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Journal of Cancer Research and Therapeutics, Vol. 6, No. 3, July-September, 2010, pp. 379-381 Case Report Signet ring cell carcinoma of gallbladder with celiac lymph node metastasis in a young man Santosh Kumar Mondal Department of Pathology, Medical College, Kolkata, West Bengal, India Correspondence Address:Santosh Kumar Mondal," Teenkanya Complex", Flat 1B, Block B, 204 RN Guha Road, Dumdum, Kolkata - 28, West Bengal, India, dr_santoshkumar@hotmail.com Code Number: cr10094 PMID: 21119284 DOI: 10.4103/0973-1482.73355 Abstract Gall bladder cancer is uncommon and histologically most of these are adenocarcinomas. Signet ring cell carcinoma is a rare malignancy of gallbladder. Only few cases of this histologic type have been published and detailed knowledge of this disease is not available. Here, signet ring cell carcinoma of the gallbladder in a 32-year-old man is being reported. The patient had metastasis in the celiac group of lymph nodes at the time of diagnosis. The patient underwent radical surgery, followed by chemotherapy but succumbed to the illness two months post-operatively. Newer treatment modalities and advanced information may improve the prognosis of the disease.Keywords: Gallbladder, signet ring cell carcinoma Introduction Carcinoma of the gallbladder is more frequent in females than males (3 to 4:1 ratio); over 90% of the patients are 50 years of age or older. [1] The incidence is high in American Indians, relatively low in whites of European origin, and very rare in blacks. Gall stones are present in 60% to 90% of gallbladder carcinoma and mostly of cholesterol type. Multivariate analysis has shown that the presence of gallstones is a risk factor independent of age and sex. Presenting symptoms of gallbladder cancer are insidious and typically indistinguishable from those with cholelithiasis: jaundice, nausea, vomiting, anorexia and abdominal pain. Carcinoma is the most common type of gallbladder cancer and adenocarcinoma is the usual type. Signet ring cell carcinoma is an unusual type adenocarcinoma with a very low incidence. Other epithelial malignancies like adenosquamous carcinoma, small cell or oat cell carcinoma, undifferentiated carcinoma are rare. Carcinosarcoma, carcinoid tumor, malignant melanoma, primary sarcoma, non Hodgkin Lymphoma have also been reported in the gall bladder. Case Report A 32-year-old man presented with right upper quadrant abdominal pain, anorexia and jaundice for three months. Radiological investigation revealed an enlarged gallbladder with a growth in the neck region. Routine hematological investigations were within normal limit except for mild anemia. Biochemical investigation showed increased bilirubin and a slightly raised alkaline phosphatase level. The patient underwent cholecystectomy with removal of two celiac lymph nodes. Pathological findings: A hugely enlarged gallbladder measuring 16.5 × 8 cm was received. A mass was seen at the neck region of the gallbladder and the lumen was filled with mucinous fluid [Figure - 1]. The tumor measured 2.8 × 1.6 cm and involved the mucosa, muscularis propria and serosal layer. Mucosa of other part of gall bladder was unremarkable, but was bile stained. Two celiac group of lymph nodes were sampled, measuring 1.6 Χ 1.2 cm and 0.6 Χ 0.4 cm respectively. Microscopic examination revealed the tumor composed of signet ring cells. The tumor arose from the sub epithelial layer of mucosa and involved all the layers of gallbladder. The signet ring cells were present diffusely involving all the layers. Nuclear atypia and mitoses were present. Periodic acid Schiff (PAS) stain highlighted the intracellular mucin in the tumor cells [Figure - 2]. Extracellular mucin was also present in a small area (< 10%). Lymphovascular emboli were detected in the subserosal layer and the larger celiac lymph node showed metastatic deposit of signet ring cells. The smaller lymph node was uninvolved. The patient received post-operative chemotherapy with 5-flurouracil (5-FU) but the patient succumbed within two months postoperatively. Discussion Gallbladder cancer, though common among gastrointestinal malignancies, is not a very a frequent cancer leading to death. There is a scarcity of knowledge about the development of gallbladder cancer. In a review of 25,871 cholecystectomies performed in patients aged 45+/-16 years, 210 had dysplasia not associated to cancer and 1038 had gallbladder cancer. All cases of dysplasia were incidental findings. In carcinomas, the incidence of metaplasia, dysplasia and carcinoma in situ observed in adjacent mucosa was 66%, 81% and 69% respectively. [2] Gallbladder carcinoma may present as focal or diffuse asymmetric wall thickening in 20-30% cases. Gallbladder wall thickening can have a list of differential diagnoses, including acute and chronic cholecystitis, and adenomyomatosis, as well as diffuse hepatic or systemic diseases such as acute hepatitis, portal hypertension, and congestive heart failure. [3] The initial detection of gallbladder carcinoma as a polypoid lesion occurs in 15-25% of cases. Malignant lesions are usually larger than 1 cm in diameter and may have a thickened implantation base. [4] In a comparative analysis; proliferative, apoptotic activity as well as of microvascular density (MVD) were measured in metaplasia, dysplasia and gallbladder carcinoma. For this immunohistochemical staining (IHC) was done using KI-67, p53 and CD34 antibodies with streptavidin-biotin method. It was found that all carcinomas were p53 positive (100%), its expression varying from 30% in papillary areas and 3-50% in undifferentiated adenocarcinoma to 80-100% in well differentiated type. MVD of 15-30 vessels/high power field (established on five representative fields) was seen in carcinomas. In contrast, five-eight vessels/high power field was seen in chronic cholecystitis in areas adjacent to pyloric metaplasias. [5] MUC1 core protein expression is significantly higher (P<0.0001) in gallbladder cancer compared to non-cancerous tissue, while, very trace in normal and inflammatory tissues. Significant lower expression is noted (P<0.0001) when the cancer did not penetrate the mucosal layer than when cancers did penetrate this layer. [6] A human gallbladder cancer cell line (FU-GBC-2) was established in tissue culture from the ascitic fluid. The tumor cells growing in tissue culture exhibited the morphological characteristics of signet ring cells in electron and phase contrast microscopy. [7] In the present case, the tumor cells (signet ring cells) involved all the layers of gallbladder wall. But the adjacent mucosa did not show any dysplastic or metaplastic changes. Inflammatory cell infiltration was absent and overlying mucosal epithelial layer had no ulceration. Though gallbladder cancer is usually seen in elderly patient, the present case was seen in a young man (32 years). The exact pathogenesis of the development of signet ring cell carcinoma in this patient was not known. Majority of gallbladder cancers also have gall stones (60-90%). But this patient had no gall stone and lumen was filled with mucin. Mucinous adenocarcinoma of gallbladder with a predominance of signet ring cells was found at autopsy in a 65-year-old male automotive worker. [8] A review of 1808 cases of gallbladder and bile duct cancers from the California Tumor Registry noted a significant association between gallbladder carcinoma and work in the automotive, rubber, wood-furnishing, textile and metal -fabricating industries. Sometimes nonneoplastic signet ring cells may be confused with signet ring cell carcinoma. The lack of nuclear atypicality, the arrangement in superficial and intraluminal nests and the admixture of histiocytes and other inflammatory cells favor signet-ring change (nonneoplastic). [9] Hyperchromatism or mitotic activity is also absent in benign signet ring cell change. [10] Nuclear atypia, mitotic figures, hyperchromatism and absence of inflammatory cell infiltration were seen in this case and confirm the diagnosis of carcinoma. Not only that, patient had lymphovascular emboli which is not detected in benign/ nonneoplastic changes. Signet ring cell carcinoma of gallbladder with metastasis is extremely rare but this patient had metastasis in celiac lymph node. [11] Ultrastructurally, signet ring cell carcinoma of gallbladder reveals mucin vacuoles and the intracytoplasmic lumina, some of which are cystically dilated. In contrast, well-differentiated adenocarcinoma recapitulates the ultrastructure of normal surface epithelium although columnar cell predominates; the narrow and dark-staining pencil-like cells are also present. Oat cell carcinoma contains neurosecretory granules but also exhibits glandular markers. [12] This patient received 5-fluorouracil infusion after surgery. But he survived only for two months. D′Angelica et al., observed poor outcomes after overaggressive surgeries such as major hepatectomies and bile duct resections performed when clinically not indicated. [13] This finding reaffirms the basic oncologic tenet that survival of gallbladder cancer patients is determined by tumor biology and not by extent of resection. [14] Further studies are needed regarding better treatment modalities of unusual gallbladder malignancies like signet ring cell carcinoma. References
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