Archives of Pathology & Laboratory Medicine - Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinoma Associated With X-Linked Hyperimmunoglobulin M Syndrome
Gastroenteropancreatic neuroendocrine tumors are uncommon tumors representing 2% of all gastrointestinal tumors. We report a case of a 21-year-old man with Xlinked hyperimmunoglobulin M (hyper-IgM) syndrome who presented with diarrhea and jaundice. An ultrasound and magnetic resonance imaging showed multiple variable- sized lesions in the liver and peripancreatic lymphadenopathy. The morphologic and immunohistochemical features of the biopsies from the liver and lymph node were consistent with poorly differentiated neuroendocrine carcinoma. Hyper-IgM syndrome is a rare primary immunodeficiency disease characterized by low serum IgG, IgA, and IgE levels with normal or elevated IgM levels. These patients are at a higher risk for developing malignancies, particularly adenocarcinoma of the gastrointestinal tract and lymphoma. A review of the literature of gastroenteropancreatic neuroendocrine tumors is presented with the discussion of a possible relationship of these tumors with immunodeficiency.
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(Arch Pathol Lab Med. 2008;132:847-850)
Neuroendocrine tumors (NETs) arise from the cells of the disseminated neuroendocrine system, which is widely distributed in the body. These are a rare and heterogeneous group of neoplasms characterized by differences in embryologic, biologic, and histopathologic aspects. 1 Gastroenteropancreatic NETs constitute about 2% to 3% of all gastrointestinal malignancies. In 2000, a new World Health Organization classification was established for gastroenteropancreatic NETs. These are now classified according to the classic structural criteria combined with proliferation index (measured by Ki-67) into well-differentiated NETs (proliferation index, 15%), poorly differentiated neuroendocrine carcinoma (>15%), mixed exocrine-endocrine tumors, and tumorlike lesions.
Hyperimmunoglobulin M (hyper-IgM) syndrome encompasses a family of congenital immunodeficiency states characterized by frequent infections and markedly low serum levels of IgG, IgA, and IgE but normal or elevated level of IgM.3 The major defect shared by all forms of the hyper-IgM syndrome is failure of immunoglobulin isotype switching. Mutations affecting at least 5 different genes have been identified to cause this immunodeficiency disorder. 4,5 These genes are involved directly or indirectly in B-cell signaling via CD40 and are required for class switching and somatic hypermutation. The most common form of hyper-IgM syndrome is X-linked and is due to mutation of the CD40 ligand (CD40L) gene.5 Most of these patients present with severe recurrent infections in early childhood. These patients are also at a higher risk for developing malignancies, particularly adenocarcinoma of the gastrointestinal tract and lymphoma.3 In this case study, we describe association of poorly differentiated gastroenteropancreatic neuroendocrine carcinoma in a patient with X-linked immunodeficiency with hyper-IgM (XHIGM).
REPORT OF A CASE
The patient was a 21-year-old man who was diagnosed with XHIGM a few weeks after birth. The patient had been on intravenous IgG and trimethoprim-sulfamethoxazole (Bactrim) prophylaxis since childhood because of his underlying immunodeficiency disorder. The patient was doing fairly well until he presented with diarrhea followed by pruritus, dark urine, and yellow discoloration of the skin and eyes. The jaundice was attributed to cholangitis caused by possible Cryptosporidium infection because of his underlying immunodeficiency state. The patient was put on treatment for presumptive Cryptosporidium infection even though the stool was negative for Cryptosporidium antigen. Laboratory data revealed elevated liver enzymes consistent with cholestasis. Carcinoembryonic antigen and CA 125 levels were within the normal reference range. Computed tomography scan and magnetic resonance imaging of the abdomen revealed multiple moderate-sized hypovascular lesions with rim enhancement in the liver and peripancreatic lymphadenopathy with compression of the common bile duct and uncinate process leading to biliary and pancreatic duct dilatation. A filling defect in the second portion of the duodenum and ampulla of Vater was present. The computed tomography scan and magnetic resonance imaging findings were suspicious for lymphoma or an adenocarcinoma arising from the duodenum or ampulla of Vater. The other findings on limited clinical workup, including chest radiography and bone scan, were within normal limits. Endoscopic-guided fineneedle aspiration biopsies were performed on the liver and peripancreatic lymph nodes.
MATERIALS AND METHODS
The endoscopic-guided fine-needle aspiration smears and biopsies from liver and peripancreatic lymph nodes were available for review. Commercially available antibodies against pan-cytokeratin (1:400; Dako, Carpinteria, Calif), synaptophysin (1:200; Dako), chromogranin (1:100; Dako), CD99 (1:700; Dako), leukocyte common antigen (1:400; Dako), trypsin (1:2000; Dako), chymotrypsin (1:750; Dako), desmin (1:200; Dako), WT-1 (1:100; Dako), and Ki-67 (1:400; Dako) were applied to further characterize the tumors. Immunohistochemical studies were performed on representative deparaffinized slides using an automated slide stainer (Ventana Benchmark, Ventana Medical Systems, Tucson, Ariz).
