An unusual uterine tumor with signet ring cell features.

In 2004, a 56-year-old woman was diagnosed with Stage IA follicular lymphoma in a cervical lymph node biopsy. The patient experienced total remission after local radiation therapy. In 2009, a control computed tomography scan evidenced a pelvic mass, prompting total hysterectomy. The latter harbored a 4.8-cm intramural uterine tumor corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells, with extensive, periodic acid-Schiff negative, signet ring cell changes, and a pan-keratin negative, CD20+, CD10+, Bcl2+, Bcl6+ immunophenotype. Molecular genetic studies showed the same clonal IGH gene rearrangement in the lymph node and the uterus, establishing the uterine tumor as a relapse of the preceding follicular lymphoma, although no signet ring cells were evidenced at presentation. Uterine localization of lymphomas is rare, and lymphomas with signet ring cell features are uncommon. This exceptional case exemplifies a diagnostically challenging situation and expands the differential diagnosis of uterine neoplasms displaying signet ring cell morphology.

An unusual uterine tumour with signet ring cell features

Objective: Lymphomas with signet ring cell features are rare, as is uterine dissemination of lymphomas. We report an exceptional case of a uterine tumor combining these two characteristics. Method: A 61-year-old female was diagnosed in 2004 with localized nodal grade 2 follicular lymphoma (stage IA). She received local radiation therapy, experienced total remission, and did well until 2009 when a systematic CT scan evidenced a pelvic anterior-lateral mass. Total enlarged hysterectomy was performed. Results: The anterior uterine wall contained a 4.8-cm fish flesh well-delineated mass corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells with extensive signet ring cell changes. Tumor cells were CD20-, CD10-, Bcl2-, and Bcl6-positive with a low proliferation rate (<10-15%); CD21 underlined a focal follicular architecture. The vacuoles were PAS-negative and did not stain for immunoglobulin; ultrastructural analysis revealed nonspecific degenerative vacuoles. No lymph nodes were identified isolated from the surgical specimen. The tumor was considered as a secondary localization of the systemic follicular lymphoma, though no signet ring cells were evidenced in the cervical lymph node biopsy (reviewed). Follow-up showed retroperitoneal tissue infiltration (PET-CT) and normal medullar biopsy. She recently started R-CHOP chemotherapy. Conclusion: This case illustrates both an unusual site of dissemination and challenging cytological characteristics in a follicular lymphoma. The signet ring cell changes challenged the adequate classification of this lymphoma as either a large B cell or a follicular B cell lymphoma.

An Unusual Uterine Tumor With Signet Ring Cell Features.

In 2004, a 56-year-old woman was diagnosed with Stage IA follicular lymphoma in a cervical lymph node biopsy. The patient experienced total remission after local radiation therapy. In 2009, a control computed tomography scan evidenced a pelvic mass, prompting total hysterectomy. The latter harbored a 4.8-cm intramural uterine tumor corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells, with extensive, periodic acid-Schiff negative, signet ring cell changes, and a pan-keratin negative, CD20+, CD10+, Bcl2+, Bcl6+ immunophenotype. Molecular genetic studies showed the same clonal IGH gene rearrangement in the lymph node and the uterus, establishing the uterine tumor as a relapse of the preceding follicular lymphoma, although no signet ring cells were evidenced at presentation. Uterine localization of lymphomas is rare, and lymphomas with signet ring cell features are uncommon. This exceptional case exemplifies a diagnostically challenging situation and expands the differential diagnosis of uterine neoplasms displaying signet ring cell morphology.

Is preoperative chemotherapy followed by surgery the appropriate treatment for signet ring cell containing adenocarcinomas of the esophagogastric junction and stomach?

BACKGROUND Recent data suggest primary resection as the preferable approach in patients with signet ring cell gastric cancer (SRC). The aim of our retrospective exploratory study was to evaluate the influence of SRC on prognosis and response in esophagogastric adenocarcinoma treated with neoadjuvant chemotherapy. METHODS A total of 723 locally advanced esophagogastric adenocarcinomas (cT3/4 N any) documented in a prospective database from two academic centers were classified according to the WHO definition for SRC (more than 50 % SRC) and analyzed for their association with response and prognosis after neoadjuvant treatment. RESULTS A total of 235 tumors (32.5 %) contained SRC. Median survival of SRC was 26.3 compared with 46.6 months (p < 0.001) for non-SRC. SRC were significantly associated with female gender, gastric localization, advanced ypT and R1/2 categories, and lower risk of surgical complications and anastomotic leakage (each p < 0.001). Clinical (21.1 vs. 33.7 %, p = 0.001) and histopathological response (less than 10 % residual tumor: 16.3 vs. 28.9 %, p < 0.001) were significantly less frequent in SRC. Clinical response (p = 0.003) and complete histopathological response (pCR) (3.4 %) (p = 0.003) were associated with improved prognosis in SRC. Clinical response, surgical complications, ypTN categories, but not SRC were independent prognostic factors in forward Cox regression analysis in R0 resected patients. Risk of peritoneal carcinomatosis was increased (p < 0.001), while local (p = 0.015) and distant metastases (p = 0.02) were less frequent than in non-SRC. CONCLUSIONS Prognosis of SRC is unfavorable. Although response to neoadjuvant chemotherapy is rare in SRC, it is associated with improved outcome. Thus, chemotherapy might not generally be abandoned in SRC. A stratification based on SRC should be included in clinical trials.

ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.

BACKGROUND: ALK rearrangement is particularly observed in signet-ring sub-type adenocarcinoma. Since fluorescence in situ hybridization (FISH) is not suitable for mass screening, we aimed to characterize the predictive utility of tumour morphology and ALK immunoreactivity to identify ALK rearrangement, in a primary lung adenocarcinoma dataset enriched for signet-ring morphology, compared with that of other morphology. METHODS: 7 adenocarcinomas from diagnostic archives reported with signet-ring morphology were assessed and compared with 11 adenocarcinomas without signet-ring features over the same time period. Growth patterns were reviewed, ALK expression was assessed by standard immunohistochemistry using ALK1 clone and Envision detection (Dako), and ALK rearrangement was assessed by FISH (Abbott Molecular). Associations between groups and predictive utility of tumour morphology and ALK expression using FISH as gold standard were calculated. RESULTS: 2 excision lung biopsy cases with pure (100%) signet-ring morphology and solid patterns demonstrated diffuse moderate cytoplasmic ALK immunoreactivity (2+) and harboured ALK rearrangements (p=0.007), unlike 5 mixed-signet-ring and 11 non-signet-ring adenocarcinomas, which showed negative or 1+ immunoreactivity; and did not harbour ALK rearrangements (p>0.1). ALK expression was not associated with ALK copy number. 6 of 7 cases with signet ring morphology stained for TTF-1. Pure signet-ring morphology and moderate ALK expression were both associated with ALK rearranged tumours. CONCLUSION: ALK rearrangement is strongly associated with ALK immunoreactivity, and was seen only in tumours with pure signet-ring morphology and solid growth pattern. Tumour morphology, growth pattern and ALK immunoreactivity appear to be good indicators of ALK rearrangement, with TTF-1 positivity aiding in proving primary pulmonary origin.

Histopathological aspects of Bovine Enzootic Hematuria in Brazil

The bladder lesions of 59 cattle, from the States of Rio de Janeiro, São Paulo, Minas Gerais, Espírito Santo, Rio Grande do Sul, Santa Catarina, Paraná and Amazon, affected by Bovine Enzootic Haematuria (BEH), were studied histologically. The objective of this study was to describe and reclassify neoplastic and non-neoplastic alterations not yet reported, according to the more complete current nomenclature used in human medicine. There was an almost complete identity with alterations observed in the bladder of man. Due to the occurrence of two or more neoplasms in the same animal, differences in the methodology and in the concept of classification, a more precise comparison was not possible. Coexistence of different types of epithelial and/or mesenchymal tumour growth was frequently seen. Rare neoplasms or differentiations not previously described were found in the bladder of some animals affected by BEH. These were trabecular carcinoma with Paneth cells differentiation, mesonephroid adenoma, mesonephroid adenocarcinoma, "signet ring" cell carcinoma, plasmocytoid carcinoma, chromophobe cell carcinoma and nested type of transitional cell carcinoma. Haemangiosarcomas originating from haemangiomas were also observed. This study also revealed the occurrence of many tumors with anaplasia and pronounced infiltrative features, but which did not metastasize. The elucidation of the cause of this "barrier against metastases" and its relationship with chemical carcinogenesis induced by the ptaquiloside, the active principle of bracken fern (Pteridium aquilinum), could be of interest to future research on the control ofneoplasia in man and animals.

Gestational protein malnutrition impairs c-myc and p63 protein expression, increases prostatic intraepithelial neoplasia incidence and prostatitis aggressiveness in adult male offspring subjected to hormonal handling

Background: Prostate cancer is the second most common cancer diagnosed in men; however its etiology remains unknown. Previous studies have shown that environmental adverse factors, such as maternal nutritional status during pregnancy, can influence fetal development and predispose people to diseases in adult life. The feeding of low-protein diets to pregnant rats result in fetal growth disturbance, androgen/estrogen unbalance and changes in the expression and sensibility of hormone receptors in male offspring. These alterations can promote permanent changes in androgen dependent organs, such as in the prostate. In this sense, we hypothesized that the hormonal unbalance that occurs during aging can lead to an increase in the susceptibility to prostatic disorders. Aim: To evaluate our hypothesis, malnourished male rat offspring were submitted to simultaneous estrogen and testosterone exposure in adulthood, to drive lesions in the rat ventral prostate gland (VP). Methods: 17 week-old Wistar rats (n=48) that received in utero normal protein diet (NP group, AIN93G=17% protein) or low protein diet (RP group, AIN93G modified=6% protein) were given implants with 17β-estradiol plus testosterone administration (NPH and RPH groups) for 17 weeks. The animals were killed at the age of 34 weeks and the VP were excised, weighted and processed for histopathological, immunohistochemical (Ki67, AR, p63, e-caderin, laminin, c-myc and GSTP), biochemical and ultrastructural analysis. Results: Both absolute and relative VP weight from NPH animals were about 30% higher than RPH. Serological data showed that estradiol levels were similar in both groups, but testosterone levels were lower in the RPH male offspring. The steroid hormone exposure in adult life promoted prostate lesions in both RPH and NPH offspring associated with reactive stroma. VP from RPH group exhibited heightened susceptibility to prostatic intraepithelial neoplasia (mainly cribriform and signet ring-cell patterns) and increased the incidence and aggressiveness of prostatitis. In this group, a higher proportion of basal cells, increased proliferation index, lower expression ofthe androgen receptor and increased focus of collagenous micronodules closely associated to epithelial neoplasias were also observed. Conclusion:These observations suggest that maternal protein restriction alters adult prostate response to androgen/estrogen handling and increases susceptibility to prostate diseases. Ethical protocol:CEEA,476/2013 IBB-UNESP; Funding Support: 2009/50204-6 and 2013/09649-0.

Aussergewöhnliche Manifestation eines Magenkarzinoms mit Meningeosis carcinomatosa und spinaler Metastase

BACKGROUND: Leptomeningeal carcinomatosis is a rare complication of solid tumors, e. g., breast, lung and gastrointestinal carcinomas. Clinical manifestations are variable with radicular pains with or without neurologic deficiencies as well as headache and hallucinations. CASE REPORT: The rare case of a 57-year-old patient with neurologic symptoms caused by a leptomeningeal carcinomatosis and a spinal metastasis of an asymptomatic signet-ring cell gastric carcinoma is reported. In spite of combined radiochemotherapy the patient died already 4 weeks after discharge from hospital due to an intracerebral hemorrhage. CONCLUSION: Until today, prognosis of leptomeningeal carcinomatosis is poor with a median survival between 3-4 months independently of the primary tumor.

Cdx2, cytokeratin 20, thyroid transcription factor 1, and prostate-specific antigen expression in unusual subtypes of prostate cancer

There are some unusual histologic variants of prostate carcinoma, including mucinous, signet-ring cells, and ductal carcinomas that can metastasize in a problematic way and simulate lung, colorectal, or bladder primaries. Currently, antibodies that are organ-specific have been used in the routine surgical pathology practice. Our aim is to study the profile of expression of Cdx2, thyroid transcription factor 1 (TTF1), and cytokeratin 20 (CK20) in prostate cancer with unusual histologic finding. Twenty-nine prostate adenocarcinomas with unusual histologic findings were submitted to immunohistochemistry with prostate-specific antigen (PSA), CK20, Cdx2, and TTF1 antibodies. There were 7 mucinous, 5 ductal, 2 signet-ring cells, and 15 usual acinar adenocarcinomas with focal mucinous differentiation. To compare the results with usual acinar adenocarcinomas, we studied 10 primary and their respective lymph node metastases in a tissue microarray, 2 unusual metastatic adenocarcinomas, and 6 usual acinar high-grade carcinomas. For tumors with special histologic finding, Cdx2 was expressed by 9 (31.0%) mucinous, signet-cell, or with focal mucinous differentiation. Thyroid transcription factor I was moderately positive in mucinous differentiation areas of 2 (6.9%) adenocarcinomas. Cytokeratin 20 was expressed by 9 (31.0%) tumors, among them, 3 ductal adenocarcinomas. Prostate-specific antigen was positive in 28 (96.6%) cases and negative in I ductal adenocarcinoma. There was only I worrisome ductal adenocarcinoma that was strongly CK20 positive and PSA negative. Almost one third of mucinous prostate carcinomas express Cdx2. Cytokeratin 20 can be positive also in one third of prostate carcinomas, especially the ductal type. Pathologist should be alert when evaluating immumohistochemical profiles of unusual histologic findings of prostate cancer, mostly in distant sites. (C) 2008 Elsevier Inc. All rights reserved.

A Validation Study for the Use of ROS1 Immunohistochemical Staining in Screening for ROS1 Translocations in Lung Cancer

INTRODUCTION: The presence of ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) rearrangements in lung cancers confers sensitivity to ROS kinase inhibitors, including crizotinib. However, they are rare abnormalities (in ∼1% of non-small cell lung carcinomas) that are typically identified by fluorescence in situ hybridization (FISH), and so screening using immunohistochemical (IHC) staining would be both cost- and time-efficient.

METHODS: A cohort of lung tumors negative for other common mutations related to targeted therapies were screened to assess the sensitivity and specificity of IHC staining in detecting ROS1 gene rearrangements, enriched by four other cases first identified by FISH. A review of published data was also undertaken.

RESULTS: IHC staining was 100% sensitive (95% confidence interval: 48-100) and 83% specific (95% confidence interval: 86-100) overall when an h-score higher than 100 was used. Patients with ROS1 gene rearrangements were younger and typically never-smokers, with the tumors all being adenocarcinomas with higher-grade architectural features and focal signet ring morphologic features (two of five). Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively.

CONCLUSION: IHC staining can be used to screen for ROS1 gene rearrangements, with patients herein showing a response to crizotinib. Patients with tumors that test positive according to IHC staining but negative according to FISH were also identified, which may have implications for treatment selection.

Adenocarcinoma in females detected in serous effusions: Cytomorphologic aspects and immunocytochemical reactivity to cytokeratins 7 and 20

OBJECTIVE: To investigate the usefulness of assessing the immunoreactivity of cytokeratins 7 (CK7) and 20 (CK20) as well as several cytomorphologic parameters in effusions with metastatic adenocarcinomas in the search for the primary site of the tumor. STUDY DESIGN: From the files of the Pathology Department, A. C. Camargo Hospital, we studied cytologic smears from 73 metastatic adenocarcinomas originally from the breast, 63 from the ovary, 40 from the lung and 32 from the stomach, looking for morphologic parameters that could have discriminant potential in suggesting the primary site in a routine situation, including intranuclear inclusions, prominent nucleoli, mitosis, signet-ring cells, psammoma bodies, nuclear crease, binucleation and multinucleation, papillary features, acinar profile (including ball cells) and single cells. Immunoreactions were performed with monoclonal antibodies to CK7 (OV-TL 12/30 and CK20 (Ks 20.8) and included morphologic analysis. Both analyses were studied in a blind fashion regarding the primary site of the tumors. RESULTS: Positivity ratios for breast, ovary, stomach and lung cases were 67.6%, 63.5%, 29.7% and 45.5%, respectively, for CK7 and 17.2%, 15.8%, 13.5% and 32.2%, respectively, for CK20. Discriminant analysis of morphologic and immunocytochemical parameters had an error rate of 42.9% in recognizing the primary site and a Wilk's lambda of .7290. CONCLUSION: The more efficient parameter with discriminant function was the papillary appearance showed by CK7, which should be used in further studies with a similar scope. The set of parameters used in this study were insufficient to discriminate the primary site of female adenocarcinomas in effusions with significant accuracy.

Mechanical modeling of Intraneural Ganglion Cyst

Intraneural Ganglion Cyst is a 200 year old mystery related to nerve injury which is yet to be solved. Current treatments for the above problem are relatively simple procedures related to removal of cystic contents from the nerve. However, these treatments may result into neuropathic pain and recurrence of the cyst. The articular theory proposed by Spinner et al., (Spinner et al. 2003) takes into consideration the neurological deficit in Common Peroneal Nerve (CPN) branch of the sciatic nerve and affirms that in addition to the above treatments, ligation of articular branch results into foolproof eradication of the deficit. Mechanical Modeling of the Affected Nerve Cross Section will reinforce the articular theory (Spinner et al. 2003). As the cyst propagates, it compresses the neighboring fascicles and the nerve cross section appears like a signet ring. Hence, in order to mechanically model the affected nerve cross section; computational methods capable of modeling excessively large deformations are required. Traditional FEM produces distorted elements while modeling such deformations, resulting into inaccuracies and premature termination of the analysis. The methods described in this Master’s Thesis are effective enough to be able to simulate such deformations. The results obtained from the model adequately resemble the MRI image obtained at the same location and shows an appearance of a signet ring. This Master’s Thesis describes the neurological deficit in brief followed by detail explanation of the advanced computational methods used to simulate this problem. Finally, qualitative results show the resemblance of mechanical model to MRI images of the Nerve Cross Section at the same location validating the capability of these methods to study this neurological deficit.

Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas.

BACKGROUND Recently, histopathological tumour regression, prevalence of signet ring cells, and localisation were reported as prognostic factors in neoadjuvantly treated oesophagogastric (junctional and gastric) cancer. This exploratory retrospective study analyses independent prognostic factors within a large patient cohort after preoperative chemotherapy including clinical and histopathological factors. METHODS In all, 850 patients presenting with oesophagogastric cancer staged cT3/4 Nany cM0/x were treated with neoadjuvant chemotherapy followed by resection in two academic centres. Patient data were documented in a prospective database and retrospectively analysed. RESULTS Of all factors prognostic on univariate analysis, only clinical response, complications, ypTNM stage, and R category were independently prognostic (P<0.01) on multivariate analysis. Tumour localisation and signet ring cells were independently prognostic only when investigator-dependent clinical response evaluation was excluded from the multivariate model. Histopathological tumour regression correlates with tumour grading, Laurén classification, clinical response, ypT, ypN, and R categories but was not identified as an independent prognostic factor. Within R0-resected patients only surgical complications and ypTNM stage were independent prognostic factors. CONCLUSIONS Only established prognostic factors like ypTNM stage, R category, and complications were identified as independent prognostic factors in resected patients after neoadjuvant chemotherapy. In contrast, histopathological tumour regression was not found as an independent prognostic marker.