Clinical and Histopathologic Features of Colorectal Adenocarcinoma in Crohn's Disease.

GOALS: The aim of this study was to assess the histopathologic characteristics of colorectal carcinomas (CRC) in patients with Crohn's disease (CD). BACKGROUND: A higher frequency of microsatellite instability (MSI) is seen in mucinous compared with nonmucinous CRC which suggests that its pathogenesis involves distinct molecular pathways. Several publications reported a higher percentage of mucinous adenocarcinoma in CD patients with CRC. So far, there has been no investigation of MSI in CD patients with mucinous CRC. STUDY: The medical records of patients who underwent surgery for CRC were reviewed and those with a history of CD identified. The data of histologic classification and MSI status of the tumor were investigated. RESULTS: Fourteen patients with CD-associated CRC were identified (5 female, 9 male) resulting in 20 CRC in total. Histologic investigation revealed 7 adenocarcinomas without a mucinous or signet ring cell component. All other CRCs harbored a mucinous (n=11) and/or signet ring cell (n=6) component. All tumors assessed for MSI were found to be microsatellite stable. CONCLUSIONS: Our data indicate that CRCs with signet ring cell and mucinous components were much more common in patients with CD than in patients with sporadic CRC. This observation suggests that CRC in CD represent an own entity with distinct histopathologic and molecular features. This may implicate potential consequences for diagnosis and therapy of CRC in CD in the future as well as new factors to identify patients with an increased risk for developing CRC in CD.

Cutaneous Apocrine Carcinoma With an In Situ Component and Histiocytoid and Signet-Ring Cells.

We present a case of cutaneous apocrine carcinoma arising in the axilla of a 71-year-old man. The tumor had a significant component of histiocytoid and signet-ring cells as well as in situ carcinoma within the apocrine glands. The cells expressed GATA3, gross cystic disease fluid protein 15, androgen receptor, and E-cadherin. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 were negative. Clinical correlation was required to rule out a metastasis from the breast or the gastrointestinal tract. Although most cutaneous apocrine carcinomas do not behave aggressively, our patient developed bone metastases and eventually died of his disease. It is debated whether histiocytoid and signet-ring cell cutaneous carcinomas should be classified as apocrine neoplasm. The presence of in situ carcinoma associated with this kind of tumor has been reported only once in the literature. This characteristic and the immunohistochemical profile are in favor of apocrine differentiation.

Primary Signet-Ring Cell/Histiocytoid Carcinoma of the Eyelid: A "Binocle" Presentation of the "Monocle Tumor".

Primary cutaneous signet-ring cell carcinoma is a rare and aggressive neoplasm which diffusely involves dermis and subcutis of the eyelid or axillae. Neoplastic cells show a signet-ring cell or histiocytoid morphology in variable number, and can be found intermingled among collagen bundles, sparing the epidermis. This neoplasm typically appears in the eyelids of elderly men, in the form of a painless infiltration and swelling but with no other specific clinical feature, and frequently causes diagnostic retardation and worse prognosis. Frequent involvement of both eyelids of the same eye has given it the name of monocle tumor. Only 29 cases have been described in English literature to date, of which 7 developed metastases, mainly on regional lymph nodes. The authors present a case of involvement of contralateral eyelid, which has only been described previously in 2 cases. The immunohistochemical profile of the involvement in the contralateral eye, and the absence of other metastasis, suggest that it is locally spread from the initial lesion. However the possibility of being a second primary tumor or metastasis cannot be readily ruled out.

[HER2-Positive Advanced Gastric Cancer with Disseminated Intravascular Coagulation and Diffuse Bone Marrow Carcinomatosis Successfully Treated with S-1/Trastuzumab Chemotherapy--A Case Report].

Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has been proven to result in a survival benefit for the treatment of patients with HER2-positive advanced gastric cancer (AGC). However, data are lacking for the treatment of those with disseminated intravascular coagulation (DIC) and diffuse bone marrow carcinomatosis. A 77-year-old woman presented with back pain and fatigue since 2 months. Esophagogastroduodenoscopy showed a scirrhous lesion in the gastric corpus, which was biopsied and identified as signet-ring cell carcinoma with HER2 overexpression on immunohistochemistry. Laboratory testing, bone scintigraphy, and bone marrow biopsy were conducted, and she was diagnosed with HER2-positive AGC with DIC and diffuse bone marrow carcinomatosis. She underwent chemotherapy with the following regimen: oral administration of 80 mg/m2 S-1 for 2 weeks and 6 mg/kg trastuzumab infusion on day 6 every 3 weeks, which significantly improved the DIC. She was discharged from the hospital 73 days after admission and survived for 438 days after diagnosis. To the best of our knowledge, this is the first case report in which HER2-positive AGC complicated by DIC with diffuse bone marrow carcinomatosis was successfully treated with combined chemotherapy consisting of S-1 plus trastuzumab.

Perspectives on signet ring stromal cell tumor and related signet ring cell lesions of the gonads.

In this article, we discuss advances in our knowledge of the pathology of signet ring stromal cell tumor and related signet ring cell lesions of the ovary and a single case of signet ring stromal cell tumor of the testis. We divide ovarian signet ring cell lesions into 3 categories that reflect differences in their pathogenesis and histologic appearance. With 1 exception, all authentic cases of signet ring stromal cell tumor have been unilateral. Cases of ovarian signet ring stromal cell tumor from the literature can arise in 2 ways. The majority of cases arise multifocally from fibroma, whereas the remainder likely arise directly from the ovarian stroma. In difficult cases, immunocytochemistry provides improved diagnostic accuracy in distinguishing signet ring stromal cell tumor and its mimics from Krukenberg tumor. The most useful antibodies in this regard are epithelial membrane antigen and vimentin.

Evaluating the significance of expression of CEA mRNA and levels of CEA and its related proteins in colorectal cancer patients.

OBJECTIVE: To explore the clinical significance of expression of CEA mRNA and serum CEA and the related proteins in colorectal cancer (CRC). METHODS: Blood samples were collected from 370 CRC patients and 350 controls. CEA mRNA was determined by RT-PCR and levels of CEA, CA19-9, CA242, and CA724 were examined with chemiluminescence. RESULTS: The positive rate of jointly detecting serum CEA, CA19-9, CA242, and CA724 was significantly higher than CEA mRNA expressions (P < 0.01), both positive rates were significantly correlated with TNM stage, lymph node, and visceral metastasis. The positive rate of jointly detecting in patients with poorly differentiated tumor was significantly higher than that in patients with highly differentiated tumor (P < 0.01). By contrast, CEA mRNA expression was not related with histopathologic grading. Postoperative follow-up found that all patients with high levels of CEA mRNA and serum CEA and the related proteins had liver, lung, pelvis, or other distant metastases. CONCLUSIONS: These results suggest that high expressions of CEA mRNA and high levels of serum CEA and the related proteins are associated with the incidence and advanced of CRC. In addition, joint detection of serum CEA and the related proteins is more sensitivity than examination of serum CEA mRNA.

Mesothelioma with signet-ring cell features: report of 23 cases.

Signet-ring cell mesothelioma is uncommon and only two case reports have been published on this mesothelioma variant, both of which were initially misdiagnosed as signet-ring cell carcinoma. Herein are reported 23 signet-ring cell mesotheliomas that were investigated by immunohistochemistry, 12 of which were also studied by electron microscopy. Twenty-one of the cases originated in the pleura and two in the peritoneum. For comparison purposes and in order to determine the value of these techniques in the differential diagnosis of these tumors, seven cases of signet-ring cell lung adenocarcinoma were also studied. All signet-ring cell mesotheliomas were positive for calretinin, keratin 5/6, keratin 7, and mesothelin, 93% for podoplanin, and 91% for WT1; whereas, none reacted for MOC-31, CEA, TAG-72, CD15, TTF-1, napsin A, or CDX2. Among signet-ring cell lung adenocarcinomas, 100% were positive for keratin 7, CEA, and napsin A, 86% each for TTF-1 and TAG-72, 71% for CD15, and 14% for mesothelin, while all were negative for calretinin, keratin 5/6, WT1, podoplanin, and CDX2. After analyzing the results, it is concluded that the panels of markers used in the differential diagnosis of this mesothelioma variant should include those markers that are usually expressed in mesotheliomas (eg, calretinin, keratin 5/6, WT1, and podoplanin), broad-spectrum carcinoma markers that are frequently expressed in adenocarcinomas regardless of their site of origin (eg, MOC-31 and CEA), and organ-associated markers (eg, TTF-1 and napsin A for lung), which allow the site of origin of a metastatic adenocarcinoma to be established. Electron microscopy can be very useful as it permits the identification of characteristic ultrastructural mesothelioma and adenocarcinoma markers, and it also allows a better understanding of the morphologic features seen on routine light microscopy. Pathologists should be aware of this mesothelioma subtype as it can potentially be confused with other tumors that exhibit signet-ring features.

Signet-ring cell/histiocytoid carcinoma of the eyelid: a case report and review of the literature.

Signet-ring cell/histiocytoid carcinomas of the eyelid are rare, slow-growing, and locally aggressive tumors. They predominantly affect elderly men and clinically resemble chronic inflammatory process such as blepharitis and chalazion. To date, the histogenesis of the tumors is still controversial. Only 27 cases of primary signet-ring cell/histiocytoid carcinomas of the eyelid are published in the literature. Local recurrence and distant metastasis occur in 8 and 7 cases, respectively. We report clinical, radiographic, and pathological features of a case of signet-ring cell/histiocytoid carcinoma of the eyelid with review of relevant literature.

Signet ring cell angiosarcoma: a hitherto unreported pitfall in the diagnosis of epithelioid cutaneous malignancies.

We report 2 cases of cutaneous epithelioid angiosarcoma featuring predominantly signet ring cells. The patients-a woman, 68 years of age, and a man, 85 years of age, respectively-were referred for slowly growing indurated plaques on their parietal and retroauricular skin. Microscopic examination showed diffuse dermal proliferations comprising polygonal cells and relatively abundant cytoplasm. Because the tumor cells often were distended by variably sized vacuoles pushing the nuclei to the periphery, the nuclear profile tended toward a crescent-like morphology. Abortive luminal formations were recognized. The tumor cells were positive for CD31, CD34, and D2-40/podoplanin, with no expression of epithelial or melanocytic markers. In 1 case, upon ultrastructural examination of paraffin-embedded tissue-cut from wax tissue and reprocessed-the optically empty spaces were surrounded by a membrane with ultrastructural features identical to those of the outer cell membrane, suggesting that these spaces corresponded to the formation of primitive intracytoplasmic lumina within the tumor cells. A few Weibel-Palade bodies also were noted. Our report offers further evidence that epithelioid angiosarcoma of the skin has a broad microscopic spectrum and that tumors displaying a preponderant population of signet ring cells pose further diagnostic challenges. A brief overview of cutaneous malignant tumors in the differential diagnosis of signet ring cell angiosarcoma is provided.

Uncorrectable ptosis: primary cutaneous signet-ring cell carcinoma.

Primary cutaneous signet-ring cell carcinoma (PCSRCC) is a rare but aggressive tumor. Our case highlights a 60-year-old man who presented with eyelid ptosis, for which he underwent multiple surgical procedures over a 3-year period prior to referral to our clinic. These procedures were complicated by scarring, delayed healing, and poor cosmetic outcome. In addition, the patient was noted to develop progressive enophthalmos. These concerning signs led to a CT scan and subsequent eyelid biopsy, which revealed a diagnosis of PCSRCC. Further management has involved an MRI and orbitotomy with biopsy revealing widespread extension of the carcinoma. Exenteration was performed to reduce the likelihood of metastasis. There are few documented case reports of PCSRCC of the eyelid in the literature. Of the 33 published cases of PCSRCC, 27 cases involve the eyelids and the other 6 cases involve the axilla. The unique clinical features of this case will be discussed, in particular the presentation as ptosis, an otherwise commonplace complaint in the oculoplastics clinic. The surgical course and histopathologic findings will be presented. The literature regarding PCSRCC will be reviewed including demographics, management, and prognosis. Although rare, PCSRCC follows an aggressive course with characteristically delayed diagnosis. Early identification and treatment likely offer a better prognosis. Thus, description of the clinical presentation of this rare tumor may aid in recognition and earlier treatment.

Expression of Forkhead box P3 in tumour cells causes immunoregulatory function of signet ring cell carcinoma of the stomach.

BACKGROUND: It was recently reported that the transcription factor Forkhead box P3 (FoxP3) is expressed not only in regulatory T cells (Tregs) but also in cancer cells. The aim of this study was to clarify the clinical significance of FoxP3 expression in gastric carcinoma. METHODS: We performed immunohistochemical staining of FoxP3 to examine the association of FoxP3 expression with clinicopathological features of 194 patients with gastric cancer who underwent surgical resection from 2000 to 2010. We also investigated the immunosuppressive function of FoxP3 using gastric cancer cell lines. RESULTS: Immunohistochemical staining indicated FoxP3-positive cells within tumour tissue including both Tregs and tumour cells. Forkhead box P3-positive tumour cells were observed in 79.3% of signet ring cell carcinoma patients, and the expression of FoxP3 showed a significant correlation with lymph node metastasis. We showed that transforming growth factor-ß augmented FoxP3 mRNA expression in cell lines derived from signet ring cell carcinoma. Indoleamine-2,3-dioxygenase and galectin-1, key effectors of Treg-mediated immunosuppression, were downregulated by FoxP3 knockdown. CONCLUSION: Our findings suggested that FoxP3 expression by tumour cells might have important roles in immune escape of gastric carcinoma, and be associated with the malignant potential of scirrhous gastric carcinoma.

ADAM 10 is associated with gastric cancer progression and prognosis of patients.

BACKGROUND: The metalloproteinase domain-containing protein 10 (ADAM 10) has been implicated in the development and progression of gastric cancer. METHODS: Expression of ADAM 10 and C-erbB-2 were examined immunochemically in 436 clinicopathologically characterized gastric cancer cases. RESULTS: Protein levels of ADAM 10 and C-erbB-2 were up-regulated in gastric cancer lesions compared with adjacent non-cancerous tissues. Positive expression of ADAM 10 correlated with age, size of tumor, location of tumor, depth of invasion, vessel invasion, lymph node, and distant metastasis and TNM stage, and also with expression of C-erbB-2. In stages I, II, and III, the 5-year survival rate of patients with high ADAM 10 expression was significantly lower than in patients with low expression. However, in stage IV, ADAM 10 expression did not correlate with the 5-year survival rate. Further multivariate analysis suggests that up-regulation of ADAM 10 and C-erbB-2 were independent prognostic indicators for the disease, along with depth of invasion, lymph node and distant metastasis and TNM stage. CONCLUSION: Expression of ADAM 10 in gastric cancer is significantly associated with lymph node and distant metastasis, high C-erbB-2 expression, and poor prognosis. ADAM 10 and C-erbB-2 proteins could be useful markers to predict tumor progression and prognosis.

Thrombotic thrombocytopenic purpura as the first manifestation of metastatic adenocarcinoma in a young woman.

Thrombotic microangiopathy occurs in 5-10% of patients with mucin-producing disseminated adenocarcinoma. A 28-year-old woman complained of fatigue, bone pain, and weight loss. There were pallor, icterus, and tenderness in the bones on physical examination. Microangiopathic hemolytic anemia, leukoerythroblastic picture, thrombocytopenia, and normal coagulation tests were detected. Thrombotic thrombocytopenic purpura (TTP) was diagnosed and therapeutic plasma exchange was performed on the patient. On day 5 a laparotomy had to be performed because of acute abdomen due to the rupture of a corpus hemorrhagicum follicle of an ovary. Signet ring cell adenocarcinoma stained with cytokeratin 7 and mucicarmine was seen on ovaries and bone marrow, after the pathological examination. The primary site of tumor could not be investigated, because of the patient's refusal. Although chemotherapy including cis-platinum, infusional 5-fluorouracil, and calcium leucovorin were administered in two courses, she died from respiratory failure. In conclusion, malignancy and bone marrow involvement should be considered when associated with leukoerythroblastic picture and TTP.

Histopathologic Analysis of Signet-ring Cell Carcinoma In Situ in Patients With Hereditary Diffuse Gastric Cancer.

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.

Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk.

Hereditary diffuse gastric cancer (HDGC) is caused by germline E-cadherin (CDH1) mutations in 25-40% of tested families. Management options for asymptomatic mutation carriers are fraught, since endoscopic surveillance can miss cancer foci and prophylactic gastrectomy has profound clinical sequelae. The aims of this study were to evaluate the impact of current surveillance practices on pre-operative diagnosis and to characterize the microscopic lesions in gastrectomy specimens to better inform clinical practice. Histological assessment and mapping of endoscopic surveillance and gastrectomy specimens were performed for eight asymptomatic CDH1 mutation carriers. E-cadherin expression and proliferation were analysed and evidence of epithelial-mesenchymal transition (EMT) was sought by immunohistochemistry for vimentin and cytokeratin 8/18. Four of eight patients had lesions detected at endoscopic surveillance. A median of 20.5 (range 0-66) signet ring foci were identified per gastrectomy (including in situ lesions and pagetoid spread). Foci were predominantly identified in the fundus and body (90% endoscopic biopsies and 85% in gastrectomy). The likelihood of detecting foci pre-operatively was positively correlated with the number of biopsies taken and the number of lesions in the gastrectomy specimen. E-cadherin expression in gastrectomy specimens was reduced or absent in all of the foci compared with the intervening gastric tissue, suggesting that these lesions are polyclonal. The foci had a low proliferative index (<2%) and there was no evidence for EMT. Multiple endoscopic biopsy sampling of the gastric mucosa increases the yield of microscopic cancer foci. The low proliferative index and lack of EMT suggests that these foci may represent an indolent stage of HDGC.

Selective targeting of signet ring cell adenocarcinomas.

Many epithelial tumors, especially signet-ring cell adenocarcinomas, produce huge amounts of mucin glycoproteins that fill cytoplasm and push nucleus to the periphery, giving a signet ring like structure to the cell. Mucin proteins are very rich of l-threonine which is essential in humans. L-threonine content can reach up to 35% of total amino acid composition of some mucin proteins. Therefore l-threonine can be the Achilles heel of signet ring cell adenocarcinomas which are one of the most malignant and agressive cancers. A modified bioisoster of l-threonine, 4-fluoro l-threonine (its fluorine can be radioactive or not), can be used to selectively kill signet ring cancer cells without harming normal cells or for diagnostic purposes.

Ovarian signet-ring stromal tumor: a potential diagnostic pitfall.

Signet-ring stromal tumor is a rare ovarian neoplasm with only 10 reported cases in the literature. We report an unusual case of ovarian signet-ring stromal tumor in a 69-year-old woman who presented with right adnexal mass and underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The diagnosis was based on histological, histochemical, immunohistochemical, and electron microscopy characteristics. The main significance is to differentiate this benign tumor from the highly malignant Krukenberg tumor, and this differential diagnosis is discussed.