Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinoma Associated With X-Linked Hyperimmunoglobulin M Syndrome
By Malhotra, Reenu K Li, Wei
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. (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, <2%), well-differentiated neuroendocrine carcinoma (proliferation index, <2% but >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).
PATHOLOGIC FINDINGS
The smears and cell block prepared from the endoscopic- guided fine-needle aspirate of the liver mass revealed a cellular tumor composed of small round blue cells with a high nuclear-cytoplasmic ratio, hyperchromatic nuclei with inconspicuous nucleoli, and frequent mitosis (7/10 high-power fields) (Figure, A). Necrosis is readily identified. The tumor also had focal areas of small glandular and acinar structures. The biopsy from the peripancreatic lymph node revealed a malignant tumor with similar features (Figure, B). Based on these morphologic features, the differential diagnosis included lymphoma, primitive neuroectodermal tumor, poorly differentiated neuroendocrine carcinoma, pancreatic acinar cell carcinoma, and desmoplastic small round cell tumor. The immunohistochemical stains revealed tumor cells to be strongly positive for pancytokeratin (Figure, C), synaptophysin (Figure, D), and chromogranin (Figure, E) with variable staining for CD99. The tumor cells were negative for leukocyte common antigen, trypsin, chymotrypsin, desmin, and WT-1. The Ki- 67 showed staining of more than 90% of the tumor population (Figure, F).
The morphologic and immunohistochemical findings were consistent with a poorly differentiated neuroendocrine carcinoma (World Health Organization 2000 classification). A subsequent computed tomography scan indicated low-density lesions in the pancreatic head and uncinate process. A computed tomography scan with contrast and pre- enhanced images to the liver showed multiple hypervascular lesions and a single cystic lesion with rim enhancement. An octreotide scan revealed multiple focal areas of increased activity throughout the liver and pericaval and periaortic space suggesting a NET. These findings were most compatible with a poorly differentiated gastroenteropancreatic neuroendocrine carcinoma with metastasis to the liver and peripancreatic lymph nodes. The exact primary site of origin of the tumor is uncertain.
COMMENT
X-linked immunodeficiency with hyper-IgM is a rare disorder characterized by reduced serum IgG, IgA, and IgE levels with normal or elevated IgM levels.3,6 It is caused by mutation in the CD40L gene and consequent failure to express CD40L on the T cells. CD40- CD40L interactions are essential for T-cell and B-cell function and isotype switching. The hypogammaglobulinemia is due to failure of B cells to initiate immunoglobulin class switching as B cells require a CD40-mediated signal. The disease is very rare with approximate incidence being 1 per 1 million. 6 These patients usually present with recurrent infections and sepsis because of deficiency of IgG and IgA. In a study consisting of large group of patients with XHIGM, the most common infections were pneumonia, recurrent sinusitis and otitis, recurrent diarrhea, and central nervous system infections. In addition, opportunistic infections with Pneumocystis carinii, cytomegalovirus, and Cryptosporidium are also common.6 Sclerosing cholangitis usually occurs in association with Cryptosporidium infection.
The patients with XHIGM are more likely to develop carcinomas of the liver, pancreas, biliary tree, and the associated neuroectodermal endocrine cells.3,6 The exact mechanism leading to development of neuroendocrine carcinomas in these patients is not known. One postulated mechanism for the high prevalence of tumors of the biliary tract in these patients is due to cholangitis caused by infections with Cryptosporidium and cytomegalovirus.7 The bile ducts, exocrine and endocrine pancreas have a common embryologic origin in the duodenum and hepatic ducts. It has been postulated that malignant transformation of bile duct epithelium occurs because of cholangitis, and differentiation of the malignancy along the embryologic pathway may impart a histologic appearance of either bile duct carcinoma or NET.3 Review of the literature also suggests that cholangitis alone is unlikely to be the only contributing factor for development of bile duct tumors. The other mechanism postulated is related to the occurrence of CD40 on several cancer cell types and absence of CD40L on the activated T cells in patients with XHIGM. The presence of CD40 in other cell types, such as follicular dendritic cells, bladder carcinoma, fibroblasts, melanomas, and endothelial cells, suggests a role of CD40- CD40L interaction in host defense. The CD40-CD40L interaction has been postulated to induce apoptosis of the infected cells thus contributing to host defense.3 Other than hepatobiliary neoplasms, there have been reports of XHIGM syndrome association with oat cell carcinoma of the colon, cutaneous sarcoidlike granulomas, and Kaposi sarcoma.8,9 Neuroendocrine gastroenteropancreatic tumors are not common and constitute 2% to 3% of all gastrointestinal malignancies. According to the World Health Organization 2000 classification, the gastroenteropancreatic NETs are classified into well-differentiated NETs (benign or uncertain malignant potential), well-differentiated neuroendocrine carcinomas (low-grade malignancy), and poorly differentiated “usually small cell” neuroendocrine carcinomas (high- grade malignancy).2 The ileum, appendix, and rectum are the most common sites of involvement followed by colon, stomach, and duodenum. The most important criteria of malignancy in pancreatic NETs are tumor size (invasion of adjacent2 cm), angioinvasion, proliferative activity (invasion of adjacent2%), invasion of adjacent organs, and metastases to the regional lymph nodes and liver.2 The presenting symptoms are nonspecific and consist of abdominal pain, nausea, diarrhea, weight loss, and carcinoid syndrome (10%).10 The most common site of metastases is regional lymph nodes. Distant metastatic sites include liver (44%), lung (14%), peritoneum (14%), and pancreas (7%). Octreotide scan can help in localization of the primary site when a NET presents as hepatic metastasis from an unknown primary. The presence of lymph node or hepatic metastasis is definitive diagnosis of malignancy. Most NETs have indolent behavior despite presence of distant metastasis with a reported 5-year survival rate of 53%.10
The case presented here is a poorly differentiated NET in a patient with XHIGM who presented with jaundice secondary to malignant biliary obstruction. Poorly differentiated neuroendocrine carcinomas constitute less than 1% of all NETs of the gastroenteropancreatic system.11 They are usually metastatic at the time of diagnosis and carry very poor prognosis irrespective of their location in the gastrointestinal tract.11,12 These tumors are less likely to be functional, and typical hormonal syndromes are not seen. Given the increased risk of development of malignancies in XHIGM patients, clinical monitoring of these patients is necessary by ultrasound and carcinoembryonic antigen levels.
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Reenu K. Malhotra, MD; Wei Li, MD, PhD
Accepted for publication December 5, 2007.
From the Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, Medical School, Houston.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Reenu K. Malhotra, MD, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, Medical School, 6431 Fannin St, MSB 2.278, Houston, TX 77030 (e- mail: reenu66@yahoo.com).
Copyright College of American Pathologists May 2008
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