College of American Pathologists
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2009 — April Case of the Month

Updated March 27, 2009


CAP Foundation April 2009 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 39-year-old woman presented with recurrent bouts of right upper quadrant pain. Radiographic studies revealed gallbladder stones. A cholecystectomy was performed. A 9.0 cm gallbladder was received containing multiple stones measuring up to 0.5 cm. The wall was diffusely thickened without masses. An immunostain for tryptase was positive in the majority of cells.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2006, Case 6 and is a Mastocytosis.

Criteria for Diagnosis and Comments:
This is a case of mastocytosis involving the gallbladder. The gallbladder is diffusely infiltrated by round to oval cells with small to medium sized centrally located oval nuclei. Most cells have abundant cytoplasm filled with fine granules. The mast cells in this case are tryptase(+), CD117(+), CD2(+) and CD25(+).

In most cases, neoplastic mast cells are accompanied by eosinophils. Rare cells show high N/C ratio and blast-like morphology may be present. Tryptase and CD117 are expressed in normal and abnormal mast cells whereas CD2 and CD25 are only expressed in systemic mastocytosis. The use of these markers is the best way to confirm the presence of mastocytosis. Systemic mastocytosis typically involves the skin, bone, lymph nodes and parenchymal organs.

Most variants of mastocytosis are clonal disorders with a range of behavior from indolent to aggressive. WHO recognizes the following subtypes; cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with an associated clonal hematologic non mast cell lineage disease, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma.

Involvement of gastrointestinal organs has been reported in 40-80% of patients with systemic mastocytosis. Studies have reported liver involvement in 12-83% with a mean of 48% of cases. Hepatomegaly has been reported as the initial manifestation of systemic mastocytosis. The percentage of cases involving the liver increases with disease aggressiveness. Involvement of the gallbladder is rare, although there are reports of systemic mastocytosis presenting as sclerosing cholangitis.

The differential diagnosis is primarily with infiltrative, infectious and inflammatory conditions. Xanthogranulomatous cholecystitis may present as a mass but could be diffuse. The lesion is often tumefactive with fistula formation. Histologically, there is diffuse infiltration by foamy histiocytes with lymphocytes and plasma cells. Multinucleated giant cells may be seen.

Eosinophilic cholecystitis may be diagnosed when there is massive infiltration of the gallbladder by eosinophils. Eosinophilic infiltrates may be seen in association with acute and chronic cholecystitis. Eosinophilic cholecystitis has been reported in association with an echinococcal cyst, but is also seen with hypereosinophilic syndrome and eosinophilic gastroenteritis. If numerous eosinophils are present, a tryptase stain may be helpful, as mast cells can be cytologically subtle, blending with other mononuclear inflammatory cells.

Atypical mycobacterial infection may show diffuse infiltration of the gallbladder by histiocytes particularly in immunocompromised individuals. This diagnosis may be confirmed with an acid-fast stain. Whipple disease may show a similar pattern of involvement with diffuse infiltration by foamy histiocytes. PAS stain is brightly positive in these cells. PCR testing for Tropheryma whippelii may also be performed to confirm the diagnosis of Whipple disease.

Langerhan cell histiocytosis may involve the gallbladder as nodules or diffusely. Confirmation of this disease may be done with immunostains for S100 protein and CD1a and by electron microscopic identification of Birbeck granules.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which entity can be diagnosed by the ultrastructural identification of Birbeck granules? A. Atypical mycobacterial infection
B. Eosinophilic cholecystitis
C. Langerhan cell histiocytosis
D. Mastocytosis
E. Whipple disease
F. Xanthogranulomatous cholecystitis
2. The cells of which entity are usually positive for tryptase and CD117? A. Atypical mycobacterial infection
B. Eosinophilic cholecystitis
C. Langerhan cell histiocytosis
D. Mastocytosis
E. Whipple disease
F. Xanthogranulomatous cholecystitis
3. PAS stain is helpful in the diagnosis of which entity? A. Atypical mycobacterial infection
B. Eosinophilic cholecystitis
C. Langerhan cell histiocytosis
D. Mastocytosis
E. Whipple disease
F. Xanthogranulomatous cholecystitis


  1. Baron TH, Koehler RE, Rodgers WH, et al. Mast cell cholangiopathy: Another cause of sclerosing cholangitis. Gastroenterology 1995:109;1677-1681.
  2. Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematology/Oncology Clinics of North America 2000:14;579-623.
  3. Mican JM, DiBisceglie AM, Fong TS, et al. Hepatic involvement in mastocytosis:Clinicopathologic correlation in 41 cases. Hepatology. 1995:22;1163-1170.
  4. Valent P, Akin C, Sperr WR, et al. Mastocytosis: Pathology, genetics, and current options for therapy. Leukemia and Lymphoma. 2005:46;35-48.
  5. Valent P, Horny HP, Escribano L, et al. Diagnositic criteria and classification of mastocytosis: a consensus proposal. Leukemia Research. 2001:25;603-625.
  6. Yam LT, Chan CH, Li CY. Hepatic involvement in systemic mast cell disease. Am J Med. 1986:80;819-826.
Raouf Nakhleh, MD
Surgical Pathology Committee
Mayo Clinic Jacksonville
Jacksonville, FL