Complete histopathologic examination of risk reduction gastrectomy specimens for CDH1 germline mutation: Is it warranted in routine clinical practice?

AIMS: CDH1 germline mutation is associated with high penetrance of hereditary diffuse gastric cancer (HDGC). Due to the lack of endoscopically identifiable lesions, routine surveillance is ineffective in the early detection of gastric cancer, and risk-reduction gastrectomy is often recommended. Many academic pathology departments elect to submit the entire gastrectomy specimen for histological examination, which is associated with significantly increased cost, technical and professional time, and turnaround time. METHODS: We present our experience with 5 completely submitted and 2 representatively submitted prophylactic total gastrectomy cases in HDGC patients. RESULTS: Multifocal intramucosal signet ring cell carcinoma was identified in all cases except one, in which only in situ carcinoma was identified. The tumoral foci (2 to 35 per case; average 14.4) were concentrated in proximal stomach. No submucosal invasion or nodal metastases was seen in any case. The final stage was either stage 0 (pTisN0cM0) or stage 1a (pT1aN0cM0). CONCLUSIONS: Our findings are in line with that reported in the literature. Considering that deeply invasive carcinoma is very rare in this situation, and no further treatment is indicated for the vast majority of those patients, complete submission and pathologic examination of the entire stomach provides little additional value for routine clinical management. We propose a two-step approach with targeted submission of the proximal stomach, and subsequent entire submission of the remaining stomach if no intramucosal carcinoma is identified during the initial targeted examination.

A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application.

Colon signet-ring cell carcinoma (SRCC) is a rare type of malignant dedifferentiated adenocarcinomas, and is associated with poor survival. However, an in-depth study of the biological features of SRCC is hindered by the lack of a reliable in vitro model of colon SRCC. Thus, the establishment of cell cultures from SRCC has become the most challenging task. Here, by harnessing the power of the organoid culture system, we describe the establishment of a human colon SRCC organoid line from a surgical sample from one patient with colon SRCC. The colon SRCC organoid line, YQ-173, was characterized for morphology, histology, ultrastructure and chromosome stability levels, showing that it resembles the histological and growth characteristics of the original tumor cells; xenografts were used to show that it also has a high tumor formation rate. RNA sequencing of YQ-173 compared with the normal tissue verified its mucinous nature. Capture-based targeted DNA sequencing combined with drug screening based on a bespoke 88 compound library identified that JAK2 might be a treatment target. An in vitro drug screening found that AT9283 and Pacritinib could be effective JAK2 inhibitors, which was consistent with the in vivo xenograft response. We report, for the first time, the establishment of an SRCC organoid line allowing in-depth study of SRCC biology, as well as a strategy to assess in vitro drug testing in a personalized fashion.

[Renal urothelial carcinoma mainly composed of signet-ring cells].

Autopsy study of an 80-year-old man has identified his renal tumor metastasizing to the heart, lung, and liver as urothelial car- cinoma; at the same time some cells in the main tumor and all cells in the metastases had a signet-ring phenotype, but neither mucicarcimine nor alcian blue stained the cell cytoplasm. The paper provides the histological and immunohistochemical pattern of the tumor and emphasizes its exclusive rarity. Attention is drawn to the possibility of signet-ring cell transformation in the cells of different tumors, including nonepithelial ones.

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.

Mucinous colorectal adenocarcinoma with signet-ring cells: immunohistochemical and ultrastructural study.

A primary mucinous colorectal adenocarcinoma tissue with signet-ring cells, as revealed after histological evaluation, was examined ultrastructurally. The authors also analyzed the immunohistochemical data of the tissue for serotonin, vasoactive intestinal polypeptide (VIP), bombesin, somatostatin, and glucagon, using the peroxidase anti-peroxidase (PAP) method and the immunogold labeling method for light and electron microscope, respectively. Electron microscopically mucinous adenocarcinoma was characterized by the formation of small lumen. Adenocarcinoma cells were full of mucous granules of varying electron density, providing a good environment for the tumor cells to grow. They also exhibited a significant loss of microvilli and intracytoplasmic junctions, which could allow the cells to disseminate. Signet-ring cells were located in the basal site of the ducts or in the lamina propria and appeared neoplastic, with mucin accumulation intracellularly and an eccentric crescent-shaped nucleus. The cytoplasmic organelles were decreased and at the periphery of the cell. The PAP method demonstrated that these cells were strongly positive for bombesin and also positive for vasointestinal polypeptide (VIP). The immunogold method detected bombesin immunoreactivity in the vacuoles as well as in other cytoplasmic membranes, whereas VIP was localized mainly in the plasma membrane. The location of signet-ring cells combined with the immunoreactivity for bombesin and VIP indicated that signet-ring cells were of neuroendocrine origin and probably dedifferentiated enterochromaffin-like endocrine cells. These findings have implications for understanding the biological behavior of these composite malignant tumors and could help in the knowledge of the origin of signet-ring cells.

[Electron microscopic examination on 50 cases of prostatic needle biopsies].

OBJECTIVE: To study the differences in ultrastructural findings between prostatic carcinoma and benign prostatic hypertrophy, and the various ultrastructural features seen in moderately to poorly differentiated prostatic carcinoma. METHODS: Utrasound-guided needle biopsies were carried out in 50 clinically suspicious cases of prostatic carcinoma. For each case, one additional core was sampled from the most suspicious area, fixed in glutaraldehyde and examined under electron microscopy. RESULTS: In the 50 cases of prostatic needle biopsies studied, there were a total of 42 cases with histologic findings of prostatic carcinoma. Thirty-one cases showed features corresponding to Gleason's score 3 to 5. In contrast to that seen in benign prostatic hypertrophy, the ultrastructural findings of the tumor cells commonly seen in prostatic carcinoma included the centrally located giant nucleoli, a direct contact with stroma, and formation of cytoplasmic microcyst. Occasionaly, there were mitotic figures seen, accompanying with fibromyxoid change of the peritumoural stroma. Amongst the 31 cases of Gleason's score 3 to 5 prostatic carcinoma, 29 cases (93.5%) demonstrated cytoplasmic prostasomes and storage vesicles. Similar to their counterparts in benign prostatic cells, prostasomes and storage vesicles in prostatic carcinoma cells were formed in the Golgi apparatus and released into the lumen by apocrine excretion and exocytosis. CONCLUSIONS: Electron microscopy is helpful in distinguishing between benign and malignant prostatic lesions. Because of the high yield of prostasomes in moderately to poorly differentiated prostatic carcinoma, prostasomes may become a potential target for cancer immunotherapy and one of the useful diagnostic indices for delineating the prostatic origin of metastatic carcinoma.

Immunohistochemical and ultrastructural characterization of the signet-ring cell carcinoma component in a case of urothelial carcinoma of the urinary bladder.

Characterization of the signet-ring cell carcinoma (sig) component of a urothelial carcinoma (UC) in the urinary bladder of a 64-year-old man, obtained by transurethral resection of bladder tumor (TUR-BT), is reported. In the present case, a characteristic sig component was detected in approximately 20% of UC, G2 tissues. The sig cells were morphologically similar to those found in gastric cancers and were positively stained with periodic acid-Schiff reaction and Alcian blue and mucicarmine stains. Immunohistochemically, the sig cells were selectively positive for carcinoembryonic antigen (CEA), MUC2, and MUC5AC. These immunohistochemical characteristics were similar to those of sig cells in the stomach, except for the positivity with MUC2. It is interesting to note that CAM5.2-positive sig cells were surrounded by CAM5.2-positive UC cells in a solid nest with no apparent associated adenocarcinoma element. In addition, the ultrastructure of sig cells showed multivacuolar cytoplasmic mucin, which proved to be similar to the ultrastructure of gastric cancers. In the present case of UC, G2 was associated with a sig component. Regarding the origin of the sig component in the bladder, it has been suggested that MUC2-positive sig cells in the bladder might be derived directly from metaplasia of UC, without an associated adenocarcinoma component. From this perspective, it may be noteworthy that sig cells in the bladder were selectively positive for MUC2, exhibiting common antigenicity with mucous cells of the gastric intestinal metaplasia. Because UC associated with a sig component carries a worse prognosis than ordinary UC, the presence of the sig component in any UC should be evaluated even within TUR-BT tissues, as in the present case.

Cutaneous metastasis of gastric adenocarcinoma: an exuberant and unusual clinical presentation.

There are different types of skin changes associated with internal malignancy. One type is the skin involvement as a result of cutaneous metastasis from an internal tumor. The skin is an uncommon site for distant metastasis; when it is present the most common sources are breast, lung, and colon. Metastasis generally occurs after an internal malignancy had been discovered and signifies disseminated disease with a poor prognosis. We report an exuberant and rare case of cutaneous metastasis from gastric adenocarcinoma as the first sign of this serious visceral cancer.

Signet-ring stromal tumor of the ovary: an immunohistochemical and ultrastructural study with a review of the literature.

Signet-ring stromal tumor is a very rare type of ovarian neoplasm. Only ten cases of this tumor have been reported in the English literature. We report here an additional case of this type of tumor that arose from the left ovary in a 76-year-old woman. By light microscopy, the tumor was composed of small round and oval cells with cytoplasmic vacuolization and a typical signet-ring appearance, focally admixed with fibromatous tissue. Special staining revealed that the vacuoles of the tumor cells contained no lipid, mucoprotein, or glycogen. Interestingly, variously sized hyaline globule-like structures positive for periodic acid-Schiff (PAS) reaction with and without diastase digestion were present in the cytoplasm of tumor cells. Immunohistochemically, the tumor cells variously expressed several markers, including CD56, inhibin-alpha, alpha-smooth muscle actin (alpha-SMA), and progesterone receptor (PR), which have been identified in ovarian sex cord-stromal neoplasms. Ultrastructurally, the hyaline globule-like structures in tumor cells appeared to be lysosomes, and the vacuoles in the cells appeared to have resulted from pseudoinclusions of extracellular edematous matrix.

Synthesis of junctional proteins in metastasizing colon cancer cells.

Various authors have reported reduced synthesis of epithelial junctional proteins during dedifferentiation, tumorigenesis and metastasis in a great variety of tumors. Consequently, it is generally accepted that loss of adhesive molecules and adhesion structures is implicated in the development of an invasive phenotype and poor patient prognosis. Colon carcinomas, on the other hand, were shown to behave differently as synthesis of main adhesive proteins continues despite the development of an invasive phenotype. In this study we used cultured cells grown under conditions that inhibited intercellular adhesion (low Ca2+ concentration) and compared these results with data obtained from metastasizing colon cancer cells (signet ring cell carcinoma). Characterization of these proteins and their structures were performed by immunoprecipitations, Western blot analysis, immunohistochemistry, pre-embedding immuno-electron microscopy, and a new method to perform immuno-electron microscopy on paraffin-embedded material, which we present in this paper. We demonstrate that synthesis carries on for both, the desmosomal and the proteins of the zonula adhaerens. While, however, the assembly of desmosomal structures in the form of half-desmosomes at the cell surface continues, those of the zonula adhaerens did not. Instead E-cadherin was found, although associated with alpha-catenin, beta-catenin, and plakoglobin, evenly distributed at the plasma membrane of the cultured cells and also at the surface of the dissociated tumor cells. We conclude from our observations that continued expression and synthesis of junctional proteins do not necessarily contribute to the suppression of tumor invasion and metastasis of colon cancer.

[Oligoastrocytoma with signet-ring cell differentiation. A morphological, ultrastructural and immunohistochemical study]. / Oligoastrocitoma con diferenciación en células en anillo de sello. Estudio morfológico, ultraestructrural e inmunohistoquímico.

We present a case of a mixed glial tumor (oligoastrocytoma) with signet-ring cells. This cellular feature is a rare differentiation in glial tumors of the central nervous system. Histological, immunohistochemical and ultrastructural findings have been analyzed. Signet-ring cells showed intense expression with GFAP, S-100 and vimentin. A differential diagnosis with other primary brain tumors and cerebral metástases with signet-ring cell differentiation was discussed.

[Primary signet ring cell carcinoma of the eccrine sweat gland in the eyelid. Immunohistochemical and ultrastructural study of a case]. / Adénocarcinome sudoral primitif de la paupière de type eccrine à cellules en bague à chaton.

We report a case of a 45-year-old woman who exhibited a primitive eccrine sweat gland carcinoma of the eyelid. Histological study showed cellular proliferation with an Indian file pattern and some signet ring cells with sialomucin secretion. Immunohistochemical study demonstrated these cells to be positive with the anticytokeratin, anti-EMA, anti-HMFG, antiestrogen receptor and antiprogesterone receptor antibodies. Ultrastructural study showed intracytoplasmic vacuoles with numerous microvilli at the apical side. Differential diagnosis with a metastasis from a mammary adenocarcinoma is difficult and a complete staging is necessary to confirm the primitive origin of the tumor. The behavior of this tumor is marked by locoregional recurrence.

Collecting-duct carcinoma of the kidney with prominent signet ring cell features.

We report a case in a 74-year-old woman of collecting-duct carcinoma of the kidney with prominent signet ring cell features. Grossly, the tumor measured 5.5 cm in greatest dimension, occupied the entire upper pole of the kidney, and was well circumscribed. Microscopically, it displayed a predominant tubulopapillary pattern of growth with a hyalinizing stroma. The tumor tubules were lined by a single layer of cells with large, pleomorphic nuclei, some of which had a hobnail appearance. Large intracytoplasmic vacuoles with compression of nuclei (signet ring cells) were present throughout the tumor. Alcian blue, mucicarmine, and periodic acid-Schiff stains failed to identify intracellular mucin or glycogen in the signet ring cells. Enlarged cells with intracytoplasmic vacuoles were also noted in the adjacent collecting ducts. The tumor cells were immunohistochemically positive for cytokeratin including cytokeratin 7, CAM 5.2, AE1/3, and 34 beta E12, vimentin, peanut lectin agglutinin, and Ulex europaeus agglutinin. Electron microscopy revealed that the intracytoplasmic vacuoles were due to intracellular edema. To the best of our knowledge, this is the first reported case of renal collecting-duct carcinoma with prominent signet ring cell features.

Adenocarcinoma with signet ring cells of the axilla showing apocrine features: a case report.

A 74-year-old Japanese man developed a reddish, indurated plaque composed of multiple nodules on his right axilla. Histopathologic examination showed a solid tumor that extended from the upper dermis into the subcutis, with both inter- and intracellular lumen formation, cellular arrangement in single files, a fibrotic reaction around the tumor cells, and the presence of mucinous material in the cytoplasm. There was both nuclear and cytoplasmic pleomorphism. Both lysozyme and GCDFP-15 were identified in the tumor cells. Electron microscopic examination showed periluminal condensation of the cytoplasm. Because thorough clinical and laboratory examinations were unremarkable, we regarded this to be a case of primary adenocarcinoma with signet ring cells of the axilla. The neoplasm might have differentiated toward the apocrine sweat glands or the mammary glands. Radiation therapy was effective to some degree. This seems to be the first reported case in which adenocarcinoma with signet ring cells of the skin affected a site other than the eyelids.

Signet-ring cell ependymoma: case report with implications for pathogenesis and differential diagnosis.

We describe light microscopic, immunohistochemical and ultrastructural features of a signet-ring cell ependymoma (WHO grade II) identified in a surgically resected left cerebellar cystic tumor from a 64-year-old man. Part of the tumor showed clear-cell differentiation. Immunohistochemical coexpression of glial fibrillary acidic protein and epithelial membrane antigen, characteristic of ependymoma, was detected in both components. Sinuous intermediate junctions, cytoplasmic lumina, and scant astroglial filaments were demonstrated by electron microscopy. Signet-ring cell change was shown to be induced by disproportionate cavitation of either microvillus-bearing cytoplasmic lumina or microrosettes. The staining qualities of clear cells were mainly due to paucity and degeneration of subcellular organelles. Therefore, signet-ring cell ependymomas represent a unique anomaly of intra- and extracellular compartmentalization to be distinguished from various unrelated forms of cytoplasmic volume increase, resulting in an optically similar "empty" appearance of tumor cells. As a clinically relevant consequence, signet-ring cell ependymoma must be included in the differential diagnosis of primary or metastatic neoplasms of the central nervous system, having in common a phenotype characterized by overdeveloped optically lucent cell bodies.

Pancreatic endocrine tumor with signet ring cell features: a case report with novel ultrastructural observations.

The case of a malignant pancreatic endocrine neoplasm with an unusual signet ring cell appearance is reported. The tumor was resected from a 30-year-old man with a 4.0-cm tumor in the body of the pancreas diagnosed by computerized tomographic (CT) scan. The resected tumor had a unique morphology characterized by numerous mucin-negative, signet ring cells, which were argyrophilic and immunoreactive for cytokeratin (CAM 5.2), chromogranin, synaptophysin, neuron specific enolase, and gastrin. Dense-core neurosecretory-type granules and numerous cytoplasmic lamellar inclusions were identified by electron microscopy. These inclusion bodies consisted of multilayered concentric osmiophilic lamellae (myelin figures), which most likely represent an abnormal accumulation of degenerating organelles. Two years later, the patient developed an abdominal recurrence of the tumor, confirming its malignant behavior. This case expands the spectrum of pancreatic endocrine tumors to include an aggressive signet ring cell tumor with a novel ultrastructural basis.

Metastatic skin cancer; a case with signet ring cell histology.

We report a 64-year-old Japanese man who developed metastatic skin cancer, in the form of 1-3 cm diameter dome-shaped tumours on his face and head. Histopathological examination demonstrated diastase-resistant periodic acid--Schiff and Alcian blue-positive signet ring cells, suggesting gastric carcinoma. Immunohistochemical staining showed that these cells were positive for carbohydrate antigen CA19-9.