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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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Clear cell carcinoid tumor of the gallbladder: A case without von Hippel-Lindau disease
From Archives of Pathology & Laboratory Medicine, 6/1/03 by Konishi, Eiichi

* A golden yellow polyp was detected in the gallbladder of a 64-year-old man who presented with epigastric pain. The lesion was composed of clear polygonal cells arranged in a trabecular and glandular pattern. The tumor invaded through the wall into the perimuscular subserosal layer. Immunohistochemical stains showed that neoplastic cells were positive for chromogranin A, synaptophysin, somatostatin, gastrin, and pancreatic polypeptide and negative for glucagon, serotonin, insulin, S100 protein, and inhibin. This tumor resembles the recently described clear cell endocrine tumors of the gallbladder and pancreas that are associated with von Hippel-Lindau disease. Our patient, however, had neither personal nor family history indicative of von Hippel-Lindau disease. Furthermore, published accounts of clear cell endocrine tumors in von Hippel-Lindau disease describe immunoreactivity for inhibin; the current case was negative for the disease. There may be a subtype of clear cell carcinoid tumor not associated with von Hippel-Lindau disease, which is characterized by its lack of immunoreactivity against inhibin.

Carcinoid tumor is a rare lesion in the gallbladder.1 Only 18 examples have been found among 3557 gastrointestinal carcinoid tumors examined during a 19-year period by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.2 Clear cell carcinoid tumor of the gallbladder is even more rare; the one example of which we are aware arose in a patient with von Hippel-Lindau disease (VHL).3 That report described histologic features similar to clear cell endocrine pancreatic tumors that are also associated with VHL,4 including immunohistochemical positivity for inhibin.

We report herein a clear cell carcinoid tumor of the gallbladder in a 64-year-old man without VHL. Although the tumor of this particular patient had features that were histologically similar to those described in the setting of VHL, immunohistochemical staining for inhibin was negative.


A 64-year-old man presented with acute onset of epigastric pain in March 2002. His medical history was remarkable only for a gastric ulcer diagnosed 3 years previously. His parents, 3 brothers, and 3 sisters had no medical history of VHL. Physical examination indicated no specific problem. Laboratory tests disclosed a nonspecific hepatobiliary disturbance. Ultrasonography of the abdomen showed 2 small gallstones (up to 5 mm in diameter) in the gallbladder with a small polypoid lesion at its neck (5 mm in diameter). The polyp was preoperatively diagnosed as a cholesterol polyp. A laparoscopic cholecystectomy was performed 6 days following his first presentation, after a diagnosis of cholelithiasis with a cholesterol polyp. After the operation, his hepatobiliary disturbance was corrected and he was well in November 2002.


Macroscopically, the wall of the gallbladder was mildly thickened. There were 2 small gallstones in the lumen. An 8-mm sessile polyp was present at the neck of the gallbladder (Figure 1). The polyp was golden yellow and had an uneven surface.

Histologically, the polyp was composed of trabecular and glandular structures, involving the gallbladder mucosa and the perimuscular subserosal layer (Figure 2). The lining cells had clear, cuboidal-to-low columnar or polygonal cytoplasm and small, round-to-oval nuclei (Figure 3). The original biliary glands were entrapped among the tumor glands (Figure 3, arrow). The lesion had a well-developed capillary network in its stroma. There was little or no desmoplastic stromal response. No aggregates of foamy macrophages were present in the stroma. Neither vascular nor lymphatic invasion was present. The tumor contained some area of pale eosinophilic cells (Figure 4). In some foci, pagetoid spreading was found in the biliary glands (Figure 5), but mitotic figure was rare. Periodic acid-Schiff stains with and without diastase demonstrated neither glycogen nor mucin in the clear cells. The rest of the specimen showed nonspecific cholecystitis.

Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue using the avidinbiotin peroxidase complex method. Specific antibodies that were used, their sources, their dilution, and the results are summarized in the Table. The tumor cells showed strong cytoplasmic positivity for chromogranin A and synaptophysin (Figure 6, A and B). They were focally positive for gastrin, somatostatin, and pancreatic polypeptide but tested negative for glucagon, serotonin, insulin, and inhibin (Figure 6, C). S100 protein also failed to demonstrate sustentacular cells in the tumor.


Clear cell carcinoid tumor of the gallbladder and clear cell endocrine pancreatic tumor have been described as a distinctive manifestation of VHL.3 Clear cell carcinoid tumors that affect patients without VHL have been discovered in the thymus,5 lung,6 stomach,7,8 and appendix.9,10 The clear appearance of the cytoplasm is not caused by glycogen; several reports5,7-10 have demonstrated excess lipid in the tumor cells. Our case was initially diagnosed as a cholesterol polyp on ultrasound examination, and the tumor showed a golden yellow color macroscopically, which also caused it to resemble a cholesterol polyp. Histologically, however, it did not contain aggregates of foamy macrophages in the stroma, which are characteristic in a cholesterol polyp. Periodic acid-- Schiff staining failed to show the presence of glycogen and mucin in the clear cytoplasm of the tumor cell. Thus, we believe the clear cell features in this particular case are due to lipid accumulation and that it is reasonable to suggest that there is a rare sporadic clear cell subtype of carcinoid tumor that can affect several organs, including the gallbladder. Because the whole specimen was processed and embedded in paraffin, we examined neither oil staining nor electron microscopy.

The clear cell carcinoid tumor and clear cell endocrine pancreatic tumor associated with VHL were diffusely immunopositive for inhibin,3,4 but our patient's tumor was negative for inhibin. Accordingly, inhibin might be a marker to differentiate the pancreatic and gallbladder clear cell tumors associated with VHL from sporadic tumors.4 At present, none of the reported cases of sporadic clear cell carcinoid in other organs were examined using immunohistochemical assays with inhibin.5-10 Further investigation about the staining quality of inhibin in additional cases of clear cell carcinoid tumor without VHL will be needed to support this hypothesis.

The differential diagnosis for clear cell tumors of the gallbladder includes adenocarcinoma (especially metastatic renal cell carcinoma) and paraganglioma. The strong positivity for neuroendocrine markers eliminates carcinoma from consideration. Paraganglioma of gallbladder is usually found incidentally and protrudes from the external surface.1 Furthermore, S100 protein usually decorates sustentacular cells in paraganglioma.

The biologic behavior of the clear cell carcinoid tumor of the gallbladder is still unclear, because, to our knowledge, there has been only one case reported, in which follow-up was not mentioned.3 The same is true of the ordinary carcinoid tumors in the gallbladder, because follow-up of the reported cases is short.1 Generally, small carcinoid tumors of the gallbladder were incidentally found in resected gallbladders for gallstones, and the tumors smaller than 1 cm did not show metastases.1 Sporadic clear cell carcinoid tumors of other organs have not shown poor prognosis; in 4 reports5,6,8,9 with follow-up for a total of 8 cases, only one patient had widespread metastases at the time of publication.5 Of course, careful follow-up is mandatory for our patient because the tumor invaded into the subserosal layer.

In conclusion, we describe clear cell carcinoid tumor of the gallbladder not associated with VHL. It has histologic features similar to clear cell carcinoid tumors associated with VHL, except for the absence of inhibin reactivity. Immunostaining for inhibin might be a useful marker for clear cell carcinoid tumors associated with VHL.4

We gratefully acknowledge the diagnostic advice of K. Krishnan Unni, MB, BS (Department of Laboratory Medicine and Pathology, Mavo Clinic, Rochester, Minn).


1. Albores-Saavedra I, Henson DE, Klimstra D. Tumors of the Gallbladder Extrahepatic Bile Ducts and Ampulla of Vater. Washington, DC: Armed Forces Institute of Pathology; 2000. Atlas of Tumor Pathology; 3rd series, fascicle 27.

2. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997;79:813-829.

3. Sinkre PA, Murakata L, Robin L, Hoang MP, Albores-Saabedra J. Clear cell carcinoid tumor of the gallbladder: another distinctive manifestation of von Hippel-Lindau disease. Am I Surg Pathol. 2001;25:1334-1339.

4. Hoang MP, Hruban RH, Albores-Saavedra JA. Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma. Am J Surg PathoL 2001;25:602-609.

5. Smith NL, Finley JL. Lipid-rich carcinoid tumor of the thymus gland: diagnosis by fine-needle aspiration biopsy. Dian Cytopathol. 2001;25:130-133.

6. Gaffey NJ, Mills SE, Frierson HF Jr, Askin FB, Maygarden SJ. Pulmonary clear cell carcinoid: another entity in the differential diagnosis of pulmonary clear cell neoplasia. Am I Surg Pathol. 1998;22:1020-1025.

7. Ordonez NG, Mackay B, EI-Naggar A, Bannayan GA, Duncan J. Clear cell carcinoid tumour of the stomach. Histopathology. 1993;22:190-193.

8. Luk IS, Bhuta S, Lewin KJ. Clear cell carcinoid tumor of stomach: a variant mimicking gastric xanthelasma. Arch Pathol Lab Med. 1997;121:1100-1103.

9. Edmonds P, Merino MJ, LiVolsi VA, Duray PH. Adenocarcinoid (mucinous carcinoid) of the appendix. Gastroenterology. 1984;86:302-309.

10. Burke AP, Sobin LH, Federspiel BH, Shekitka KM. Appendiceal carcinoids: correlation of histology and immunohistochemistry. Mod Pathol. 1989;2:630637.

Eiichi Konishi, MD, PhD; Yasuaki Nakashima, MD, PhD; Thomas C. Smyrk, MD; Seiji Masuda, MD

Accepted for publication January 29, 2003.

From the Department of Laboratory Medicine, Saiseikai Kyoto Hospital, Nagaokakyo, Japan (Dr Konishi); Laboratory of Anatomic Pathology, Kyoto University Hospital, Kyoto, Japan (Dr Nakashima); Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn (Dr Smyrk); and Department of Surgery, Kyowa Hospital, Kyoto, Japan (Dr Masuda).

Reprints: Eiichi Konishi, MD, PhD, Department of Laboratory Medicine, Saiseikai Kyoto Hospital, 8 Imazato-Minamihirao, Nagaokakyo, Kyoto, 617-0814 Japan (e-mail:

Copyright College of American Pathologists Jun 2003
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