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Von Hippel-Lindau disease

Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply. more...

VACTERL association
Van der Woude syndrome
Van Goethem syndrome
Varicella Zoster
Variegate porphyria
Vasovagal syncope
VATER association
Velocardiofacial syndrome
Ventricular septal defect
Viral hemorrhagic fever
Vitamin B12 Deficiency
VLCAD deficiency
Von Gierke disease
Von Hippel-Lindau disease
Von Recklinghausen disease
Von Willebrand disease


Features of VHL are:

  • angiomatosis - little knots of capillaries in various organs. These tend to be cavernous hemangiomas, which are sharply defined, sponge-like tumors composed of large, dilated, cavernous vascular spaces.
  • hemangioblastomas - tumors of the central nervous system (CNS, especially the cerebellum). These tumors, whether benign (usual) or malignant (rarer), may cause problems, for example angiomas in the brain or spinal cord may press on nerve or brain tissue. As an angioma grows, the walls of the blood vessels may weaken and leak, causing damage to surrounding tissues. Blood leakage from angiomas in the retina can interfere with vision. Cysts may also grow around angiomas.
  • pheochromocytoma - tumors of the adrenal medulla that often produce catecholamines
  • renal cell carcinoma - in some forms

Untreated, VHL may result in blindness and permanent brain damage, death is usually caused by complications of malignant tumors in the brain or kidney.


There are various subtypes (see OMIM):

  • Type 1 (angiomatosis without pheochromocytoma)
  • Type 2 (angiomatosis with pheochromocytoma)
    • Type 2A (with renal cell carcinoma)
    • Type 2B (without renal cell carcinoma)
    • Type 2C (only pheochromocytoma and no angiomatosis or renal cell carcinoma)


The disease is caused by mutations of the VHL gene on the short arm of the third chromosome (3p26-p25). The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor gene. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiongenic factors. In turn, this leads to unregulated blood vessel growth, one of the prerequesites of a tumour.

VHL is an autosomal dominant disorder, but there is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from one parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development.

As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. If a mutation occurs in the second copy of the VHL gene during a person's lifetime, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel-Lindau syndrome to develop.


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Pathologic Quiz Case: An 82-Year-Old Woman With a Renal Mass
From Archives of Pathology & Laboratory Medicine, 1/1/04 by Lee, Lawrence

An 82-year-old woman presented with anorexia and a 40-pound weight loss during a 6-week period. The patient denied hematuria or flank pain. Abdominal computed tomography scan showed an 8-cm mass in the upper pole of the right kidney. Work-up for metastatic disease was negative.

A right nephrectomy was performed and revealed a 7.5 × 6.5 × 6.5-cm variegated solid mass. Several white circumscribed nodules (Figure 1, arrow), constituting 30% of the mass, were embedded in a yellow, hemorrhagic, and necrotic tumor. The mass focally extended into the proximal renal vein but did not penetrate the renal capsule or involve the renal pelvis.

Microscopically, the yellow/hemorrhagic areas and the white nodules of the mass corresponded with clear cell and eosinophilic cell areas, respectively. The clear and eosinophilic cell areas were sharply separated from each other with or without a thin fibrous band (Figure 2). Numerous arborizing capillaries were present in the clear cell areas but not in the eosinophilic cell areas (Figure 2). The clear cell areas consisted of smaller tumor cells with moderate amount of clear cytoplasm and centrally placed moderately atypical nuclei with distinct to prominent nucleoli. The eosinophilic cell areas were comprised of large tumor cells with ample eosinophilic cytoplasm and eccentrically placed nuclei with macronucleoli. The eosinophilic cytoplasm sometimes condensed to form intracytoplasmic inclusions or globules (Figure 3, A, arrow). Some cells demonstrated leukophagocytosis (Figure 3, B). No striadons or pigment were present in these eosinophilic cells. Immunohistochemical studies showed that the clear cells were positive for vimentin (Figure 4, A), neuron-specific enolase, AE1/AE3, and CAM 5.2 and negative for cytokeratin 7. The eosinophil cells were positive for vimentin (Figure 4, B, arrow to an intracytoplasmic inclusion) and neuron-specific enolase, and negative for AE1/AE3, CAM 5.2, and cytokeratin 7.

What is your diagnosis?

Pathologic Diagnosis: Renal Cell Carcinoma With Rhabdoid Features

Rhabdoid tumor was first described in 1978 as a rare malignancy of the kidney in children, especially in infants.1- The descriptive term "rhabdoid" refers to tumor cells that morphologically resemble, but are ultrastructurally and immunohistochemically different from, rhabdomyoblastic cells. Subsequently, extrarenal rhabdoid tumors were reported at many different body sites, including skin, soft tissue, urogenital tract, liver, thymus, and central nervous system, among many others.3 In addition, many tumors were found to contain a portion of rhabdoid tumor. These tumors with rhabdoid features, also known as composite tumors, have been described in carcinomas (ie, transitional cell carcinoma, colorectal adenocardnoma, renal cell carcinoma, Merkel cell carcinoma, and undifferentiated carcinoma of the vulva), melanoma, lymphomas, mesothelioma, meningioma, and sarcomas (eg, endometrial stromal sarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, myxoid chondrosarcoma, and desmoplastic small round cell tumor).3

Our case is an example of conventional (clear cell) renal cell carcinoma (RCC) with rhabdoid features, an uncommon neoplasm with only a few reports in the literature.4-6 Unlike pure rhabdoid tumor in children, RCC with rhabdoid features occurs in adults with a mean age of 61.8 years (age range, 33-84 years).4 The prominence of the rhabdoid cell component varies considerably. Gokden et al4 identified 23 (4.7%) RCCs with rhabdoid features among 480 cases of RCC. The rhabdoid component ranged in size from 1 mm to more than 2 cm in maximum dimension and constituted 1% to 50% of the entire RCC. Kuroiwa and Tsuneyosh5 found 8 (3.2%) of 253 cases of RCC had rhabdoid features; however, cases were excluded if the rhabdoid element was less than 10% of the renal carcinoma. The rhabdoid areas constituted 10% to 90% of the tumor mass.

The gross appearance, histology, immunohistochemistry, and electron microscopy of the rhabdoid cells in RCC with rhabdoid features are similar to that of the pediatric rhabdoid tumor of the kidney.3-7 Macroscopically, the white firmer areas with homogenous cut surface often represent the rhabdoid components while the hemorrhagic areas are composed of conventional RCC, reflecting the greater vascularity of the conventional RCC component. The growth patterns seen in the pure pediatric rhabdoid tumor of the kidney (ie, organoid/sheetlike, pseudoglandular, lymphomatoid, spindle cell, and mixed types) are also present in cases of RCC with rhabdoid features; however, the organoid/sheetlike pattern predominates. Abundant arborizing vasculature of the conventional RCC is absent in the rhabdoid areas. Cytologically, the rhabdoid cells have an epithelioid appearance, large paranuclear intracytoplasmic hyaline globules or inclusions, and eccentric vesicular nuclei with macronucleoli. Often, the rhabdoid cells are of higher nuclear grade than the surrounding RCC component, which is most often of the conventional (clear cell) type. Rhabdoid cells contain abundant glycogen but minimal lipid, while clear cells are rich in both glycogen and lipid. Immunohistochemically, the rhabdoid cells have diffuse strong staining for vimentin; variable positive staining for neuron-specific enolase, pancytokeratin, epithelial membrane antigen, and S100 protein; rare positive staining for cytokeratin 7 and smooth muscle actin; and negative staining for CK20, desmin, muscle-specific actin, glial fibrillary acidic protein, and HMB-45.4 Ultrastructurally, the paranuclear intracytoplasmic hyaline globules or inclusions contain whorled aggregates of intermediate filaments and/or coalesced degraded organelles.4,5 Shannon et al6 studied loss of heterozygosity and single-stranded conformation polymorphism in three RCC cases with rhabdoid features. Loss of heterozygosity analysis showed loss of chromosome 3p in both the clear cell and rhabdoid components in one case. In this and another case, single-stranded conformation polymorphism analysis exhibited the same mutations of the von Hippel-Lindau (VHL) gene on chromosome 3 in both the clear cells and rhabdoid cells. The third case did not have chromosome 3p loss or VHL mutation. These observations suggested that the RCC clear cells and the rhabdoid cells were from the same clone and exhibited divergent differentiation.

Renal cell carcinoma with rhabdoid features tends to have a worse prognosis than RCC without rhabdoid component.4-7 Gokden et al4 noticed that RCC with rhabdoid features was more likely to be associated with RCC of higher nuclear grade, had a twofold greater chance of extrarenal extension, and showed higher risk for metastatic disease. Kuroiwa and Tsuneyoshr noted that the rhabdoid component had a significantly higher MIB-1 proliferation index compared with the conventional RCC areas. Seven of 8 patients in their series were stage III to IV and four died within 8 months of surgery. Shannon et al6 proposed that RCC with rhabdoid features should be considered as a clinically important form of RCC separate from, but analogous to, RCC with sarcomatoid change.


1. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms' tumor: results from the first notional Wilms' tumor study. Cancer. 1978;41:1937-1948.

2. Haas JE, Palmer NF, Weinbergh AG, Beckwith JB. Ultrastructure of malignant rhahdoid tumor of the kidney. A distinct renal tumor of children. Hum Palhol. 1981;12:646-657.

3. Weiss SW, Coldblum JR. Malignant soft tissue tumors of uncertain type. In: Weiss SW, Goldblum JR, eds. Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St Louis, Mo: Mosby; 2001:1545-1552.

4. Gokden N, Nappi O, Swanson PE, et al. Renal cell carcinoma with rhabdoid features. Am J Surg Pathol. 2000;24:1329-1 338.

5. Kuroiwa K, Tsuneyoshi M. Renal cell carcinoma with rhabdoid features: an aggressive neoplasm. Histopathology. 2002;41:538-548.

6. Shannon B, Wisniewski ZS, Bentel J, Cohen RJ. Adult rhabdoid renal cell carcinoma. Arch Pathol Lab Med. 2002;126:1506-1510.

7. Murphy WM, Beckwith JB, Farrow GM. Rhabdoid tumor. In: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology; 1994:82-89. Atlas of Tumor Pathology; 3rd series, fascicle 11.

Lawrence Lee, MD; William L. Marsh, Jr, MD; Ping Wen, MD, PhD

Accepted for publication August 21, 2003.

From the Department of Pathology, The Ohio State University Medical Center, Columbus.

Corresponding author: Ping Wen, MD, PhD, Ohio State University Medical Center, E-410 Doan Hall, 410 West 10th Ave, Columbus, OH 43210 (e-mail:

Reprints not available from the author.

Copyright College of American Pathologists Jan 2004
Provided by ProQuest Information and Learning Company. All rights Reserved

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