Osteopontin expression in pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by fibrocellular intimal proliferation and thrombus formation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. Osteopontin (OPN) is a multifunctional cytokine and adhesive protein, and has been demonstrated to be implicated in fibrosis, neointima formation, arterial occlusion by thrombus, and tumor metastases in cooperation with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Herein is described an autopsy case of gastric adenocarcinoma with severe pulmonary hypertension due to PTTM. Histologically, tumor cell emboli markedly induced both fibromuscular intimal thickening and thrombosis, resulting in luminal stenosis and occlusion of small pulmonary arteries and arterioles. Tumor cells, both in the PTTM lesions and primary gastric carcinoma, had positive immunoreactivity for OPN, PDGF, and VEGF. In addition, proliferating fibromuscular intimal cells also showed expression of OPN, PDGF, and VEGF. These findings suggest that OPN may be involved in fibrocellular intimal proliferation and thrombus formation in PTTM together with PDGF and VEGF. To the best of the authors' knowledge this is the first report to demonstrate the possible involvement of OPN in PTTM. It is postulated that OPN is one of the candidate molecules for the development of PTTM.     

Primary signet ring cell carcinoma of the breast

Three examples of primary signet ring cell carcinoma of the breast are described. This form of breast carcinoma deserves recognition as an entity because its prognosis may differ from colloid carcinoma of the breast and because of potential difficulty in distinguishing it from metastatic carcinoma.     

Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: An analysis of 6 autopsy cases and review of the literature

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension (PH). Its histological features include widespread tumor emboli of the small arteries and arterioles of the lung, associated with thrombus formation and fibrocellular and fibromuscular intimal proliferation. Although PTTM has drawn increased attention as a fatal complication of gastric carcinoma (GC), comprehensive studies are still lacking. In order to clarify clinical and pathological features of GC-induced PTTM, recent autopsy cases were analyzed with a review of the literature. Of 36 autopsy cases with GC, 6 (16.7%) were affected by PTTM. Four were male and 2 female, with a mean age of 72.7 years. Three patients presented with PTTM-related clinical manifestations and died of PTTM. They showed clear morphological evidence of PH. The other 3 patients had PTTM as an incidental finding irrespective of clinical manifestations or PH. No patient was diagnosed antemortem as PTTM. All PTTM cases were associated with advanced GC, with a histology of adenocarcinoma of poorly differentiated type (n = 4) or signet-ring cell type (n = 2). Expression of tissue factor and vascular endothelial growth factor was confirmed immunohistochemically in tumor cells in all cases. The results were all in line with previous studies. In addition, the current study revealed vascular lesions characteristic of PTTM morphology to be present exclusively in the lung. In conclusion, our study shows a 16.7% incidence of PTTM in GC patients, with half of them developing PH and dying of PTTM, confirming a clinical significance as a non-negligible lethal complication of GC. In addition to many known clinicopathological characteristics of PTTM, the current study pointed to some PTTM issues requiring clarification, including the pathogenesis of the exclusive pulmonary distribution of vascular lesions of PTTM. Since details remain to be elucidated, interdisciplinary research is a high priority with a close collaboration between pathologists and clinicians in order to overcome this lethal condition.     

Chromogranin A expression correlates with tumour cell type and prognosis in signet ring cell carcinoma of the stomach

Aims:  To investigate neuroendocrine (NE) differentiation in gastric signet ring cell carcinoma (SRCC) using chromogranin A (CgA) as an indicator of a well-differentiated NE phenotype and to determine its relationship to cell type, stage and prognosis.
Methods and results:  102 SRCCs were categorized into five subtypes according to the predominant cell type in the World Health Organization classification. 38 cases (37.3%) showed focal or diffuse CgA positivity. The positive cells were mostly histiocytoid and eosinophilic SRCC cells and some were classical SRCC cells. Small cell and anaplastic-type SRCC cells were only rarely immunopositive. There was no significant relationship between CgA expression and the extent of invasion or presence of metastasis. However, a significant positive correlation existed between CgA positivity and favourable prognosis, with a tendency for greater positivity to be associated with better overall survival. Multivariate analysis showed expression of CgA to be an independent prognostic factor.
Conclusion:  CgA expression is restricted to certain tumour cell types and may help to predict prognosis in gastric SRCCs.     

Pulmonary tumor thrombotic microangiopathy caused by a gastric carcinoma expressing vascular endothelial growth factor and tissue factor

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension. Its histological features include widespread tumor emboli along with fibrocellular intimal proliferation and thrombus formation in the small arteries and arterioles of the lungs. The result is occlusion or stenosis of the pulmonary vasculature, but the detailed pathogenesis has yet to be clarified in spite of the serious clinical manifestations. Herein is described the case of a 62-year-old man with a gastric adenocarcinoma who died of sudden cardiopulmonary arrest. The autopsy revealed advanced cancer disease as well as findings of PTTM, which seemed to be the cause of his unexpected death. The carcinoma cells were immunohistochemically positive for vascular endothelial growth factor (VEGF) and also for tissue factor (TF). There is another report suggesting that TF might play an important role in the pathogenesis of PTTM. Also, VEGF has been reported to be involved in a variety of forms of pulmonary hypertension and to be upregulated by TF. These findings suggest that VEGF and TF may be involved in the pathogenesis of PTTM. The present PTTM case, in which the tumor cells demonstrate the coexpression of VEGF and TF, is important in facilitating understanding of the lethal disorder in the future.     

Primary signet ring cell carcinoma of the pancreas: Cytopathology review of a rare entity

Primary signet ring cell carcinoma of the pancreas (PSRCCP) is an extremely rare diagnosis that has not been extensively studied in literature. Primary and metastatic neoplasms to the pancreas may exhibit cytomorphological similarities to signet ring cells, posing diagnostic challenges. In this article, we review PSRCCP and provide a study of several primary pancreatic neoplasms that may mimic the appearance of PSRCCP upon cytopathology evaluation, shedding light on the existence of this dilemma, and helping cytopathologists in navigating similar scenarios in their practice.     

原发性膀胱印戒细胞癌1例

 目的 探讨原发性膀胱印戒细胞癌的临床特点、诊疗方法。方法 报告1例原发性膀胱印戒细胞癌患者的临床特征及诊治方法,结合文献进行复习。结果 患者术前经活检明确诊断为膀胱印戒细胞癌,相关检查排除转移性印戒细胞癌,行经腹腔镜全膀胱切除及盆腔淋巴结清扫术。术后予以全身化疗。结论 原发性膀胱印戒细胞癌临床表现及影像学特征缺乏特征性,恶性程度高,预后差,早期行根治性膀胱切除术,结合全身化疗等治疗效果较好。     

Combined signet ring cell and glassy cell carcinoma of the uterine cervix arising in a young Japanese woman: a case report with immunohistochemical and histochemical analyses

Signet ring cell carcinoma and glassy cell carcinoma are both rare histological subtypes of uterine cervical cancer. This report is of a case of uterine cervical carcinoma arising in a 29-year-old woman who had major components of signet ring cell carcinoma and glassy cell carcinoma within the same tumor. Histochemical and immunohistochemical analyses, including high and low molecular weight cytokeratins, p63 and MUC5AC, additionally demonstrated the squamous and adenocarcinomatous differentiation in the neoplastic cells, which showed otherwise unclassifiable morphology on the haematoxylin-eosin sections. A wide range of differentiation described above supports the speculation that glassy cell carcinoma may arise from the multipotential immature cells that can differentiate into both squamous and glandular cells. It would be precise to classify this tumor as adenosquamous carcinoma. Although adenosquamous carcinoma is not a rare histological subtype in the uterine cervix, it should be necessary to report the presence of glassy cells and signet ring cells when present because the presence of both components is associated with an unfavorable clinical behavior.     

前列腺原发性印戒细胞癌的病理诊断和形态发生机制

目的：探讨前列腺原发性印戒细胞癌的组织发生、病理特征和鉴别诊断。方法：在262例经穿刺活检证实的前列腺癌中选出10例印戒细胞癌,用SP法作前列腺特异性抗原（PSA）、前列腺酸性磷酸酶（PAP）、雄激素受体（AR）等9种免疫组织化学标记和AB／PAS,黏液卡红染色,3例作电镜观察,并与10例胃肠道印戒细胞癌作比较。结果：10例中仅1例为纯印戒细胞癌,9例与经典型前列腺癌混合,印戒细胞癌成分均大于癌总量的25％。按形态特征和形成机制,可将印戒细胞分为胞质内空泡或内腔形成和胞质内PSA、PAP分泌物积聚二种类型,二种类型印戒细胞均缺乏胞质内黏液,故不同于消化道印戒细胞癌。结论：原发性印戒细胞癌是来自前列腺腺泡上皮的低分化特殊组织学类型腺癌。在穿刺活检中可以与来自消化道,泌尿道的浸润性或转移性印戒细胞癌鉴别,也不同于放疗或内分泌治疗后经典型前列腺癌的空泡变性。     

A mode of incipient growth in chemically induced signet ring cell carcinoma of the canine stomach.

A 31-month-old female mongrel dog was orally administered with 50 mg or 100 mg of N-nitrosobutylurea (NBU) in gelatin-capsule 3 times per week for 19 months with interposing periods of complete suspension. Thirty-four foci of signet ring cell carcinoma were found in the antral region of the stomach. The majority of the foci (31 foci) were early cancer, and the remaining foci were invasive cancer. In addition to these lesions, there was "a single gland cancer" in which a row of cancer cells was confined to a single gland. The whole gland was composed of two cell layers; the inner layer facing the lumen was normal gastric cells and the outer layer was atypical or neoplastic cells underlaid by the basement membrane. Mitosis was frequently observed on the bottom of the gland. Atypical or neoplastic cells seemed to mature gradually through a process of upward migration with increase in cytoplasmic Alcian blue-PAS and HID-AB positive mucin. Some of the cells rich in mucin moved into the lamina propria. The other cells remained in the flow of the regular cell renewal system of the normal gastric cells and reached the top of the gland. This observation revealed a mode of incipient gastric cancer growth, which starts and spreads within a single gland, before it invades the surrounding lamina propria.     

Primary signet ring cell adenocarcinomas of the lung: a clinicopathological study of 15 cases

AIMS: We describe the clinicopathological characteristics of 15 cases of primary signet ring cell adenocarcinoma of the lung and highlight the importance of recognizing that not all adenocarcinomas with signet ring cell features represent metastatic adenocarcinomas. METHODS AND RESULTS: We evaluated the clinicopathological and immunohistochemical features of 15 cases of signet ring cell adenocarcinoma of the lung. The patients were 12 men and three women, age 30-75 years (mean 52.5 years). No evidence of a primary tumour elsewhere could be found on thorough clinical examination. Nine patients underwent resection and the remainder were biopsied. The tumours ranged from 18 to 80 mm in greatest dimension. Microscopically, two distinct patterns of growth were recognized: acinar and diffuse. The tumours were characterized by the presence of >75% signet ring cells. Periodic acid-Schiff and mucicarmine showed strong intracellular positive staining. Immunohistochemical stains for TTF-1 (6/6) and CEA (9/9) showed strong positive reaction in all cases evaluated. Three out of six cases were also positive for cytokeratin 7. All the tumours (6/6) were negative for cytokeratin 20, ER, PR and GCDFP-15. Follow-up information was obtained in 11 patients; six patients died within 1 year and five patients were alive from 3 to 36 months after initial diagnosis. CONCLUSION: These cases highlight an unusual histological growth pattern of primary lung adenocarcinoma that may be mistaken for a metastasis from an occult primary. The recognition of this pattern of lung tumours is important for proper treatment.     

The role of cytokeratins 20 and 7 and estrogen receptor analysis in separation of metastatic lobular carcinoma of the breast and metastatic signet ring cell carcinoma of the gastrointestinal tract

Metastatic signet ring cell carcinomas of unknown primary site can represent a clinical problem. Gastrointestinal signet ring cell carcinomas and invasive lobular carcinomas of the breast are the most common sources of these metastases. Immunohistochemical algorithms have been successfully used in the search for the unknown primary adenocarcinomas. In the present study a series of primary invasive lobular breast carcinomas (79 cases) and their metastases and a series of gastrointestinal signet ring cell carcinomas (22 primary and 13 metastases) were stained with monoclonal antibodies for cytokeratin (CK) 20 and CK7 and for estrogen receptors (ER). The staining was evaluated as negative (no staining), focally (less than 10% of the tumor cells stained) or diffusely positive. All the primary and metastatic gastrointestinal signet ring cell carcinomas proved to be CK20 positive, while only 2/79 (3%) of the primary and 1/21 metastatic lobular carcinomas (5%) stained positively for this CK. None of the gastrointestinal carcinomas and the majority of the lobular carcinomas expressed ER. The majority of the tumors were CK7+. Using CK20 alone, 33 of 34 metastases could be properly classified as gastrointestinal (CK20+) or mammary (CK20-). ER identified 31/34 of breast cancer metastases. By combining the results of CK20 and ER staining all the metastases could be properly classified as the CK20+/ER- pattern identified all the gastrointestinal tumors.     

Cytopathology of anaplastic carcinoma of the pancreas: Review of a rare entity and description of a variant with signet ring cell features

Anaplastic carcinoma of the pancreas (ACP) is a rare and aggressive variant of pancreatic ductal adenocarcinoma (PDAC). Several studies have attempted to characterize this subtype through case series or single case reports; however, ACP remains underrecognized by cytopathologists in particular, and often lumped under the umbrella of classic PDAC. Here, we review the most up to date data that literature provides about ACP, to bring familiarity with this entity to the cytopathology practice, and to elucidate the role cytopathologists can play in recognizing and diagnosing this subtype on pancreatic aspiration biopsy, before surgical resection. We also describe a rare case of ACP, demonstrating signet ring cell features, that was diagnosed on fine needle aspiration of a pancreatic mass.     

Signet ring cell carcinoma of the eyelid - the monocle tumour

We report the clinical and histopathological characteristics of two cases of signet ring cell carcinoma of the eye lids, and discuss the histogenesis of this neoplasm. Two 72-year-old Caucasian males both presented with slowly growing tumours of the eyelids. The tumours were excised and specimens were examined using light- and transmission electron microscopic techniques. Clinically, the tumours infiltrated both eyelids on one side of the face with swelling and periocular inflammation, creating a monocle-like appearance. Extensive clinical work-up excluded periocular metastases. Histopathologically, the tumours were composed of rather bland cells with mainly histiocytoid morphology. A minor proportion had a signet ring cell appearance. The cytoplasmic inclusions giving the signet ring morphology were PAS- and colloidal iron positive. The tumour cells reacted with antibodies against cytokeratins, carcinoembryonic antigen, epithelial membrane antigen, gross cystic disease fluid protein-15 and lysozyme. Transmission electron microscopy demonstrated tumour cells containing intracytoplasmic vacuoles lined by microvilli. The tumour cells aggregated in duct-like clusters. A diagnosis of primary signet ring cell carcinoma was made in both cases. Histopathological, immunohistological and ultrastructural findings indicated that the tumours were of sweat gland origin.     

Cell proliferation and differentiation in intramucosal and advanced signet ring cell carcinomas of the human stomach

Summary In order to study the progression of signet ring cell carcinomas in the human stomach, we compared cell proliferation and differentiation between small and large intramucosal cancers, and between intramucosal and advanced cancers. Fine-structurally, signet ring cells were differentiated to 3 cell types: a foveolar, a glandular and an intestinal type. In the mucosa, the foveolar-type cells and glandular-type cells were distributed at the superficial and the deep zone, respectively. In the small mucosal cancers, intestinal-type cells were rare and a layered structure was often seen. In this structure, the mode of cell production resembled that in the normal gastric mucosa; the foveolar-type signet ring cells in the superficial layer were not proliferative and the proliferating cells were small cells in the middle layer and a few glandular-type cells in the deep layer. In the large mucosal and advanced cancers, intestinal-type cells and proliferating small round cells were often distributed throughout the depth of the mucosa, and signet ring cells of the foveolar type were also proliferative. These findings indicated that large part of the signet ring cell carcinomas initially form the layered structure and that it becomes indistinct while intestinal-type cells appear as the tumour grows. However, we found several small advanced cancers, lacking both the layered structure and the intestinal-type cells. These cancers appear to start without the layered structure and progress very rapidly.     

The probable origin of an anemone cell tumor: metastatic transitional cell carcinoma producing HCG

A neoplasm of unknown origin in cervical and axillary lymph nodes was diagnosed as anemone cell tumor by ultrastructural examination. Three years after the initial diagnosis of anemone cell tumor, a high-grade transitional cell carcinoma of the bladder was discovered. The results of immunoperoxidase staining of the cervical lymph node, axillary lymph node, and bladder tumors for keratin, carcinoembryonic antigen, and human chorionic gonadotropin (HCG) strongly suggest that the anemone cell tumors in this case represent metastases of bladder carcinoma cells capable of producing HCG.     

Distribution of Lgr5‐positive cancer cells in intramucosal gastric signet‐ring cell carcinoma

Leucine‐rich repeat‐containing G‐protein‐coupled receptor 5 (Lgr5) is a putative intestinal stem cell marker that is also expressed in various tumors. To analyze its pathological characteristics in mucosal gastric signet‐ring cell carcinoma (SRCC), we investigated Lgr5 expression in 35 intramucosal gastric SRCC patients using RNAscope, a newly developed RNA in situ hybridization technique. Lgr5 expression in individual tumor cells was scored semi‐quantitatively from 0 to 400. Ki67 was also examined by immunohistochemistry, with a linear arrangement of Ki67‐expressing cells present in 20 of 35 cases. This area of Ki67‐expressing cells was topographically divided into upper, middle, and lower regions. All cases with linear Ki67 expression patterns also had Lgr5‐positive cells arranged in a linear fashion in the lower area—which was distinct from the area of high Ki67 expression. The rate of Ki67 positivity in Lgr5‐positive cells was significantly lower than that of Lgr5‐negative cells in areas of high Ki67 expression. In intramucosal SRCC, the low mitotic activity of Lgr5‐positive cells suggests that they may represent cancer stem cells as seen in other types of stomach carcinomas. Intramucosal SRCC may therefore contain stem cells expressing Lgr5 in the lower area of the lamina propria, akin to normal gastric pyloric mucosa.