|Year : 2019 | Volume
| Issue : 8 | Page : 163-166
Adrenal adenoma in von Hippel–Lindau syndrome: A case report with review of literature
Rajan Palui1, Sadishkumar Kamalanathan1, Jayaprakash Sahoo1, Lalgudi Narayanan Dorairajan2, Bhawana Badhe3, Debasis Gochhait3
1 Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Urology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
|Date of Web Publication||22-Mar-2019|
Dr. Jayaprakash Sahoo
Department of Endocrinology, 4th Floor, Super Speciality Building, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
Source of Support: None, Conflict of Interest: None
A 29-year-old hypertensive male with von Hippel–Lindau (VHL) syndrome came to the Endocrinology department for evaluation. Contrast-enhanced computed tomography of the abdomen revealed an adrenal mass, bilateral renal cell carcinoma, and multiple pancreatic cysts. The hormonal investigations for adrenal mass were normal. He underwent left-sided adrenalectomy, and the histopathological report was suggestive of an adrenocortical adenoma. Genetic analysis of VHL gene in this patient revealed a heterogeneous 5' splice site variation of intron 1 of the VHL gene that affects splice site of exon 1 (c. 340 + 1G > A). Adrenocortical adenoma is very rare in VHL syndrome. Only two cases of adrenocortical adenoma in VHL have been reported in the literature, and both were associated with pheochromocytoma. This is probably the first reported case of adrenocortical adenoma in VHL syndrome without accompanying pheochromocytoma.
Keywords: Adrenocortical adenoma, Renal cell carcinoma, Type 1 von Hippel–Lindau syndrome
|How to cite this article:|
Palui R, Kamalanathan S, Sahoo J, Dorairajan LN, Badhe B, Gochhait D. Adrenal adenoma in von Hippel–Lindau syndrome: A case report with review of literature. J Can Res Ther 2019;15, Suppl S1:163-6
|How to cite this URL:|
Palui R, Kamalanathan S, Sahoo J, Dorairajan LN, Badhe B, Gochhait D. Adrenal adenoma in von Hippel–Lindau syndrome: A case report with review of literature. J Can Res Ther [serial online] 2019 [cited 2021 Jul 25];15:163-6. Available from: https://www.cancerjournal.net/text.asp?2019/15/8/163/244437
| > Introduction|| |
Von Hippel–Lindau (VHL) syndrome is an autosomal dominant neoplastic syndrome which involves multiple systems. It occurs due to germline mutation of VHL tumor suppressor gene located on chromosome 3. The incidence of VHL syndrome is about 1 in 36,000 live births. The most common tumors associated with this syndrome are central nervous system (CNS) hemangioblastoma, retinal haemangioma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors.
Although most common adrenal tumor in a patient with VHL syndrome is pheochromocytoma, adrenal cortical adenoma can also be rarely seen. Till now, only two cases of adrenal adenoma in VHL syndrome are reported in the literature and in both cases, adrenal adenoma was associated with concomitant pheochromocytoma (Type 2 VHL), not in isolation., Here, we are reporting probably the first case of solitary adrenal adenoma in a VHL patient without pheochromocytoma (Type 1 VHL).
| > Case Report|| |
A 29-year-old hypertensive male with genetic proven VHL syndrome came to the Endocrinology department for evaluation. There was neither any history of paroxysm of sweating or palpitation nor any stigmata of hypercortisolism. He had undergone surgery for cervical (C2–C3) hemangioblastoma 2 years back. His elder sister also had features suggestive of Type 1 VHL syndrome (cerebellar hemangioblastomas, RCC of the left kidney, bilateral renal cysts, and pancreatic serous cystic neoplasm). However, her adrenal glands were normal. None of the other family members have features suggestive of VHL syndrome.
Noncontrast computed tomography of the abdomen of our patient revealed a well-defined hypodense (<10 Hounsfield Unit) lesion of 3.2 cm × 3 cm in the left adrenal gland having central necrosis. There was more than 50% washout in postcontrast delayed image suggestive of adrenal adenoma [Figure 1]. In bilateral kidneys, there were multiple hypodense lesions with intense enhancement (RCC) along with nonenhancing cystic areas (renal cysts). Pancreas also showed multiple well-defined fluid attenuating cysts. On hormonal evaluation, plasma-free metanephrine (51.1 pg/ml; Normal < 65 pg/ml) and free normetanephrine (87.3 pg/ml; Normal < 180 pg/ml) levels were within normal limits. Serum dehydroepiandrosterone sulfate (267 μg/dl; Normal 167–591 μg/dl) and electrolytes were also normal. Normal values of 8 am serum cortisol (16.89 μg/dl), midnight awake cortisol (1.96 μg/dl) and overnight 1 mg dexamethasone suppression test (0.81 μg/dl) ruled out the possibility of endogenous hypercortisolism. Although biochemically there was no evidence of pheochromocytoma, metaiodobenzylguanidine (MIBG) scintigraphy was done on high suspicion of it for an adrenal mass in an established case of VHL. However, MIBG scan failed to show any abnormal tracer uptake in the abdomen.
|Figure 1: Computed tomography scan of adrenal adenoma. (a) Plain computed tomography abdomen showing homogenous, well defined left adrenal mass. (b) Early postcontrast image showing peripheral enhancement of the left adrenal mass. (c) Delayed postcontrast image showing more than 50% washout of contrast|
Click here to view
Then, the patient underwent left-sided adrenalectomy after controlling hypertension. On gross examination of the adrenal mass, an encapsulated gray-brown lesion measuring 3 cm × 3 cm × 3 cm in size with areas of hemorrhage was found. On microscopic examination, the tumor cells with clear cytoplasm were arranged in a nesting pattern [Figure 2]a. There was no significant atypia of the tumor cells and mitotic figures were also absent. On immunohistochemistry, the tumor cells were positive for Inhibin and Melan A [Figure 2]b and [Figure 2]c and negative for synaptophysin, thereby confirming adrenocortical adenoma and excluding pheochromocytoma. The adjacent adrenal gland was normal. For the largest focus of RCC, right-sided partial nephrectomy was done 3 months later. On histopathological examination, the tumor was circumscribed and measured 4 cm × 3 cm × 2 cm in dimensions. The cut section showed areas of hemorrhage and congestion without any areas of necrosis. On microscopy, the tumor had a sharp demarcation from normal parenchyma and the renal capsule without any evidence of infiltration [Figure 3]a. The tumor cells had minimal atypia, abundant clear/vacuolated cytoplasm, low nuclear grade, and rare mitosis. The morphological features were compatible with the clear cell type of RCC [Figure 3]b.
|Figure 2: Histopathology of adrenal tumor. (a) H and E stain (×200) of adrenal tumor showing tumor cells with clear cytoplasm arranged in a nesting pattern. (b) Immunohistochemistry of Melan A (×100) of adrenal tumor showing diffuse cytoplasmic positivity in tumor cells. (c) Immunohistochemistry of Inhibin (×100) of adrenal tumor showing strong cytoplasmic positivity in tumor cells|
Click here to view
|Figure 3: Histopathology of renal tumor. (a) The low magnification image (H and E stain ×100) of renal tumor shows the sharp demarcation between the tumor (left side) and adjacent normal renal parenchyma (right side). (b) The high magnification image (H and E ×400) of renal tumor shows the tumor cells with clear cytoplasm, low nuclear grade, intricate capillary network and lakes of red blood cells|
Click here to view
Genetic analysis of VHL gene in this patient revealed a heterogeneous 5' splice site variation of intron 1 of the VHL gene that affects splice site of exon 1 (c. 340 + 1G > A). This mutation was pathogenic for VHL syndrome and previously reported in a few cases.,,
| > Discussion|| |
Multiple tumors arising from different organ systems are usually seen in VHL syndrome. CNS hemangioblastomas are seen in 60%–80%, retinal hemangiomas in 49%–62%, RCC or renal cysts in 30%–70%, pheochromocytomas in 10%–20%, pancreatic tumor or cysts in 35%–70%, epididymal cystadenomas in 25%–60%, and endolymphatic sac tumor of ears in 6%–15% of the VHL patients. Pheochrmocytomas are the most common adrenal tumor in VHL syndrome and can have varied presentations ranging from a garden variety of symptomatic nonmalignant ones to that of silent malignant ones. Depending on whether pheochromocytoma is present or not, VHL syndrome is classified phenotypically as Type 2 and Type 1, respectively. Our patient had cervical hemangioblastoma, bilateral RCC, cysts in kidneys and pancreas, and left-sided adrenal cortical adenoma with a positive family history of similar disease in elder sister. Phenotypically, both the patient and his elder sister are likely to have Type 1 VHL syndrome as pheochromocytoma was absent in both of them.
Adrenal adenoma is rarely associated with VHL syndrome. In literature, only two cases of adrenal adenoma in VHL syndrome has been reported., Bernini et al. reported a case of adrenal adenoma in a 69-year-old Caucasian woman. This patient presented with hypertension and bilateral adrenal masses were discovered in imaging. Hormonal evaluations for both adrenal cortical and medullary functions were normal. The patient underwent right-sided adrenalectomy which revealed a compound adrenal pheochromocytoma and ganglioneuroma in the same gland. Left-sided adrenalectomy was not done as imagings were suggestive of a benign adrenal cortical adenoma. As patient also had vertebral and hepatic hemangiomas, genetic analysis was done and a new intronic single nucleotide polymorphism 5557A >G was found in VHL gene. In another case report, Ercolino et al. reported a right adrenal compound pheochromocytoma, ganglioneuroma and a separate cortical adenoma in the same gland detected incidentally during evaluation of cholelithiasis. Although the patient was clinically asymptomatic on hormonal evaluation, she has elevated 24 h urinary metanephrine and free cortisol and elevated plasma cortisol. The patient underwent right adrenalectomy and histology showed a compound adrenal medullary neoplasm having both pheochromocytoma and ganglioneuroma components, associated with a separate cortical adenoma appearing as a distinct nodule in the same adrenal gland. Neoplasm in other organs was absent in this case, but in genetic analysis, a novel missense mutation L198V (594C >G) was found in exon 3 of VHL gene. These reported cases are of Type 2 VHL syndrome as pheochromocytoma was present along with adrenal adenoma whereas in our case, pheochromocytoma is absent (Type 1 VHL syndrome).
VHL syndrome follows the classic “two-hit” pathway of tumorigenesis, and biallelic mutation is found in most cases. Genetically, Type 1 syndrome is associated with larger deletions and nonsense truncation mutations whereas missense mutations are most common in Type 2 syndrome. VHL gene is a tumor suppressor gene which encodes a protein, VHL protein (pVHL) with E3 ubiquitin ligase activity and generally inhibits Hypoxia-Inducible Factor-mediated tumorigenesis pathway. The role of pVHL in the development of pheochromocytoma is different from the development of RCC and hemangioblastoma. Mutant pVHL in Type 2 VHL syndrome, fails to downregulate apoptosis antagonist molecule c-Jun and prevents physiological apoptosis of sympathetic neuronal precursor cells. These culling excess neuronal precursor cells act as a focus for development of pheochromocytoma in later life. Type 2 VHL syndrome mutations retain some essential function of pVHL, which is needed for the survival of abnormal neural crest precursor cells with defective apoptosis function, whereas complete loss of pVHL function (Type 1 VHL syndrome mutation) prevents survival of this precursor cells. Lack of any abnormal neural crest precursor cells due to larger deletion mutations in VHL gene might explain the absence of pheochromocytoma in Type 1 VHL syndrome.
The genetic mutation (c. 340 + 1G > A) found in our patient, is located at the first exon-intron junction of the VHL gene. This mutation destroys the conserved intronic donor splice site and most likely leads to premature protein termination. The role of genetic mutations in VHL gene (3p) in the pathogenesis of adrenal cortical adenoma has not been reported in literature. However, loss of heterozygosity for 3p locus has been reported in adrenocortical carcinoma.
To conclude, only two cases of adrenal adenoma have been reported in Type 2 VHL syndrome in the literature. To the best of our knowledge, this patient is the first reported case of adrenocortical adenoma in Type 1 VHL syndrome.
Written informed consent has been taken from the patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al.
Von Hippel-Lindau disease. Lancet 2003;361:2059-67.
Bernini GP, Moretti A, Mannelli M, Ercolino T, Bardini M, Caramella D, et al.
Unique association of non-functioning pheochromocytoma, ganglioneuroma, adrenal cortical adenoma, hepatic and vertebral hemangiomas in a patient with a new intronic variant in the VHL gene. J Endocrinol 2005;28:1032-7.
Ercolino T, Becherini L, Valeri A, Maiello M, Gaglianò MS, Parenti G, et al.
Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations. Clin Endocrinol (Oxf) 2008;68:762-8.
Losonczy G, Fazakas F, Pfliegler G, Komáromi I, Balázs E, Pénzes K, et al.
Three novel germ-line VHL mutations in Hungarian von Hippel-Lindau patients, including a nonsense mutation in a fifteen-year-old boy with renal cell carcinoma. BMC Med Genet 2013;14:3.
Losonczy G, Fazakas F, Pfliegler G, Komaromi I, Berta A. Identification of novel germline mutations in the VHL gene in Hungarian von Hippel-Lindau patients. Acta Ophthalmologica. 2011;89.
Hes FJ, van der Luijt RB, Janssen AL, Zewald RA, de Jong GJ, Lenders JW, et al.
Frequency of von Hippel-Lindau germline mutations in classic and non-classic von Hippel-Lindau disease identified by DNA sequencing, southern blot analysis and multiplex ligation-dependent probe amplification. Clin Genet 2007;72:122-9.
Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JS, et al.
Areview of von Hippel-Lindau syndrome. J Kidney Cancer VHL 2017;4:20-9.
Colvin A, Saltzman AF, Walker J, Bruny J, Cost NG. Metastatic pheochromocytoma in an asymptomatic 12-year-old with von Hippel-Lindau disease. Urology 2018. pii: S0090-4295(17) 31324-9.
Barontini M, Dahia PL. VHL disease. Best Pract Res Clin Endocrinol Metab 2010;24:401-13.
Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, et al.
Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996;8:348-57.
Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, et al.
Neuronal apoptosis linked to eglN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer. Cancer Cell 2005;8:155-67.
Fogt F, Vargas MP, Zhuang Z, Merino MJ. Utilization of molecular genetics in the differentiation between adrenal cortical adenomas and carcinomas. Hum Pathol 1998;29:518-21.
[Figure 1], [Figure 2], [Figure 3]