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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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Gallbladder Paraganglioma: A Case Report With Review of the Literature
From Archives of Pathology & Laboratory Medicine, 4/1/05 by Mehra, Shveta

We report a case of gallbladder paraganglioma that was discovered during nonrelated surgery. Retrospective study disclosed a family history of pheochromocytoma. The occurrence of gallbladder paraganglioma in the presence of family history of endocrine neoplasia supports that gallbladder paraganglioma may indeed occur as a part of the multiple endocrine neoplasm syndrome. Gallbladder paraganglioma is a rare tumor, and so far to our knowledge only 6 cases have been reported in the literature. Three cases were discovered incidentally during cholecystectomy for cholelithiasis, 2 presented with right upper quadrant pain, and 1 manifested with gastrointestinal bleeding. We herein review all reported cases of paraganglioma of gallbladder and biliary system.

(Arch Pathol Lab Med. 2005;129:523-526)

During embryogenesis, neural crest cells migrate to diverse locations in the body and differentiate into chief and sustentacular cells, which are designated as paraganglia.

Paragangliomas are rare extra-adrenal tumors of the paraganglia, and they are found in association with sympathetic and parasympathetic nerves. Paragangliomas in the head, neck, and mediastinum are usually associated with the parasympathetic system and are chromaffin negative and nonfunctional. Extra-adrenal retroperitoneal paraganglia are usually associated with the sympathetic system and are chromaffin positive and functional.1 No difference in survival is noticed in functional versus nonfunctional paragangliomas. However, extra-adrenal tumors are more likely to be malignant than adrenal tumors.2,3

Paragangliomas can occur in a variety of locations including the orbit, nose, ear, carotid area, vagus nerve, larynx, mediastinum, retroperitoneum, organ of Zuckerkandl, urinary bladder, cauda equina, duodenum, prostate, cheek, and thyroid. Among the reported cases of gallbladder paraganglioma,4-7 the association with other endocrine neoplasias has not been well documented.


A 36-year-old man was admitted for a Roux-eivY gastric bypass procedure for morbid obesity. His medical history was significant for hypertension, obstructive sleep apnea, hypothyroidism, asthma, and depression. He had a history of cocaine intake and smoking in the past but denied any alcohol abuse. Physical examination was unremarkable except for morbid obesity. Results of routine admission laboratory tests, including liver function profile, were unremarkable. Two months prior to admission, the patient had experienced vague right upper quadrant discomfort. An ultrasound of the gallbladder at that time did not demonstrate stones or mass.

At operation, a round mass of 1.5-cm diameter was noted in the wall of the gallbladder. The gallbladder was otherwise normal in appearance. Cholecystectomy was performed, and frozen section of the mass demonstrated gallbladder paraganglioma and extensive cholesterolosis. Permanent sections confirmed the diagnosis of gallbladder paraganglioma. His pre-operative blood pressure was 170/98 mm Hg, and postsurgical blood pressure remained in a range of 134/76 to 142/78 mm Hg. This suggested that his hypertension might be related to the tumor. However, there was no record regarding changes in blood pressure postprandially or during the operation. Because the tumor was found incidentally during the gastric bypass surgery, serum norepinephrine or urinary vanillylmandelic acid levels were not measured. The patient's postoperative course was uncomplicated, and he was discharged on the 6th day after admission. No further therapy was thought to be indicated. Retrospective follow-up study revealed no other tumor but disclosed a family history of pheochromocytoma in one of the patient's siblings.


Grossly, the gallbladder measured 10.5 cm in length and 4.5 cm in maximum diameter. The serosal surface was smooth, shiny, and congested. A mass of 1.5 cm in diameter was palpable at the fundus of the gallbladder. On opening the gallbladder, the mucosa revealed diffuse cholesterolosis, and there was a well-circumscribed round intramural mass. The cut surface of the mass was tan-red and focally hemorrhagic, and it appeared to be situated within the wall without involving mucosal or serosal surfaces.

Microscopically, the tumor was highly vascular and completely surrounded by a thin fibrous capsule. The tumor cells were arranged in small islands forming ZeIlballen nests (Figure 1, a). The alveolar nesting pattern is accentuated by reticulin stain (Figure 1, b). Individual cells were round to polygonal, with finely granular eosinophilic to amphophilic cytoplasm and centrally located ovoid nuclei with stippled "salt and pepper" chromatin and small inconspicuous nucleoli. Grimelius stain demonstrates many distinct fine cytoplasmic argyrophilia. Occasional tumor cells contain globules positive for periodic acid-Schiff in the cytoplasm (Figure I, c). There was no tumor necrosis or cellular pleomorphism, and the mitotic activity was very low. In addition to extensive cholesterolosis, chronic cholecystitis was present. The immunohistochemlcal stains for chromogranin and synaptophysin were strongly positive in the tumor cells (Figure 2, a), and stain for SlOO was positive only in sustentacular cells (Figure 2, b). Stain for CD34 was positive only in vascular channels, and stains for keratin and smooth muscle actin were negative. On the basis of typical histopathologic and immunohistochemical findings, a diagnosis of gallbladder paraganglioma was made. There was no vascular or lymphatic invasion, and the serosal and surgical resection margins were free of the tumor.


Review of all 7 reported cases (including our case) of gallbladder paraganglioma indicates that all 6 cases except ours presented with signs and symptoms related to gallbladder disorder (Table 1). Three of these 7 cases presented with cholelithiasis, and paraganglioma was an incidental finding. Two cases presented with upper abdominal pain, and a mass was seen on radiologie investigation. The sixth case presented with recurrent hematemesis from cholecystoduodenal fistula, which resulted from scarring associated with gallbladder paraganglioma. The present case did not have any signs and symptoms related to gallbladder. None of these 7 cases had clinical manifestations related to the sympathetic system. The size of these tumors ranged from 1.3 to 3 cm. Two of the 7 cases were located at the fundus, whereas 1 was in the neck of the gallbladder. The tumor location was not mentioned in the other 4 cases. The tumor was present subscrosally in 4, whereas 1 tumor was located in the submucosa. In 2 cases, the position was not mentioned. Cholecystectomy was adequate treatment in all these cases. Our patient had a family history of pheochromocytoma in a sister. However, no other endocrine tumor or family history was described in previously reported cases.

Three cases of hepatic duct paraganglioma have been reported.1,8,9 Two of these cases presented with obstructive jaundice, whereas the third case did not have any signs and symptoms related to obstruction. Instead, this patient presented with right upper quadrant pain. The authors attributed the absence of obstructive features to the early stage of the tumor. Farrell et al10 reported a nonfunctioning paraganglioma simultaneously involving the liver, gallbladder, common bile duct, celiac, and portal lymph nodes. The features of all these tumors are summarized in Table 2.

Biliary system paragangliomas are predominantly seen in females and are discovered in the fifth to sixth decade of life. Although they are usually small in size, the largest reported tumor was 5 cm in diameter. Because these tumors are nonfunctioning, they are typically discovered secondary to their complications, such as obstructive jaundice, right upper quadrant pain, and gastrointestinal bleeding, or incidentally during gallbladder or unrelated surgery. When found in the gallbladder, they are most commonly located in subserosa. Interestingly, all these tumors are nonfunctioning. Thus, they mimic chromaffin-negative extra-adrenal tumors found in the head, neck, and mediastinal region, as opposed to the extra-adrenal retroperitoneal paragangliomas.

So far, no familial association has been reported in any of the paragangliomas of the biliary system. To our knowledge, our patient is the first case of biliary system paraganglioma with a family history of multiple neuroendocrine neoplasm syndrome. Hereditary paraganglioma is a rare genetic disease characterized by development of mostly benign tumors in the head and neck regions. Familial paragangliomas may occur in the absence or presence of other familial disease syndromes such as multiple endocrine neoplasia (MEN), type 2A (most common); MEN, type 2B; von Recklinghausen disease; and von Hippel-Lindau syndrome.11 They are most commonly observed after the third decade of life, although they can be seen in the early teen years. Another characteristic feature of familial tumors is multicentricity and bilaterality. A peculiar pattern of inheritance called genomic imprinting has been seen in Dutch families. The disease gene is mapped to approximately 6Mb critical region on chromosome band Ilq23 (PGLl] and has shown deletion at the involved site.12

Because extra-adrenal tumors are more commonly malignant than adrenal tumors, gallbladder paraganglioma should not be misinterpreted as a secondary deposit, specifically in the setting of MEN syndrome, where multiple tumors are present. Distinguishing malignant tumors from benign paraganglioma is not histologically easy. None of the suggested histologie features can independently predict the biological behavior of tumors. However, coarse nodularity, absence of hyaline globules positive for periodic acid-Schiff, and an extra-adrenal location are known to be suggestive of a malignant nature. Other features suggestive of malignant behavior are alveolar pattern, decrease in sustentacular cells, extra-adrenal location, high mitotic count (3/30 per high-power field), large size of the tumor, hemorrhage and tumor necrosis, male sex, local aggressiveness, multicentricity, bilaterality, pleomorphism, and capsular and vascular invasion. Distant metastasis is the most reliable and definitive indicator of malignancy.3,13 DNA ploidy studies have suggested that benign tumors can be euploid or aneuploid, whereas malignant tumors are aneuploid.14

Primary gallbladder paragangliomas theoretically arise from primordia of hepatic plexus, which innervates the gallbladder, and are formed from sympathetic and parasympathetic fibers of the left vagus nerve and celiac plexus.4 It is important to realize that primary gallbladder paraganglioma, although rare, may occur, and it should be considered in the differential diagnosis of gallbladder lesions. A careful search should be carried out, as in this case, for the possible association with MEN syndrome.


1. Caceres M, Mosquera LF, Shih JA, O'Leary JP. Paraganglioma of the bile duct. South Med J. 2001:94:515-518.

2. Sclafani LM, Woodruff JM, Brennan MF. Extraadrenal retroperitoneal paragangliomas: natural history and response to treatment. Surgery. 1990:108:1124-1129: discussion 1129-1130.

3. Pommier RF, Vetto JT, Billingsly K, Woltering EA, Brennan MF. Comparison of adrenal and extraadrenal pheochromocytomas. Surgery. 1993:114:1160-1165; discussion 1165-11 66.

4. Miller TA, Weber TR, Appelman HD. Paraganglioma of the gallbladder. Arch Surg. 1972:105:637-639.

5. WoIff M. Paraganglioma of the gallbladder [letter]. Arch Surg. 1973;107: 493.

6. Cho YU, Kim JY, Choi SK, et al. A case of hemorrhagic gallbladder paraganglioma causing acute cholecystitis. Yonsei Med J. 2001:42:352-356.

7. Hirano T. Paraganglioma of the gallbladder: report of a rare case. Am I Gastroenterol. 2000:95:1607-1608.

8. Hitanant S, Sriumpai S, Na-songkla S, Pichyangkula C, Sindhavananda K, Viranuvatti V. Paraganglioma of the common hepatic duct. Am I Gastroenterol. 1984:79:485-488.

9. Sarma DP, Rodriguez FH |r, Hoffmann EO. Paraganglioma of the hepatic duct. South Med]. 1980:73:1677-1678.

10. Farrell KD, NgA, Rouch D, Chua CT. Nonfunctioning paraganglioma of the liver, gallbladder and common bile duct [review]. Indiana Med. 1990:83: 822-824.

11. Wenig BM, Heffess CS, Adair CF. Pheochromocytoma. Philadelphia, Pa: WB Saunders Co; 1997.

12. Baysal BE, van Schothorst EM, Farr JE, et al. Repositioning the hereditary paraganglioma critical region on chromosome band 11q23. Hum Genet. 1999; 104:219-225.

13. Linnoila Rl, Keiser HR, Steinberg SM, Lack EE. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologie features. Hum Pathol. 1990;21:11 681180.

14. Pang LC, Tsao KC. Flow cytometric DNA analysis for the determination of malignant potential in adrenal and extra-adrenal pheochromocytomas or paraangliomas. Arch Pathol Lab Med. 1993;! 17:1142-1147.

Shveta Mehra, MD; Moonja Chung-Park, MD

Accepted for publication October 14, 2004.

From the Department of Pathology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio. Dr Mehra is currently with the Department of Pathology at Henry Ford Hospital in Detroit, Mich.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Shveta Mehra, MD, Cytopathology, Division of Pathology, Room WC608, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, Ml 48202 (e-mail:

Copyright College of American Pathologists Apr 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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