Background
This rare disease is autosomal dominantly inherited and contains a spectrum of clinical signs and symptoms. There are multiple clear cell neoplasms in various organs including retinal and central nervous system hemangioblastomas, renal cell carcinomas, pheochromocytomas, pancreatic endocrine tumors, and cysts.
OUTLINE
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION BRAIN Suprasellar hemangioblastoma in a patient with von Hippel-Lindau disease confirmed by germline mutation study. Case report and review of the literature.
Goto T, Nishi T, Kunitoku N, Yamamoto K, Kitamura I, Takeshima H, Kochi M, Nakazato Y, Kuratsu J, Ushio Y.
Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto, Japan
Surg Neurol 2001 Jul;56(1):22-6 Abstract quote
BACKGROUND Hemangioblastoma (HBL) in the suprasellar region is extremely rare.
CASE DESCRIPTION A suprasellar mass was found in a 33-year-old woman with retinal HBL and bilateral adrenal pheochromocytomas. The diagnosis of von Hippel-Lindau (VHL) disease was confirmed preoperatively not only by these clinical manifestations but also by germline mutation study. The existence of VHL disease indicated a diagnosis of HBL for the suprasellar mass. The results of our mutation study indicated that this patient had type II VHL disease, suggesting that careful follow-up is essential for the early detection of renal cell carcinoma, which is often associated with type II VHL disease. Here, we summarize the previously reported features of sellar and suprasellar HBLs.
CONCLUSIONS HBLs in this region may be one manifestation of VHL disease. Genetic testing of the VHL gene of our patient could provide useful information to determine appropriate medical care and management.
GALLBLADDER Clear Cell Carcinoid Tumor of the Gallbladder Another Distinctive Manifestation of Von Hippel-Lindau Disease
Prasanna A. Sinkre, M.D.; Linda Murakata, M.D.; Lionel Rabin, M.D.; Mai P. Hoang, M.D.; Jorge Albores-Saavedra, M.D.
From the Division of Anatomic Pathology (P.A.S., M.P.H., J.A.-S.), University of Texas Southwestern Medical Center, Dallas, Texas; and the Department of Hepatic and GI Pathology (L.M., L.R.), Armed Forces Institute of Pathology, Washington, DC, U.S.A.
Am J Surg Pathol 2001;25:1334-1339 Abstract quote
We describe a morphologically distinctive carcinoid tumor of the gallbladder that occurred in a 38-year-old man with von Hippel-Lindau (VHL) disease.
The carcinoid tumor was composed predominantly of lipid-containing clear cells arranged in nests and tubules with pagetoid spread into the biliary epithelium and was interpreted as metastatic renal cell carcinoma. The neoplastic cells showed diffuse immunoreactivity for chromogranin, synaptophysin, cytokeratins (cytokeratin 7 and AE1/AE3) and, unexpectedly, for inhibin, but were negative for monoclonal carcinoembryonic antigen, serotonin and a variety of peptide hormones.
This clear cell carcinoid tumor of the gallbladder was histologically similar to the recently described clear cell endocrine pancreatic tumor associated with VHL. Four cases of the latter tumor, which were also inhibin positive showed, in addition, focal and variable reactivity for the pancreatic hormones. Two classical carcinoid tumors of the gallbladder, two renal cell carcinomas associated with VHL and 11 of 13 sporadic endocrine pancreatic tumors (not associated with VHL) did not show immunoreactivity for inhibin. Inhibin appears to be an immunohistochemical marker for gallbladder clear cell carcinoid and clear cell endocrine pancreatic tumors associated with VHL and is a useful tool to distinguish these tumors from metastatic renal cell carcinoma. However, the basis for the inhibin positivity in these endocrine tumors is unknown.
KIDNEY Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma.
Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W, Wetterauer U, Ferstl FJ, Herbst EW, Schwarzkopf G, Hes FJ, Lips CJ, Lamiell JM, Masek O, Riegler P, Mueller B, Glavac D, Brauch H.
Department of Medicine, Albert-Ludwigs-Universitat, Freiburg, Germany
J Urol 1998 Oct;160(4):1248-54 Abstract quote
PURPOSE: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel-Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology.
MATERIALS AND METHODS: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, representing 80% of von Hippel-Lindau families, and register B, 62% living patients, to identify von Hippel-Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease.
RESULTS: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p < 0.001 each). In von Hippel-Lindau disease metastases occurred only in tumors larger than 7 cm.
CONCLUSIONS: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.
MIDDLE EAR Endolymphatic Sac Tumor Associated with a Von Hippel-Lindau Disease Patient: An Immunohistochemical Study
Hidehisa Horiguchi, M.D., Ph.D., Toshiaki Sano, M.D., Ph.D., Hiroyuki Toi, M.D., Teruyoshi Kageji, M.D., Ph.D., Mitsuyoshi Hirokawa, M.D., Ph.D. and Shinji Nagahiro, M.D., Ph.D.
Departments of Pathology and NeurosurgeryUniversity of Tokushima School of Medicine, Kuramoto, Tokushima, Japan
Mod Pathol 2001;14:727-732 Abstract quote
The authors report a case of endolymphatic sac tumor (ELST) associated with Von Hippel-Lindau disease (VHL).
A 20-year-old female VHL patient received a resection of a cerebellar hemangioblastoma 3 years ago and she had a co-existing of left petrous tumor. The petrous tumor showed a remarkable progression in 3 years and was resected subtotally. Histologically, the resected petrous tumor showed a papillary structure containing cuboidal or columnar cells with fibrous stroma and numerous microvessels and destructed temporal bone, all of which are consistent with ELST.
We studied the expression of various kinds of cytokeratins (CKs) immunohistochemically and found distinct expression of CKs (CAM 5.2, 34ßE-12, CK7, CK8 and CK19), but not for CK10/13 or CK20. Vascular endothelial growth factor and neuron specific enolase showed strong immunoreactivity in the tumor cells. CD34 also had weak expression. Ki-67 antigen (MIB-1) immunoreactivity was found in focal areas, and the labeling index in the highest-density area was 48.9%.
These findings suggest that vascular endothelial growth factor overexpression is an important factor for angiogenesis in ELST, much like other VHL-associated tumors, and that ELST may have a more highly aggressive component than the low-grade malignancy noted in previous reports.
PANCREAS Pancreatic cystic manifestations in von Hippel-Lindau disease.
Girelli R, Bassi C, Falconi M, De Santis L, Bonora A, Caldiron E, Sartori N, Salvia R, Briani G, Pederzoli P.
Surgical Department, Borgo Roma University Hospital, University of Verona, Italy
Int J Pancreatol 1997 Oct;22(2):101-9 Abstract quote
CONCLUSION: In view of the frequent absence of symptoms related to pancreatic lesions, screening tests for VHL should always include assessment of the pancreas and, considering the frequency of polycystic manifestations, VHL should always be borne in mind in the differential diagnosis of multiple pancreatic cysts, especially when occurring in young patients and in the absence of a positive history of pancreatic disease.
BACKGROUND: Von Hippel-Lindau disease (VHL) is a hereditary disease transmitted with an autosomal dominant character and characterized by hemangioblastomas of the central nervous system and retina, renal tumors and cysts, and pheochromocytoma. Pancreatic manifestations of VHL are reported in the literature with incidences ranging from 16 to 29% of cases and consist mainly in cystadenomas of the serous type and in multiple cystic lesions, often with complete replacement of the gland.
METHODS AND RESULTS: We report five cases of VHL with a polycystic pancreas as the main or only manifestation, all devoid of symptoms related to involvement of the pancreas, who were referred to our Pancreatic Surgery center with diagnoses of multiple pancreatic pseudocysts of undefined origin.
Clear Cell Endocrine Pancreatic Tumor Mimicking Renal Cell Carcinoma A Distinctive Neoplasm of Von Hippel–Lindau Disease
Mai P. Hoang, etal.
Am J Surg Pathol 2001;25:602-609 Abstract quote
The dominantly inherited von Hippel–Lindau disease is characterized by clear cell neoplasms in various organs including the kidney and pancreas. Determination of primary versus metastatic lesion in this setting can be a diagnostic dilemma.
The authors present five cases of clear cell endocrine pancreatic tumor (EPT) closely mimicking renal cell carcinomas in five patients with a family history or histologic evidence of von Hippel–Lindau disease. In fact, two of these tumors were confused with metastatic renal cell carcinoma by fine-needle aspiration.
All five tumors had a component of clear cells arranged in nests, cords, and tubules with central hemorrhage separated by thin-wall vessels resembling renal cell carcinoma. However, these tumors also exhibited cords and festoons and a gyriform pattern suggestive of an endocrine neoplasm, and expressed chromogranin and synaptophysin. Vascular invasion was identified in four tumors, one of which metastasized. The concurrent primary renal cell carcinomas and the multicentric microcystic adenomas found in three patients did not show reactivity for the neuroendocrine markers. Focal clear cell change was noted in only one of 29 endocrine pancreatic tumors arising in patients without von Hippel–Lindau disease. Eleven metastatic renal cell carcinomas in the pancreas did not show immunoreactivity with the endocrine markers.
Clear cell EPTs closely mimicking renal cell carcinoma are distinctive neoplasms of von Hippel–Lindau disease. In contrast to clear cell EPT, metastatic renal cell carcinoma does not express neuroendocrine markers and lacks neurosecretory granules by electron microscopy. Von Hippel–Lindau disease should be strongly suspected in patients with renal cell carcinoma, clear cell EPT, and multifocal microcystic serous adenomas.
RETINA
Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, Beroud C, Dureau P, Gaudric A, Landais P, Richard S.
Federation de Genetique, Ophthalmology Department, Hopitaux Universitaires de Strasbourg, Strasbourg, France
Invest Ophthalmol Vis Sci 2002 Sep;43(9):3067-74 Abstract quote PURPOSE: To assess the natural history of retinal manifestations in von Hippel-Lindau (VHL) disease and to study the genotype-phenotype correlation.
METHODS: Data concerning 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations were extracted from the French VHL database. A retrospective study was performed by questionnaire. Patients were classified into three visual morbidity groups. Molecular analysis of the VHL gene was performed in 196 patients.
RESULTS: The mean age of ocular manifestations detection was 24.8 years. In half of the cases, the ocular manifestations revealed the disease. Half of the cases had bilateral involvement. Visual morbidity was significantly associated with the retinal hemangioblastoma count but not with other ocular or general characteristics. One third of the patients were classified in the worst visual morbidity group at the end of follow-up. Mutations were detected in 81% of patients with retinal hemangioblastomas and in 71% of patients without retinal involvement. Using a Poisson model and a marginal approach, the number of hemangioblastomas, age-adjusted, was 2.1 times higher in patients who had a substitution than in patients with a truncation (95% CI, 1.05-4.44; P < 0.05).
CONCLUSIONS: Visual loss remains one of the major complications of VHL disease, confirming the importance of early ophthalmologic screening. Visual morbidity was not related to the type of extraocular manifestation but appeared to be related to the type of germline mutation. However, only further genetic and clinical studies in a larger series of patients will clearly determine the genotype-phenotype relationship.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel-Lindau disease.Hamazaki S, Nakashima H, Matsumoto K, Taguchi K, Okada S.
Department of Pathology, Okayama University Hospital, Japan.
Pathol Int 2001 Dec;51(12):948-53 Abstract quote Here we report tumor-to-tumor metastases identified in two patients with von Hippel-Lindau (VHL) disease.
The first patient had bilateral renal carcinomas and multiple cerebellar hemangioblastomas, and the second patient had a renal carcinoma and multiple hemangioblastomas in the retina, cerebellum and spinal cord. A cerebellar lesion from the first patient and a spinal lesion from the second patient contained two distinct components. The inner part of these tumors consisted of a nested mass of polygonal clear cells that expressed cytokeratin and epithelial membrane antigen, while the outer part of the tumors showed proliferation of capillaries and intervening foamy stromal cells that were negative for cytokeratin and epithelial membrane antigen. The tumors were thus considered to be hemangioblastomas complicated by metastatic lesions of renal cell carcinoma of clear cell type.
These cases indicate that tumor-to-tumor metastasis should be considered when hemangioblastoma contains a clear cell carcinoma component in the setting of VHL disease, and that immunohistochemical staining for cytokeratin and epithelial membrane antigen is useful for the diagnosis.
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