Cytologic features of low-grade cribriform cystadenocarcinoma of the submandibular gland: a case report.

BACKGROUND: Low-grade cribriform cystadenocarcinomas (LGCCC) are rare salivary gland tumors, classified into a variant of cystadenocarcinoma by the 2005 WHO classification. All previously reported cases arose from parotid glands, except for a case from a minor salivary gland. We report here for the first time a case of LGCCC arising from the submandibular gland. CASE: A 65-year-old man presented with a 4-cm multicystic mass in the left submandibular gland. Smears from fine-needle aspiration cytology showed tumor cells, appearing solitarily or partly in clusters, with thick cytoplasm and central nuclei. Some clustering tumor cells showed large cytoplasmic vacuoles and peripherally dislocated nuclei. Although these findings indicated a possible mucoepidermoid carcinoma in the submandibular gland, the final diagnosis of the resected specimen was LGCCC. CONCLUSION: LGCCC can arise not only from the parotid glands, but also in the submandibular glands. LGCCC is thought to be of low-grade malignancy; no reported cases have shown tumor metastasis and there are no patients who are known to have died of this disease. Thus, differential diagnosis of this tumor from other malignant salivary gland tumors is quite important; however, this might be difficult when based solely on cytological findings.

[A case of Barrett's esophageal carcinoma treated with combined therapy].

During a routine health examination, a 50-year-old man was found to have an elevated lesion at the esophagogastric junction. Poorly differentiated adenocarcinoma was diagnosed from the biopsy findings. Computed tomography showed metastases in the mediastinal, intra-abdominal, and paraaortic lymph nodes. The clinical stage diagnosis was cT2, cN4, cM0, cStage IVa. Combination chemotherapy with docetaxel, CDDP, and 5-FU (DCF) was started initially. After 2 courses of DCF, the primary lesion and mediastinal lymph nodes had decreased in size, but the intra-abdominal lymph node had grown. A curative operation with paraaortic lymph node dissection was considered possible; thus, video-assisted thoracoscopic surgery of the esophagus with 3-field lymph node dissection was performed. The final findings revealed Barrett's esophageal carcinoma, EG, 0-III,23×18 mm, mod-por, CT-pT1b (sm3) pN4, sM0, fStage IV. Histologically, the mediastinal lymph node metastases disappeared with chemotherapy, but no reduction was observed in the abdominal lymph nodes. After surgery, 2 courses of combination adjuvant chemotherapy with CDDP and 5-FU were administered along with 50 Gy of radiotherapy. Subsequently, the treatment was changed to tegafur-gimeracil-oteracil potassium alone on an outpatient basis. The patient remains recurrence free 22 months postsurgery.

Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment.

Secondary resistance of gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors occurs after several years' administration. However, the mechanism of resistance has not been fully clarified. In this study, we analyzed the genotypes and the histologic and immunohistochemical phenotypes of metastatic GISTs with and without imatinib treatment, and clarified the pleomorphic nature of metastatic GISTs. We examined 31 autopsy cases in which the patients died of multiple metastases of GISTs, and two surgically resected specimens with and without imatinib treatment. A total of 152 primary and metastatic lesions in 33 cases of GISTs were examined for histologic and immunohistochemical expression of KIT and CD34. We analyzed the expression of other receptor tyrosine kinases (RTKs) in KIT-negative lesions, including human EGFR-related 2 (HER2), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), platelet-derived growth factor receptor-alpha (PDGFRA), and platelet-derived growth factor receptor-beta (PDGFRB). Fifteen lesions in seven cases (9.9%) lacked KIT expression, and 74 (49%) in 22 cases lacked CD34 expression. Eight KIT-negative lesions in five cases expressed PDGFRB, one of which also expressed EGFR, and three lesions in one case expressed MET. Results for the other RTKs were negative. Missense point mutations at PDGFRB gene exon 12 were detected in one PDGFRB-positive case. Our results indicate that histomorphology, immunohistochemical phenotypes, and genotypes of metastatic GISTs vary among lesions, even in cases without imatinib treatment. A KIT-independent mechanism, such as activation of other RTKs, might participate in the proliferation of late-stage GISTs and might be a cause of secondary imatinib resistance.

Aberrant methylation status of known methylation-sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c-kit and PDGFRA gene mutations and their malignancy.

To identify additional alterations to c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes in gastrointestinal stromal tumors (GIST), we investigated the methylation status of nine known methylation-sensitive CpG islands (p15, p16, p73, 0-6-methylguanine-DNA methyltransferase, E-cadherin, mutL homolog 1, colon cancer nonpolyposis type 2 (escherichia), methylated in tumors [MINT]1, MINT2, and MINT31), and compared the results with the malignant potential and gain-of-function mutation types of GIST. Thirty-five GIST (c-kit mutations in 25 cases, PDGFRA mutations in seven cases, and lacking either mutation in three cases) were subjected to methylation-specific polymerase chain reaction to detect the methylation status of the nine methylation-sensitive CpG islands. Aberrant DNA methylation of these loci was found in 94% of all GIST. The rates of DNA methylation at each locus were as follows: hMLH1, 60%; MINT2, 51%; MGMT, 49%; p73, 49%; p16, 20%; E-cadherin, 14%; MINT1, 9%; p15, 6%; and MINT31, 0%. CpG islands methylator phenotype, which was defined as methylation involving more than three gene promoters, was found in 57% of GIST with c-kit or PDGFRA gene mutations. According to the risk categories, CpG islands methylator phenotype was present in 55% of low-risk GIST, and in 58% of high-risk GIST. Our results suggested that in addition to c-kit or PDGFRA mutations, the aberrant methylation of CpG islands, especially of mismatch-repair genes, may have a role in the tumorigenesis of GIST.

An Oncocytic Variant of Intraductal Papillary Neoplasm of the Bile Duct that Formed a Giant Hepatic Cyst.

Intraductal papillary neoplasms of the bile duct (IPNB) is the collective term used to refer to papillary bile duct tumors, mucin producing bile duct tumors, and cystic bile duct tumors. Pathologically, these tumors may be considered a highly differentiated adenocarcinoma or a tumor of borderline malignant potential. IPNB is classified into one of four variants based on cell differentiation. The rarest, oncocytic, is characterized by oxyphilic granular cytoplasm and no mucous cell differentiation. The patient, a 59-year old man, was admitted with a complaint of abdominal fullness and a 30×25 cm cystic mass in the right hepatic lobe demonstrated on computed tomography (CT). The mass had no malignant features on CT or magnetic resonance imaging; however, a portion was FDG avid on (18)F-fluorodeoxyglucose positron emission tomography scan (FDG-PET). A fenestration operation was performed for the presumed diagnosis of a hepatic cyst. Pathological examination of the cyst contents demonstrated some atypical cells suspicious for malignancy. After eight months of observation, abnormal FDG uptake was again observed at the residual cyst. A partial hepatectomy was performed to excise the cyst. Pathological examination demonstrated adenocarcinoma in situ derived from an oncocytic IPNB variant. Following the resection, the patient remained disease free for 40 months. This is an extremely rare case of an oncocytic variant of IPNB that was difficult to distinguish clinically from a solitary hepatic cyst.

Progressive transformation of the germinal center of extranodal organs: a clinicopathological, immunohistochemical, and genotypic study of 14 cases.

Progressive transformation of germinal center (PTGC) usually affects the peripheral lymph nodes. Little is known about the extranodal PTGC. To clarify the clinicopathological and molecular findings of extranodal PTGC, we studied 14 such cases. Using formalin-fixed, paraffin-embedded sections, we carried out histological and immunohistochemical examinations, as well as in situ hybridization (ISH) and polymerase chain reaction (PCR). Eleven patients were female, and three were male. They were between 44 and 77 years old, with a mean age of 62 years. The large intestine (n=7) was the most frequently involved tissue, followed by skin (n=2) and subcutaneous soft tissue (n=2). Oral cavity, Waldeyer ring, and orbit were affected in one case each. Histologically, 13 cases contained both early stage PTGC and late stage PTGC. The remaining 14th case contained only late stage PTGC. Expansion of the marginal zone was identified in three cases. Immunohistochemical study demonstrated the reactive nature of the B-cells in all 14 lesions. However, PCR study revealed immunoglobulin heavy chain (IgH) gene rearrangement in one of our 14 cases. There was no development of B-cell lymphoma in one lesion with IgH rearrangement. ISH study demonstrated Epstein-Barr virus-encoded small RNA+ cells in three lesions. Compared with PTGC of the peripheral lymph node, PTGC of extranodal sites was characterized by a female predominance, an older age group, and the presence of numerous PTGC at the affected sites. However, the histological findings of extranodal PTG were similar to those of lymph node PTGC. The clinicopathological findings of the extranodal PTGCs appeared to be different from those of lymph node PTGC.

Clinicopathological and immunohistochemical characteristics of esophageal carcinosarcoma.

BACKGROUND: Esophageal carcinosarcoma is a very rare neoplasm and its clinicopathological characteristics and the prognostic factors that influence the clinical outcome of the patient remain a matter of controversy. PATIENTS AND METHODS: Twenty patients with esophageal carcinosarcoma were referred to our institutions. Tissue blocks were reviewed and sections containing both carcinomatous and sarcomatous components were stained for epithelial and mesenchymal markers and a proliferating cell marker. The prognosis of the esophageal carcinosarcoma patients was compared with 142 cases of esophageal squamous cell carcinoma. RESULTS: In the carcinomatous component, the expression of cytokeratin, epithelial membrane antigen, vimentin, smooth muscle actin, and S100 were detected in 20, 20, 1, 1, and 1 case, respectively, whereas in the sarcomatous component, expression of these were detected in 4, 2, 18, 15, and 3 cases, respectively. The Ki-67 labeling index of carcinomatous and sarcomatous components was 35.5% and 41.8%, respectively. The 5-year survival rate was not statistically different between squamous cell carcinoma and carcinosarcoma (p=0.219). However, for T1 cases only, carcinosarcoma patients had statistically poorer prognosis than did squamous cell carcinoma patients (p=0.008). CONCLUSION: The sarcomatous component shows various histological and immunohistochemical forms. In comparison with squamous cell carcinoma patients, carcinosarcoma patients had poorer prognosis amongst the T1 cases. For the treatment of esophageal carcinosarcoma, it is important to monitor lymph nodes and be watchful for hematogenous metastasis, as in cases of esophageal squamous cell carcinoma.