S P E C I A L C l i n i c a l
C a s e
F E A T U R E S e m i n a r
Von Hippel-Lindau Disease Associated Pulmonary Carcinoid with Cranial Metastasis Chao Zhang,* Andrew I. Yang,* Lucas Vasconcelos, Seog Moon, Chunzhang Yang, Cody L. Nesvick, Lola Saidkhodjaeva, Ziedulla Abdullaev, Svetlana D. Pack, Arunima Ghosh, Prashant Chittiboina, John D. Heiss, Zhengping Zhuang, Martha M. Quezado, and Kareem A. Zaghloul Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (C.Z., A.I.Y., C.Y., C.L.N., P.C., J.D.H., Z.Z., K.A.Z.), and Laboratory of Pathology, National Cancer Institute (L.V., S.M., L.S., Z.A., S.D.P., A.G., M.M.Q.), National Institutes of Health, Bethesda, Maryland 20892; and Department of Orthopedics (C.Z.), Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China
Context: Carcinoids have rarely been described in von Hippel-Lindau (VHL) disease. Objective: We describe the first reported case of a patient with VHL who developed a pulmonary carcinoid that subsequently metastasized to a pre-existent cranial hemangioblastoma. Results: Histological and immunohistochemical features of the metastatic lesion were similar to the primary carcinoid. Both lesions demonstrated heterozygous VHL gene deletions with fluorescence in situ hybridization analysis. Conclusions: This case provides direct molecular genetic evidence of an association between VHL and carcinoids. (J Clin Endocrinol Metab 99: 2633–2636, 2014)
on Hippel-Lindau (VHL) disease is an autosomaldominant, familial disorder in which affected individuals are predisposed to develop a variety of tumors in multiple organ systems, with an incidence of 1 in 36 000 of all live births (1). It is caused by a germline mutation in the VHL tumor suppressor gene located on chromosome 3p25, which encodes for the VHL protein (pVHL) (2). pVHL plays a central role in the mammalian oxygen-sensing pathway through ubiquitination of hypoxia-inducible factors (HIFs) (3). Dysregulation of this pathway, leading to stabilization of HIFs and transcriptional activation of their target genes, plays a key role in tumorigenesis and angiogenesis (4). Frequently reported VHL-associated tumors include craniospinal and retinal hemangioblastomas (HBs), pancreatic tumors/cysts, renal cell carcinomas/ cysts, pheochromocytomas, endolymphatic sac tumors, and broad ligament/epididymal cystadenomas (5). Carcinoids are rare tumors derived from enterochromaffin cells, and therefore can be found distributed widely
V
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received March 13, 2014. Accepted May 13, 2014. First Published Online May 30, 2014
doi: 10.1210/jc.2014-1732
in the body. Annual incidence is 2 cases in 100 000 people, with the most common primary sites being the gastrointestinal (60%) and bronchopulmonary tracts (25%) (6). Carcinoid tumors of the gallbladder or the biliary tree have been described in VHL disease, but there has been no evidence demonstrating a link between VHL gene mutations and carcinoids (7–10). Here, we report a case of primary carcinoid in the lungs, with secondary metastasis to a pre-existent cranial hemangioblastoma, and provide genetic evidence of a causal association between the carcinoid and VHL.
Case Report The study was conducted in accordance with a National Institutes of Health Institutional Review Board-approved protocol, and informed consent was obtained from the subject. History and examination The patient is a 30-year-old white male with VHL disease diagnosed based on family history and genetic testing * C.Z. and A.I.Y. contributed equally. Abbreviations: CT, computed tomography; FISH, fluorescence in situ hybridization; HB, hemangioblastoma; H&E, hematoxylin and eosin; HIF, hypoxia-inducible factor; pVHL, VHL protein; VHL, von Hippel-Lindau.
J Clin Endocrinol Metab, August 2014, 99(8):2633–2636
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VHL-Associated Carcinoid
J Clin Endocrinol Metab, August 2014, 99(8):2633–2636
Figure 1. Contrast-enhanced CT image of the chest in the axial plane (A) demonstrates a 2.2cm enhancing lesion (Ca) within the right lower lobe, adjacent to the interlobar artery (I), and with mass effect on the distal bronchus intermedius (Bi) and proximal lower lobe bronchus (L). Contrast-enhanced T1-weighted magnetic resonance image of the brain in the axial plane reveals a 3.5-mm, enhancing lesion in the obex (B) found incidentally at age 19. This lesion had grown to 5 mm (C) by age 27, at the time of surgical resection of the primary lung carcinoid. Images in axial (D) and sagittal planes (E), immediately before surgical resection of the obex lesion at age 30, demonstrate its rapid growth (13 mm), with surrounding edema within the dorsal brainstem and cervical spine and an internal cyst. H&E staining of the obex lesion (F) shows the presence of a HB with an encased carcinoid. Scale bar ⫽ 10 m.
at age 16. At that time he was treated for retinal HBs with laser photocoagulation and subsequently underwent a left and right partial adrenalectomy for bilateral pheochromocytomas at ages 23 and 29, respectively. He had been followed for asymptomatic HBs of the obex (3.5 mm; Figure 1B) and right cerebellar tonsil (⬍1 mm) that were incidentally found on magnetic resonance imaging at ages 19 and 22, respectively. At age 27, the patient presented with a 6-month history of worsening hemoptysis. Computed tomography (CT) of the chest revealed an enhancing lesion with mass effect on the right lower lobe bronchus (Figure 1A). Further evaluation with bronchoscopy demonstrated a friable, multilobulated, polypoid lesion within the right lower lobe bronchus. Operative findings indicated extension of the peribronchial components of the tumor to the right middle lobe bronchus. The patient was treated with complete resection of the right middle and right lower lobes. Pathological diagnosis of the lesion was well-differentiated (typical) carcinoid with regional lymph node metastasis (one of four lymph nodes). No further evidence of recurrence or metastasis was identified during follow-up. At the time of surgical resection of the lung carcinoid, the obex HB measured 5 mm (Figure 1C). At age 30, the patient presented for routine follow-up with complaints of occasional dysphagia on swallowing
pills. He was neurologically intact at this time and exhibited no focal deficits. Magnetic resonance imaging demonstrated significant enlargement of the obex HB, now measuring 13 mm in its maximum diameter, with development of an internal cyst and surrounding edema of the dorsal brainstem and cervical spine (Figure 1, D and E). CT of the chest, abdomen, and pelvis did not demonstrate any other pathology. Based on his symptoms and the rapid expansion of the lesion, surgical resection of the obex HB was recommended. The patient underwent a suboccipital craniectomy and C1 laminectomy for en bloc resection of the obex lesion, and underwent an uneventful recovery.
Pathological findings The gross surgical specimen from the brain was a spherical, red-pink nodule measuring 1.6 ⫻ 1.5 ⫻ 1.5 cm. Bisection revealed a soft, heterogeneous, tan-pink, hemorrhagic, cystic surface. Hematoxylin and eosin (H&E) staining demonstrated the presence of both a HB and a neuroendocrine tumor (Figure 1F). The HB was composed of stromal cells with vacuolated cytoplasm, contained many congested vessels, and stained positive for inhibin and neuron-specific enolase (data not shown). The encased neuroendocrine tumor had cells arranged in nests and tubules with salt-and-pepper nuclei, characteristic of a well-differentiated neuroendocrine, and stained positive for chromogranin and thyroid transcription factor-1 (Figure 2, A, C, and E). The neuroendocrine tumor shared similar histological and immunohistochemical features with the previously resected typical carcinoid of the lungs (Figure 2, B, D, and F). Genetic testing of the metastatic carcinoid upon resection revealed mutation of the VHL gene (Tyr98His, cDNA 292T⬎C) (Figure 3A). Tumor specimens were also evaluated for abnormalities of the VHL gene using fluorescence in situ hybridization (FISH) (11). The primary lung carcinoid (Figure 3C), metastatic brain carcinoid (Figure 3D), HB (Figure 3E), and pheochromocytomas (Figure 3F) all demonstrated heterozygous deletions of the VHL gene.
Discussion There are only four reported cases of carcinoid tumors arising in patients with VHL, which were located in the
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doi: 10.1210/jc.2014-1732
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In our patient, an obex HB was found incidentally at age 19 (3.5 mm) and grew slowly until age 27 (5 mm), at which time the lung carcinoid was identified and resected. In the subsequent 3 years, the HB grew rapidly from 5 to 13 mm. Histopathology demonstrated a brainstem lesion consisting of both HB (periphery) and carcinoid (central) elements. The carcinoid shared similar histopathological features with the previously resected lung carcinoid, providing strong evidence that it represented metastasis from the primary. The only tumor type that has been previously reported to metastasize to craniospinal HBs is VHL-associated renal cell carcinomas (14). In general, tumor types that represent the most common recipients in cases of tumor-to-tumor metastasis, such as meningiomas and renal cell carcinomas, are characterized by high vascularity, an indolent slowgrowing nature, and high glycogen content, all of which also characterize HBs (14 –16). Moreover, much like renal cell carcinomas, the carciFigure 2. Both HB and carcinoid were present within the obex lesion (A). The brain carcinoid noid in this case may have shared a shared similar histological features to the previously resected lung carcinoid (B). In both similar propensity to metastasize specimens, H&E staining showed cells arranged in nests and tubules with salt-and-pepper nuclei, into HBs. consistent with carcinoid. The HB was composed of stromal cells with vacuolated cytoplasm and The tumor suppressor protein was rich in congested vessels. The brain carcinoid was positive for chromogranin (C) and thyroid transcription factor-1 (E), as was the case for the previously resected lung carcinoid (D and F). pVHL is the substrate-recognizing Scale bars ⫽ 10 m. component of the E3 ubiquitin ligase complex (3), which ubiquitinates gallbladder, biliary tree, or at an unknown primary site HIFs in normoxia, leading to their rapid degradation with hepatic metastasis (7–10). To our knowledge, this is through the ubiquitin-proteasome pathway (17). The the first report of a primary lung carcinoid with metastasis identified mutation of the VHL gene (Tyr98His, cDNA into the brain, more specifically a pre-existent cranial he292T⬎C) is a loss-of-function mutation that disrupts inmangioblastoma, in a patient with VHL disease. Typical teraction between pVHL and its substrate HIF-␣, promotcarcinoids of the lungs, as in our case, are generally indolent. The associated frequency of metastasis is less than ing tumor growth and development through up-regula15%, with the most common sites being regional lymph tion of the downstream products of HIFs (18). Previous studies have demonstrated that VHL-associnodes, liver, bone, and skin (6). A pulmonary primary site ated tumors demonstrate loss of heterozygosity (5), as preaccounts for most intracranial metastases, but metastatic intracranial carcinoids are in general highly unusual, with dicted by the two-hit hypothesis of tumorigenesis (19). In an incidence of 1.5% among patients with primary car- these tumors, an allele with an inherited germline mutacinoids of any site, and occur with a highly variable time tion and deletion of the second wild-type allele are idencourse (12). Patients with intracranial metastases experi- tifiable. In the present case, FISH demonstrated allelic deence a worse prognosis than those with extracranial me- letions of the VHL gene not only in the VHL-associated tastases, with reported 1-year survival rates ranging from HB and pheochromocytomas, but also in the primary and 33 to 42% and a median survival of 7–19 months (12, 13). metastatic carcinoids. Although carcinoids may have sim-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 02 September 2014. at 01:36 For personal use only. No other uses without permission. . All rights reserved.
2636
Zhang et al
VHL-Associated Carcinoid
J Clin Endocrinol Metab, August 2014, 99(8):2633–2636
References 1. Maher ER, Iselius L, Yates JR, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28:443– 447. 2. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260:1317–1320. 3. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the -domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000;2:423– 427. 4. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991–5004. Figure 3. Genetic testing of the metastatic carcinoid (A) reveals heterozygous mutation of the 5. Lonser RR, Glenn GM, Walther M, et al. VHL gene (Tyr98His, cDNA 292T⬎C; arrow). B, Healthy control. Heterozygous VHL gene von Hippel-Lindau disease. Lancet. deletions (arrows) detected by FISH during metaphase in the primary lung carcinoid (C), 2003;361:2059 –2067. metastatic brain carcinoid (D), HB (E), and pheochromocytoma (F). The ␣-satellite centromeric 6. Kulke MH, Mayer RJ. Carcinoid tumors. marker (CEP3, green) is a specific marker for chromosome 3, whereas the chromosome 3p25.3 N Engl J Med. 1999;340:858 – 868. BCA probe (red) marks the VHL gene. Tumor cells show one red signal, in contrast to two red 7. Fellows IW, Leach IH, Smith PG, Toghill signals in normal somatic cells. Scale bars ⫽ 1 m. PJ, Doran J. Carcinoid tumour of the common bile duct–a novel complication of von Hippel-Lindau syndrome. Gut. 1990;31:728 –729. ilar histological cell components to those observed in 8. Nafidi O, Nguyen BN, Roy A. Carcinoid tumor of the common bile VHL-associated pancreatic neuroendocrine tumors (20), duct: a rare complication of von Hippel-Lindau syndrome. World J Gastroenterol. 2008;14:1299 –1301. it is not known whether an association exists between 9. Sinkre PA, Murakata L, Rabin L, Hoang MP, Albores-Saavedra J. VHL gene mutations and the development of carcinoid Clear cell carcinoid tumor of the gallbladder: another distinctive tumors. The heterozygous allelic deletions demonstrated manifestation of von Hippel-Lindau disease. Am J Surg Pathol. 2001;25:1334 –1339. in the primary lung and metastatic brain carcinoids pro10. Kees A. Malignant carcinoid and phaeochromocytoma in von-Hipvide genetic evidence for a possible role of the VHL gene pel-Lindau’s disease–a case report [in German]. Wien Klin Wochenin the pathogenesis of carcinoids. schr. 1980;92:218 –221. 11. Pack SD, Zhuang Z. Fluorescence in situ hybridization: application in cancer research and clinical diagnostics. Methods Mol Med. 2001; 50:35–50. 12. Hlatky R, Suki D, Sawaya R. Carcinoid metastasis to the brain. Acknowledgments Cancer. 2004;101:2605–2613. 13. Mallory GW, Fang S, Giannini C, Van Gompel JJ, Parney IF. Brain We thank Dr Mark Lega for support and advice. carcinoid metastases: outcomes and prognostic factors. J Neurosurg. 2013;118:889 – 895. Address all correspondence and requests for reprints to: Ka14. Mottolese C, Stan H, Giordano F, Frappaz D, Alexei D, Streichenreem A. Zaghloul, MD, PhD, Surgical Neurology Branch, Naberger N. Metastasis of clear-cell renal carcinoma to cerebellar hemangioblastoma in von Hippel Lindau disease: rare or not investitional Institute of Neurological Disorders and Stroke, National gated? Acta Neurochir (Wien). 2001;143(10):1059 –1063. Institutes of Health, Building 10, Room 3D20, 10 Center Drive, 15. Caroli E, Salvati M, Giangaspero F, Ferrante L, Santoro A. IntraBethesda, MD 20892–1414. E-mail: [email protected]. meningioma metastasis as first clinical manifestation of occult priOr, Martha M. Quezado, MD, Laboratory of Pathology, Namary breast carcinoma. Neurosurg Rev. 2006;29(1):49 –54. tional Cancer Institute, National Institutes of Health, Building 16. Sella A, Ro JY. Renal cell cancer: best recipient of tumor-to-tumor 10, Room 2A10, 10 Center Drive, Bethesda, MD 20892–1414. metastasis. Urology. 1987;30(1):35–38. 17. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducE-mail: [email protected]. ible factor 1␣ is mediated by an O2-dependent degradation domain A.I.Y. is supported through the National Institutes of Health via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA. (NIH) Medical Research Scholars Program, a public-private 1998;95:7987–7992. partnership supported jointly by the NIH and generous contri18. Stebbins CE, Kaelin WG Jr, Pavletich NP. Structure of the VHLbutions to the Foundation for the NIH from Pfizer Inc, The Doris ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284:455– 461. Duke Charitable Foundation, The Alexandria Real Estate Eq19. Knudson AG. Hereditary cancer, oncogenes, and antioncogenes. uities Inc and Mr and Mrs Joel S. Marcus, and the Howard Cancer Res. 1985;45:1437–1443. Hughes Medical Institute. 20. Lubensky IA, Pack S, Ault D, et al. Multiple neuroendocrine tumors Disclosure Summary: The authors report no conflict of inof the pancreas in von Hippel-Lindau disease patients: histopathoterest concerning the materials or methods used in this study or logical and molecular genetic analysis. Am J Pathol. 1998;153:223– the findings specified in this paper. 231.
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C a s e
F E A T U R E S e m i n a r
Von Hippel-Lindau Disease Associated Pulmonary Carcinoid with Cranial Metastasis Chao Zhang,* Andrew I. Yang,* Lucas Vasconcelos, Seog Moon, Chunzhang Yang, Cody L. Nesvick, Lola Saidkhodjaeva, Ziedulla Abdullaev, Svetlana D. Pack, Arunima Ghosh, Prashant Chittiboina, John D. Heiss, Zhengping Zhuang, Martha M. Quezado, and Kareem A. Zaghloul Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (C.Z., A.I.Y., C.Y., C.L.N., P.C., J.D.H., Z.Z., K.A.Z.), and Laboratory of Pathology, National Cancer Institute (L.V., S.M., L.S., Z.A., S.D.P., A.G., M.M.Q.), National Institutes of Health, Bethesda, Maryland 20892; and Department of Orthopedics (C.Z.), Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China
Context: Carcinoids have rarely been described in von Hippel-Lindau (VHL) disease. Objective: We describe the first reported case of a patient with VHL who developed a pulmonary carcinoid that subsequently metastasized to a pre-existent cranial hemangioblastoma. Results: Histological and immunohistochemical features of the metastatic lesion were similar to the primary carcinoid. Both lesions demonstrated heterozygous VHL gene deletions with fluorescence in situ hybridization analysis. Conclusions: This case provides direct molecular genetic evidence of an association between VHL and carcinoids. (J Clin Endocrinol Metab 99: 2633–2636, 2014)
on Hippel-Lindau (VHL) disease is an autosomaldominant, familial disorder in which affected individuals are predisposed to develop a variety of tumors in multiple organ systems, with an incidence of 1 in 36 000 of all live births (1). It is caused by a germline mutation in the VHL tumor suppressor gene located on chromosome 3p25, which encodes for the VHL protein (pVHL) (2). pVHL plays a central role in the mammalian oxygen-sensing pathway through ubiquitination of hypoxia-inducible factors (HIFs) (3). Dysregulation of this pathway, leading to stabilization of HIFs and transcriptional activation of their target genes, plays a key role in tumorigenesis and angiogenesis (4). Frequently reported VHL-associated tumors include craniospinal and retinal hemangioblastomas (HBs), pancreatic tumors/cysts, renal cell carcinomas/ cysts, pheochromocytomas, endolymphatic sac tumors, and broad ligament/epididymal cystadenomas (5). Carcinoids are rare tumors derived from enterochromaffin cells, and therefore can be found distributed widely
V
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received March 13, 2014. Accepted May 13, 2014. First Published Online May 30, 2014
doi: 10.1210/jc.2014-1732
in the body. Annual incidence is 2 cases in 100 000 people, with the most common primary sites being the gastrointestinal (60%) and bronchopulmonary tracts (25%) (6). Carcinoid tumors of the gallbladder or the biliary tree have been described in VHL disease, but there has been no evidence demonstrating a link between VHL gene mutations and carcinoids (7–10). Here, we report a case of primary carcinoid in the lungs, with secondary metastasis to a pre-existent cranial hemangioblastoma, and provide genetic evidence of a causal association between the carcinoid and VHL.
Case Report The study was conducted in accordance with a National Institutes of Health Institutional Review Board-approved protocol, and informed consent was obtained from the subject. History and examination The patient is a 30-year-old white male with VHL disease diagnosed based on family history and genetic testing * C.Z. and A.I.Y. contributed equally. Abbreviations: CT, computed tomography; FISH, fluorescence in situ hybridization; HB, hemangioblastoma; H&E, hematoxylin and eosin; HIF, hypoxia-inducible factor; pVHL, VHL protein; VHL, von Hippel-Lindau.
J Clin Endocrinol Metab, August 2014, 99(8):2633–2636
jcem.endojournals.org
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2633
2634
Zhang et al
VHL-Associated Carcinoid
J Clin Endocrinol Metab, August 2014, 99(8):2633–2636
Figure 1. Contrast-enhanced CT image of the chest in the axial plane (A) demonstrates a 2.2cm enhancing lesion (Ca) within the right lower lobe, adjacent to the interlobar artery (I), and with mass effect on the distal bronchus intermedius (Bi) and proximal lower lobe bronchus (L). Contrast-enhanced T1-weighted magnetic resonance image of the brain in the axial plane reveals a 3.5-mm, enhancing lesion in the obex (B) found incidentally at age 19. This lesion had grown to 5 mm (C) by age 27, at the time of surgical resection of the primary lung carcinoid. Images in axial (D) and sagittal planes (E), immediately before surgical resection of the obex lesion at age 30, demonstrate its rapid growth (13 mm), with surrounding edema within the dorsal brainstem and cervical spine and an internal cyst. H&E staining of the obex lesion (F) shows the presence of a HB with an encased carcinoid. Scale bar ⫽ 10 m.
at age 16. At that time he was treated for retinal HBs with laser photocoagulation and subsequently underwent a left and right partial adrenalectomy for bilateral pheochromocytomas at ages 23 and 29, respectively. He had been followed for asymptomatic HBs of the obex (3.5 mm; Figure 1B) and right cerebellar tonsil (⬍1 mm) that were incidentally found on magnetic resonance imaging at ages 19 and 22, respectively. At age 27, the patient presented with a 6-month history of worsening hemoptysis. Computed tomography (CT) of the chest revealed an enhancing lesion with mass effect on the right lower lobe bronchus (Figure 1A). Further evaluation with bronchoscopy demonstrated a friable, multilobulated, polypoid lesion within the right lower lobe bronchus. Operative findings indicated extension of the peribronchial components of the tumor to the right middle lobe bronchus. The patient was treated with complete resection of the right middle and right lower lobes. Pathological diagnosis of the lesion was well-differentiated (typical) carcinoid with regional lymph node metastasis (one of four lymph nodes). No further evidence of recurrence or metastasis was identified during follow-up. At the time of surgical resection of the lung carcinoid, the obex HB measured 5 mm (Figure 1C). At age 30, the patient presented for routine follow-up with complaints of occasional dysphagia on swallowing
pills. He was neurologically intact at this time and exhibited no focal deficits. Magnetic resonance imaging demonstrated significant enlargement of the obex HB, now measuring 13 mm in its maximum diameter, with development of an internal cyst and surrounding edema of the dorsal brainstem and cervical spine (Figure 1, D and E). CT of the chest, abdomen, and pelvis did not demonstrate any other pathology. Based on his symptoms and the rapid expansion of the lesion, surgical resection of the obex HB was recommended. The patient underwent a suboccipital craniectomy and C1 laminectomy for en bloc resection of the obex lesion, and underwent an uneventful recovery.
Pathological findings The gross surgical specimen from the brain was a spherical, red-pink nodule measuring 1.6 ⫻ 1.5 ⫻ 1.5 cm. Bisection revealed a soft, heterogeneous, tan-pink, hemorrhagic, cystic surface. Hematoxylin and eosin (H&E) staining demonstrated the presence of both a HB and a neuroendocrine tumor (Figure 1F). The HB was composed of stromal cells with vacuolated cytoplasm, contained many congested vessels, and stained positive for inhibin and neuron-specific enolase (data not shown). The encased neuroendocrine tumor had cells arranged in nests and tubules with salt-and-pepper nuclei, characteristic of a well-differentiated neuroendocrine, and stained positive for chromogranin and thyroid transcription factor-1 (Figure 2, A, C, and E). The neuroendocrine tumor shared similar histological and immunohistochemical features with the previously resected typical carcinoid of the lungs (Figure 2, B, D, and F). Genetic testing of the metastatic carcinoid upon resection revealed mutation of the VHL gene (Tyr98His, cDNA 292T⬎C) (Figure 3A). Tumor specimens were also evaluated for abnormalities of the VHL gene using fluorescence in situ hybridization (FISH) (11). The primary lung carcinoid (Figure 3C), metastatic brain carcinoid (Figure 3D), HB (Figure 3E), and pheochromocytomas (Figure 3F) all demonstrated heterozygous deletions of the VHL gene.
Discussion There are only four reported cases of carcinoid tumors arising in patients with VHL, which were located in the
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doi: 10.1210/jc.2014-1732
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2635
In our patient, an obex HB was found incidentally at age 19 (3.5 mm) and grew slowly until age 27 (5 mm), at which time the lung carcinoid was identified and resected. In the subsequent 3 years, the HB grew rapidly from 5 to 13 mm. Histopathology demonstrated a brainstem lesion consisting of both HB (periphery) and carcinoid (central) elements. The carcinoid shared similar histopathological features with the previously resected lung carcinoid, providing strong evidence that it represented metastasis from the primary. The only tumor type that has been previously reported to metastasize to craniospinal HBs is VHL-associated renal cell carcinomas (14). In general, tumor types that represent the most common recipients in cases of tumor-to-tumor metastasis, such as meningiomas and renal cell carcinomas, are characterized by high vascularity, an indolent slowgrowing nature, and high glycogen content, all of which also characterize HBs (14 –16). Moreover, much like renal cell carcinomas, the carciFigure 2. Both HB and carcinoid were present within the obex lesion (A). The brain carcinoid noid in this case may have shared a shared similar histological features to the previously resected lung carcinoid (B). In both similar propensity to metastasize specimens, H&E staining showed cells arranged in nests and tubules with salt-and-pepper nuclei, into HBs. consistent with carcinoid. The HB was composed of stromal cells with vacuolated cytoplasm and The tumor suppressor protein was rich in congested vessels. The brain carcinoid was positive for chromogranin (C) and thyroid transcription factor-1 (E), as was the case for the previously resected lung carcinoid (D and F). pVHL is the substrate-recognizing Scale bars ⫽ 10 m. component of the E3 ubiquitin ligase complex (3), which ubiquitinates gallbladder, biliary tree, or at an unknown primary site HIFs in normoxia, leading to their rapid degradation with hepatic metastasis (7–10). To our knowledge, this is through the ubiquitin-proteasome pathway (17). The the first report of a primary lung carcinoid with metastasis identified mutation of the VHL gene (Tyr98His, cDNA into the brain, more specifically a pre-existent cranial he292T⬎C) is a loss-of-function mutation that disrupts inmangioblastoma, in a patient with VHL disease. Typical teraction between pVHL and its substrate HIF-␣, promotcarcinoids of the lungs, as in our case, are generally indolent. The associated frequency of metastasis is less than ing tumor growth and development through up-regula15%, with the most common sites being regional lymph tion of the downstream products of HIFs (18). Previous studies have demonstrated that VHL-associnodes, liver, bone, and skin (6). A pulmonary primary site ated tumors demonstrate loss of heterozygosity (5), as preaccounts for most intracranial metastases, but metastatic intracranial carcinoids are in general highly unusual, with dicted by the two-hit hypothesis of tumorigenesis (19). In an incidence of 1.5% among patients with primary car- these tumors, an allele with an inherited germline mutacinoids of any site, and occur with a highly variable time tion and deletion of the second wild-type allele are idencourse (12). Patients with intracranial metastases experi- tifiable. In the present case, FISH demonstrated allelic deence a worse prognosis than those with extracranial me- letions of the VHL gene not only in the VHL-associated tastases, with reported 1-year survival rates ranging from HB and pheochromocytomas, but also in the primary and 33 to 42% and a median survival of 7–19 months (12, 13). metastatic carcinoids. Although carcinoids may have sim-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 02 September 2014. at 01:36 For personal use only. No other uses without permission. . All rights reserved.
2636
Zhang et al
VHL-Associated Carcinoid
J Clin Endocrinol Metab, August 2014, 99(8):2633–2636
References 1. Maher ER, Iselius L, Yates JR, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28:443– 447. 2. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260:1317–1320. 3. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the -domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000;2:423– 427. 4. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991–5004. Figure 3. Genetic testing of the metastatic carcinoid (A) reveals heterozygous mutation of the 5. Lonser RR, Glenn GM, Walther M, et al. VHL gene (Tyr98His, cDNA 292T⬎C; arrow). B, Healthy control. Heterozygous VHL gene von Hippel-Lindau disease. Lancet. deletions (arrows) detected by FISH during metaphase in the primary lung carcinoid (C), 2003;361:2059 –2067. metastatic brain carcinoid (D), HB (E), and pheochromocytoma (F). 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