 Octreotide whole body scan with SPECT/CT scan of the neck, chest, abdomen, and pelvis revealed a lobulated upper mediastinal mass with enlarged paratracheal and prevascular lymph nodes and no thyroid abnormailties. Metyrapone, a cortisol lowering therapy, was prescribed.
Materials and Methods and Results Cytology A fine-needle aspiration (FNA) of paratracheal soft tissue was performed by interventional radiology. On-site Diagnostic Cytopathology, Vol. 00, No 00
1
Diagnostic Cytopathology DOI 10.1002/dc
FALK ET AL.
immediate assessment was performed. Alcohol- fixed and air-dried smears were prepared and stained using Papanicolaou (Pap) and Diff-Quik (DQ) stains, respectively. Examination of aspirate material from the paratracheal soft tissue revealed highly cellular smears. The small to intermediate sized monotonous cells were arranged in loosely cohesive clusters and as single cells (Fig. 1A). The nuclei were round or oval, eccentrically placed, with finely granular “salt-and-pepper” chromatin, occasional prominent nucleoli, and abundant slightly granular cytoplasm (Fig. 1B). A cell block was made, and sections were stained with hematoxylin and eosin (H&E). Tumor cells with round or oval somewhat eccentrically placed nuclei, finely granular chromatin, occasional prominent nucleoli, and abundant oncocytic cytoplasm were seen (Fig. 1C). Immunohistochemical stains were performed on cell block sections, which showed tumor cells to be diffusely positive for CAM 5.2 (Fig. 2A), synaptophysin (Fig. 2B), chromogranin (Fig. 2C), and focally positive for ACTH (Fig. 2D). The proliferation index was 7% of tumor cells (Fig. 2E). Five months later and after three cycles of etoposide and cisplatin, the thymus was removed.
Histology The thymic mass measured 6.5 cm 3 4.5 cm 3 3.5 cm and had a pale pink homogeneous cut surface. At low magnification, the thymic tumor infiltrated into the surrounding adipose tissue. It was composed of nests of tumor cells surrounded by fibrovascular septa (Fig. 3A). The neoplastic cells were predominantly round with abundant cytoplasm and eccentrically placed round nuclei with finely granular chromatin and occasional nucleoli (Fig. 3B). The cytologic and histologic findings in this case were those of a well-differentiated TNC with oncocytic features as exhibited by the neuroendocrine nuclear features, absent mitoses, low proliferation index, and no surrounding necrosis.
Discussion Grossly, TNCs are an average diameter of 10 cm with a tan and homogeneous surface.3,5 Well differentiated TNC, which is the rarest type,5 histologically has an organoid architecture surrounded by thick fibrovascular septa. The cytologic smears are highly cellular and the small to medium sized monotonous cells are in groups or as single cells. The sometimes eccentric nuclei are uniformly round to oval with finely granular “salt and pepper” chromatin and indistinct nucleoli, however rare macronucleoli may be observed. There is a moderate amount of finely granular eosinophilic cytoplasm with well-defined cell borders.1–3,5–10 Rosettes, cytoplasmic inclusion-like paranuclear structures, spindle 2
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Fig. 1. Paratracheal fine-needle aspirate smear demonstrates loosely cohesive clusters and as single cells (Papanicolaou, 1003) (A) and cells with eccentric round to oval nuclei, granular chromatin, prominent nucleoli, and abundant cytoplasm (Papanicolaou, 4003) (B). Cell block section showing tumor cells with round or oval somewhat eccentrically placed nuclei, finely granular chromatin, occasional prominent nucleoli, and abundant oncocytic cytoplasm (H&E, 4003) (C). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
cells, and prominent capillaries have been reported, but were not appreciated in this case.5,7,8,11 Moderately-differentiated TNC is the most commonly seen sub-type. The smears show larger intact cells
Diagnostic Cytopathology DOI 10.1002/dc
ONCOCYTIC THYMIC NEUROENDOCRINE CARCINOMA
Fig. 2. Paratracheal fine-needle aspirate showing immunohistochemical positivity in tumor cells for CAM 5.2 (1003) (A), synaptophysin (1003) (B), chromogranin (1003) (C), ACTH (1003) (D), and a low Ki-67 proliferation index of approximately 7% of tumor cells (1003) (E). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
with smaller apoptotic cells. The nuclei have occasionally prominent nucleoli with more scant cytoplasm. Poorly-differentiated TNC has a loss of the organoid pattern histologically. Cytologically, small cell neuroendocrine carcinoma has small- to medium-sized cells with “molding” of nuclei and crush artifact. The nucleoli are inconspicuous. Large cell neuroendocrine carcinoma cells may have slightly more cytoplasm and prominent nucleoli. Additional features that may occasionally be seen include spindle cell features,
melanin pigment deposition, an angiectatic growth pattern, cystic features, extracellular mucin deposition, cytoplasmic lipid vacuoles, and oncocytic features.1–3,5,6,9,10,12 Histologic sections, or cell blocks, are used for mitotic counts as mitotic counts are not validated on cytologic smears.5 Similar to lung primaries, less than two, less than ten, and greater than ten mitoses per ten high power fields are seen in well-, moderately-, and poorly-differentiated neuroendocrine carcinomas, respectively. Increasing Diagnostic Cytopathology, Vol. 00, No 00
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Fig. 3. Histologic section of the thymic mass showing nests of tumor cells surrounded by fibrovascular septa (H&E, 403) (A) and tumor cells with eccentrically placed round nuclei with finely granular chromatin, occasional nucleoli, and abundant cytoplasm (H&E, 2003) (B). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
amounts of necrosis are also seen with moderately- and poorly-differentiated neuroendocrine carcinoma.1,2,5,10,13,14 Primary TNCs are usually positive for CAM5.2 lowmolecular weight cytokeratin. Approximately 60% of cases are positive for both synaptophysin and chromogranin. Neuron-specific enolase positivity may also be appreciated.1,3,15,16 Immature cell junctions and dense-core neurosecretory granules are seen ultrastructurally.17 The differential diagnosis of oncocytic TNC includes medullary thyroid carcinoma,1,14,16,18 thymoma,5,7,8,10,19 metastatic neuroendocrine neoplasms,20 metastatic carcinomas particularly kidney,21 breast,22 and hepatocellular carcinoma fibrolamellar variant,23,24 metastatic malignant melanoma,14,23 malignant mesothelioma,1,14,16,25 paraganglioma,14,23 parathyroid adenoma,14 and thyroid H€urthle cell neoplasms (Table I). The neoplastic cells of TNC may rarely be embedded in an eosinophilic amyloid-like stroma as in medullary thyroid carcinoma.2–4 The incidence of ectopic thyroid in the anterior mediastinum is 3–20% and a case of mediastinal medullary thyroid carcinoma presenting with ectopic adrenocorticotropic syndrome has been reported.26 Oncocytic neuroendocrine neoplasms are rare and could include thyroid, lung, larynx, stomach, parathyroid, pituitary, and pancreatic primaries, which can also be hormonally active.20 Oncocytic renal neoplasms include oncocytoma, chromophobe renal cell carcinoma, and clear cell renal cell carcinoma.21 Metastatic oncocytic breast carcinomas include lobular and apocrine carcinomas.22 Thirty percent of TNCs are associated with endocrinopathies.27–29 In their study of 22 cases of primary TNCs
Table I. Comparison of Clinical Presentation, Cytologic Findings, and Positively Staining Immunohistochemical Profile of Thymic Neuroendocrine Carcinoma and the Differential Diagnosis Neoplasm Thymic Neuroendocrine Carcinoma Medullary Thyroid Carcinoma
Thymoma Metastatic Hepatocellular Carcinoma, Fibrolamellar Variant Metastatic Malignant Melanoma Malignant Mesothelioma Paraganglioma
Parathyroid Adenoma
4
Distinguishing clinical and cytologic findings
Positive immunohistochemical stains
Male > female; 6th decade Monotonous cell groups or single cells, eccentric nucleoli, “salt and pepper” chromatin, eosinophilic cytoplasm Sporadic (average age 50 years) or hereditary (younger, autosomal dominant) Oncocytic epithelioid or spindle cells, red cytoplasmic granules, amyloid Lymphocytes and epithelial cells (varying amounts and morphology depending on type) Young patients without cirrhosis Large eosinophilic polygonal cells with prominent nucleoli, cytoplasmic “pale bodies” and bile pigment; hyalinized fibrous tissue bands Dyshesive cells with eccentric nuclei with occasional intranuclear inclusions, prominent nucleoli, multinucleation and melanin pigment Female > male; 6th–7th decade Epithelioid, spindle or biphasic cells; cell clusters with “knobby” edges; “windows” between cells Epithelioid, spindle and ganglion cells with “salt and pepper” chromatin and cytoplasmic hyaline globules; loose cell clusters (Zellballen) surrounded by sustentacular cells Round nuclei, coarsely granular chromatin, moderately abundant granular cytoplasm
Cytokeratin CAM 5.2, synaptophysin, chromogranin, neuron specific enolase
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Cyokeratin, calcitonin, carcinoembryonic antigen, chromogranin, thyroid transcription factor-1 Cytokeratin 5/6 and p63 (epithelial cells) Arginase-1, glypican-3, hep-par 1
S-100, HMB-45, mart-1, melan-A CD 5/6, calretinin, wilms tumor 1, thrombomodulin, podoplanin, D2–40 Chromogranin, synaptophysin, S-100 (sustentacular cells) Parathyroid hormone
Diagnostic Cytopathology DOI 10.1002/dc
ONCOCYTIC THYMIC NEUROENDOCRINE CARCINOMA
with oncocytic features, Moran and Suster found one case to be associated with Cushing syndrome. Most of the cases were well-differentiated, and the association with Cushing syndrome did not alter the tumor behavior.16 Patients with TNC associated with paraneoplastic syndromes have a 65% 5-year mortality rate as opposed to 35% in non-syndromic patients.4 Serum hormone levels and immunohistochemical findings may not always correlate.30 When TNC is associated with Cushing syndrome, medical management should be attempted before bilateral adrenalectomy is performed.17,28,31 The initial treatment for TNC is thymectomy with mediastinal lymph node sampling. A median sternotomy may be indicated for aggressive local resection. The use of and timing of radiation and chemotherapy is controversial.17,28,31 This patient received neoadjuvant chemotherapy with etoposide and cisplatin, which ended two months prior to his tumor resection. The primary mass grew slightly, however, the morphology of the tumor was unchanged without increased mitoses or necrosis. His postoperative course was complicated by aspiration pneumonia and the development of a seroma in the soft tissue of his neck. Eventually his steroids were weaned, and he was discharged one month post-operatively. The prognosis of TNC is worse than similar tumors in other locations. Intermediate and poorly differentiated TNCs have a progressively worse prognosis than the welldifferentiated tumors, and the poorly differentiated TNCs have a 65% 10-year mortality rate.8 Approximately 90% of patients with poorly differentiated TNCs die from the disease, and the median survival is 15 months with or without treatment. Metastases have been seen most frequently in lymph nodes, lungs, and bone.2–4,17,29 TNCs rarely cause metastatic effusions where similar features to FNA are seen.29 Close follow-up with metastatic workup every 6–12 months is recommended for up to 10 years.2–4,17,29 This case is unique in that the cytopathologist made the initial diagnosis of this patient’s well-differentiated TNC as the first tissue diagnosis is commonly made from CT-guided core needle biopsies instead.5 Interesting findings in this case included the presentation with Cushing syndrome and prominent oncocytic cytologic features. The pathologist must consider various primary and metastatic neoplasms. Recognizing TNC is paramount, due to the poor prognosis when compared to other sites of primary neuroendocrine carcinoma, particularly when the tumor is associated with paraneoplastic syndromes.
References 1. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000;114:100–110. 2. Suster S, Moran CA. Neuroendocrine neoplasms of the mediastinum. Am J Clin Pathol 2001;115 (Suppl):S17–S27.
3. Moran CA. Primary neuroendocrine carcinomas of the mediastinum: Review of current criteria for histopathologic diagnosis and classification. Semin Diagn Pathol 2005;22:223–229. 4. Ruffini E, Oliaro A, Novero D, Campisi P, Filosso PL. Neuroendocrine tumors of the thymus. Thorac Surg Clin 2011;21:13–23. 5. Wakely PE, Jr. Fine needle aspiration in the diagnosis of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008;22:433– 442. 6. Kalhor N, Moran CA. Mediastinal neuroendocrine tumours. Diagn Histopathol 2010;16:237–242. 7. Wang DY, Kui SH, Chang DB, et al. Fine needle aspiration cytology of thymic carcinoid tumor. Acta Cytol 1995:434–427. 8. Nichols GL, Jr, Hopkins MB, III, Geisinger KR. Thymic carcinoid. Reports of a case with diagnosis by fine needle aspiration biopsy. Acta Cytol 1997;41:1839–1844. 9. Wakely PE, Jr. Cytopathology–histopathology of the mediastinum II. Mesenchymal, neural, and neuroendocrine neoplasms. Ann Diagn Pathol 2005;9:24–32. 10. Wakely PE, Jr. Cytopathology of thymic epithelial neoplasms. Semin Diagn Pathol 2005;22:213–222. 11. Gherardi G, Marveggio C, Placidi A. Neuroendocrine carcinoma of the thymus: Aspiration biopsy, immunocytochemistry, and clinicopathologic correlates. Diagn Cytopathol 1995;12:158–164. 12. Smith NL, Finley JL. Lipid-rich carcinoid tumor of the thymus gland: Diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 2001;25:130–133. 13. DeMay RM. Mediastinum. In: The art and science of cytopathology. 2nd ed. Chicago: American Society for Clinical Pathology; 2012. p 1218–1248. 14. Cibas ES, Ducatman BS. Cytology diagnostic principles and clinical correlates. 3rd edition. Philadelphia: Saunders Elsevier; 2009. 537 p. 15. Hallmann RS, Schneeweiss LG, Correa E, Zamora J. Fine needle aspiration biopsy of thymic carcinoid tumor: A case with immunocytochemical correlation. Acta Cytol 1998;42:1042–1043. 16. Moran CA, Suster S. Primary neuroendocrine carcinoma (thymic carcinoid) of the thymus with prominent oncocytic features: A clinicopathologic study of 22 cases. Mod Pathol 2000;13:489–494. 17. Chaer R, Massad MG, Evans A, Snow NJ, Geha AS. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg 2002;74:1733– 1740. 18. Pusztaszeri MP, Bongiovanni M, Faquin WC. Update on the cytologic and molecular features of medullary thyroid carcinoma. Adv Anat Pathol 2014;21:26–35. 19. Renshaw AA, Haja JC, Neal MH, Wilbur DC, Cytopathology Resource Committee CoAP. Distinguishing carcinoid tumor of the mediastinum from thymoma: Correlating cytologic features and performance in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. Arch Pathol Lab Med 2006;130:1612–1615. 20. Volante M, La Rosa S, Castellano I, Finzi G, Capella C, Bussolati G. Clinico-pathological features of a series of 11 oncocytic endocrine tumours of the pancreas. Virchows Arch 2006;448:545–551. 21. Abrahams NA, Tamboli P. Oncocytic renal neoplasms: Diagnostic considerations. Clin Lab Med 2005;25:317–339, vi. 22. Damiani S, Dina R, Eusebi V. Eosinophilic and granular cell tumors of the breast. Semin Diagn Pathol 1999;16:117–125. 23. Sarode VR, Castellani R, Post A. Fine-needle aspiration cytology and differential diagnoses of fibrolamellar hepatocellular carcinoma metastatic to the mediastinum: Case report. Diagn Cytopathol 2002; 26:95–98. 24. Crowe A, Knight CS, Jhala D, Bynon SJ, Jhala NC. Diagnosis of metastatic fibrolamellar hepatocellular carcinoma by endoscopic ultrasound-guided fine needle aspiration. Cytojournal 2011;8:2. Diagnostic Cytopathology, Vol. 00, No 00
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FALK ET AL. 25. Suster S, Moran CA. Applications and limitations of immunohistochemistry in the diagnosis of malignant mesothelioma. Adv Anat Pathol 2006;13:316–329. 26. Wang X, Mu Y, Dou J, et al. Medullar thyroid carcinoma in mediastinum initially presenting as ectopic ACTH syndrome. Neuroendocrinol Lett 2011;32:421–424. 27. de Perrot M, Spiliopoulos A, Fischer S, Totsch M, Keshavjee S. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome. Ann Thorac Surg 2002;73:675–681. 28. Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus—Experience with 12 patients over 25 years. J Clin Endocrinol Metab 2012;97:2223–2230.
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29. Cameron SE, Alsharif M, McKeon D, Pambuccian SE. Cytology of metastatic thymic well-differentiated neuroendocrine carcinoma (thymic carcinoid) in pleural fluid: Report of a case. Diagn Cytopathol 2008;36:333–337. 30. Shahani S, Nudelman RJ, Nalini R, Kim H, Samson SL. Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: A case report and review of the literature. Diagn Pathol 2010;5:56. 31. Morris LF, Harris RS, Milton DR, et al. Impact and timing of bilateral adrenalectomy for refractory adrenocorticotropic hormonedependent Cushing’s syndrome. Surgery 2013;156:1174–1183;discussion 83–84.
