A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer.

The PMS2 gene is involved in DNA repair by the mismatch repair pathway. Deficiencies in this mechanism have been associated with Lynch Syndrome (LS), which is characterized by a high risk for colorectal, endometrial, ovarian, breast, and other cancers. Germinal pathogenic variants of PMS2 are associated with up to 5% of all cases of LS. The prevalence is overestimated for the existence of multiple homologous pseudogenes. We report the case of a 44-year-old woman diagnosed with breast cancer at 34 years without a relevant cancer family history. The presence of pathogenic variant NM_000535.7:c.1A > T, (p.Met1Leu) in PMS2 was determined by next-generation sequencing analysis with a panel of 322 cancer-associated genes and confirmed by capillary sequencing in the patient. The variant was determined in six family members (brothers, sisters, and a son) and seven non-cancerous unrelated individuals. Analysis of the amplified region showed high homology of PMS2 with five of its pseudogenes. We determined that the variant is associated with the PMS2P1 pseudogene following sequence alignment analysis. We propose considering the variant c.1A > T, (p.Met1Leu) in PMS2 for reclassification as not hereditary cancer-related, given the impact on the diagnosis and treatment of cancer patients and families carrying this variant.

[Third National Ovarian Consensus. 2011. Grupo de Investigación en Cáncer de Ovario y Tumores Ginecológicos de México "GICOM"]. / Tercer Consenso Nacional de Cáncer de Ovario 2011. Grupo de Investigación en Cáncer de Ovario y Tumores Ginecológicos de México "GICOM".

INTRODUCTION: Ovarian cancer (OC) is the third most common gynecologic malignancy worldwide. Most of cases it is of epithelial origin. At the present time there is not a standardized screening method, which makes difficult the early diagnosis. The 5-year survival is 90% for early stages, however most cases present at advanced stages, which have a 5-year survival of only 5-20%. GICOM collaborative group, under the auspice of different institutions, have made the following consensus in order to make recommendations for the diagnosis and management regarding to this neoplasia. MATERIAL AND METHODS: The following recommendations were made by independent professionals in the field of Gynecologic Oncology, questions and statements were based on a comprehensive and systematic review of literature. It took place in the context of a meeting of two days in which a debate was held. These statements are the conclusions reached by agreement of the participant members. RESULTS: No screening method is recommended at the time for the detection of early lesions of ovarian cancer in general population. Staging is surgical, according to FIGO. In regards to the pre-surgery evaluation of the patient, it is recommended to perform chest radiography and CT scan of abdomen and pelvis with IV contrast. According to the histopathology of the tumor, in order to consider it as borderline, the minimum percentage of proliferative component must be 10% of tumor's surface. The recommended standardized treatment includes primary surgery for diagnosis, staging and cytoreduction, followed by adjuvant chemotherapy Surgery must be performed by an Oncologist Gynecologist or an Oncologist Surgeon because inadequate surgery performed by another specialist has been reported in 75% of cases. In regards to surgery it is recommended to perform total omentectomy since subclinic metastasis have been documented in 10-30% of all cases, and systematic limphadenectomy, necessary to be able to obtain an adequate surgical staging. Fertility-sparing surgery will be performed in certain cases, the procedure should include a detailed inspection of the contralateral ovary and also negative for malignancy omentum and ovary biopsy. Until now, laparoscopy for diagnostic-staging surgery is not well known as a recommended method. The recommended chemotherapy is based on platin and taxanes for 6 cycles, except in Stage IA, IB and grade 1, which have a good prognosis. In advanced stages, primary cytoreduction is recommended as initial treatment. Minimal invasion surgery is not a recommended procedure for the treatment of advanced ovarian cancer. Radiotherapy can be used to palliate symptoms. Follow up of the patients every 2-4 months for 2 years, every 3-6 months for 3 years and anually after the 5th year is recommended. Evaluation of quality of life of the patient must be done periodically. CONCLUSIONS: In the present, there is not a standardized screening method. Diagnosis in early stages means a better survival. Standardized treatment includes primary surgery with the objective to perform an optimal cytoreduction followed by chemotherapy Treatment must be individualized according to each patient. Radiotherapy can be indicated to palliate symptoms.

High prevalence of human papillomavirus and European variants of HPV 16 infecting concomitantly to cervix and oral cavity in HIV positive women.

OBJECTIVE: Identify the prevalence of HPV infections in the uterine cervix and oral cavity and HPV16 variants in HIV+ women. METHODS: A total of 174 HIV+ women attended an HIV+ specialized clinic in Mexico City. Cells were obtained from the oral cavity and cervix to extract DNA. Polymerase chain reaction (PCR) was used to amplify the HPV sequence with generic primers. We detected specific HPV types using the INNO-LiPA HPV Genotyping Extra II Kit (INNOGENETICS). The identification of variants was studied by sequencing the E6 gene with a Big Dye Terminator Kit and an Applied Biosystems 3500/3500xL genetic analyzer. RESULTS: HPV infection was very high in the uterine cervix (168/174, 96.6%) and oral cavity (161/174, 92.5%). The prevalence of HPV concurrent infections in the cervix and oral cavity was 155/174 (89.1%). We found hrHPVs to be more prevalent than low-risk HPVs (lrHPVs) in the oral cavity (90.2% versus 45.4%) and that infections simultaneously affected the cervix (94.3% versus 36.2%) and oral cavity (85.1% versus 20.1%). Surprisingly, only European variants of HPV type 16 were found in the uterine cervix of women and the oral cavity of all tested samples (52 oral cavity samples and 52 uterine cervix samples). CONCLUSIONS: The high prevalence of HPV, multiple infections and presence of the EP350G intravariant in both anatomical regions are strongly related to the persistence of the virus, which is fundamental for the development of cancer. Therefore, it is very important to control and monitor this high-risk population as well as implement programs for the early detection of HPV and vaccination.

PARIETAL PERITONEUM GRAFT FOR DUODENUM INJURIES IN AN ANIMAL MODEL.

BACKGROUND: Duodenal injuries and their surgical procedure cause a high morbidity and mortality. AIM: To assess the overall effectiveness of the auto-graft of peritoneum in the treatment of the perforation of the duodenum, aiming to reduce surgery time, costs, complexity and mortality. METHODS: Twelve New Zealand rabbits, ages 4-6 months, both sexes, underwent designed surgical grade III duodenal injuries that were repaired 18 h after. Rabbits were surgically treated with the proposed auto-graft of peritoneum. RESULTS: No postoperative deaths were observed; the animals presented corporal weight increase and were euthanized six months later. There was no significant difference between both groups relating to the postoperative evolution or in the histological changes. CONCLUSION: Auto-graft of the peritoneum and posterior fascia is a useful option for duodenal repair and that is worth of evaluation for humans.

Neuroendocrine carcinomas of the pancreas with 'Rhabdoid' features.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Parietal peritoneum graft for duodenum injuries in an animal model / Enxerto de peritônio parietal em lesão duodenal: modelo animal

ABSTRACT Background: Duodenal injuries and their surgical procedure cause a high morbidity and mortality. Aim: To assess the overall effectiveness of the auto-graft of peritoneum in the treatment of the perforation of the duodenum, aiming to reduce surgery time, costs, complexity and mortality. Methods: Twelve New Zealand rabbits, ages 4-6 months, both sexes, underwent designed surgical grade III duodenal injuries that were repaired 18 h after. Rabbits were surgically treated with the proposed auto-graft of peritoneum. Results: No postoperative deaths were observed; the animals presented corporal weight increase and were euthanized six months later. There was no significant difference between both groups relating to the postoperative evolution or in the histological changes. Conclusion: Auto-graft of the peritoneum and posterior fascia is a useful option for duodenal repair and that is worth of evaluation for humans.

RESUMO Racional: Lesões duodenais e seu procedimento cirúrgico causam alta morbimortalidade. Objetivo: Avaliar a eficácia geral de retalho peritoneal no tratamento da perfuração do duodeno, visando reduzir o tempo, os custos, a complexidade e a mortalidade cirúrgicas. Métodos: Doze coelhos da raça Nova Zelândia, com idades entre 4-6 meses, ambos os sexos, foram submetidos a lesões duodenais cirúrgicas de grau III, que foram reparadas 18 h depois. Coelhos foram tratados cirurgicamente com a proposta de auto-enxerto de peritônio. Resultados: Não foram observados óbitos pós-operatórios; os animais apresentaram aumento de peso corporal e foram eutanasiados seis meses depois. Não houve diferença significativa entre os dois grupos em relação à evolução pós-operatória ou nas alterações histológicas. Conclusão: A auto-enxertia do peritônio e da fáscia posterior é uma opção útil para o reparo duodenal e vale a pena ser avaliada em seres humanos.

A high body mass index is not a worse prognostic factor for endometrial carcinoma in a predominantly obese population.

AIM: We investigate if body mass index (BMI, kg × m(2)) is related to clinical-pathological characteristics in primary tumor and disease outcome in endometrial cancer. BACKGROUND: Endometrial cancer incidence is increasing in industrialized countries. High BMI is associated with worse prognosis for many diseases. INTRODUCTION: Endometrial carcinoma is the most common gynecological malignancy in industrialized countries and the incidence has been increasing over the last few decades associated with obesity, however, it is not clear if a high BMI is associated with poor prognosis. PATIENTS AND METHODS: In total, 147 women primarily treated for endometrial carcinoma at the Instituto Nacional de Cancerología during 2000-2005 were studied. Body mass index was available for all patients and related to comprehensive clinical and histopathological data. RESULTS: High BMI was related to endometrioid histology and low/intermediate grade, and overweight/obese women had the same survival as the normal/underweight women. In survival analysis adjusting for age, histological subtype and grade, BMI showed no independent prognostic impact. CONCLUSION: High BMI was significantly associated with markers of non-aggressive disease and women with high BMI had the same survival time in univariate analysis.

Ovarian undifferentiated carcinoma with voluminous mesenteric presentation.

INTRODUCTION: About 5% of ovarian cancers are so poorly differentiated and difficult to classify that they are called undifferentiated carcinomas and usually have disseminated disease at presentation. Extra pelvic debulking it is difficult to complete. PRESENTATION OF CASE: We report a case of a rare ovarian tumor presented as a large mesenteric tumor of 14cm diameter in a 73 years old woman. DISCUSSION: Undifferentiated carcinomas are usually large, solid with hemorrhage and necrosis, bilateral and most are difficult to classify histologically. Rarely are pure, generally identified through the extensive sampling of lesions, some other components of surface epithelial carcinoma and usually the predominant element is the latter. Cases with predominantly undifferentiated component are rare. CONCLUSION: The treatment and diagnostic approach is the same as for other high-grade epithelial tumors of the ovary, but in this particular case the differential diagnosis and diagnostic approach is that of a mesenteric tumor.

Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases.

Hybrid oncocytic/chromophobe tumors (HOCT) of the kidney have been described in patients with Birt-Hogg-Dubé syndrome (BHD) and in association with renal oncocytosis without BHD. HOCT in patients without evidence of BHD or renal oncocytosis is exceedingly rare, and these cases have been poorly characterized. We have identified and studied 14 cases of HOCT from previously diagnosed renal oncocytomas (398 cases) and chromophobe renal cell carcinomas (351 cases) without evidence of BHD or renal oncocytosis. Immunohistochemical, ultrastructural, and molecular genetic studies analyzing numerical chromosomal changes, loss of heterozygosity for chromosome 3p, and mutation status of VHL, c-kit, PDGFR, and folliculin (FLCN) genes were performed. HOCTs were identified in nine men and five women (age range 40-79 years). The size of tumors ranged from 2 to 11 cm. All tumors displayed a solid alveolar architecture and were composed of cells with abundant granular eosinophilic oncocytic cytoplasm with perinuclear halos. Occasional binucleated neoplastic cells were present, but irregular, hyperchromatic, wrinkled (raisinoid) nuclei were absent. The cytoplasm contained numerous mitochondria of varying sizes, but only sparse microvesicles with amorphic lamellar content were found. Tumors were positive for CK7 (12/14), AE1-AE3 (14/14), anti-mitochondrial antigen (14/14), E-cadherin (11/13), parvalbumin (12/14), and epithelial membrane antigen (14/14). Tumors were generally negative for racemase, CK20, CD10, and carboanhydrase IX. Interphase fluorescence in situ hybridization revealed multiple chromosomal losses and gains with a median of four (range 1-9) chromosomal aberrations per case. Monosomy of chromosome 20 was common and found in 7 of 14 cases. Monosomy of chromosomes 6 and 9 was present in 4 of 14 cases each, of which two cases displayed monosomy for both chromosomes 6 and 9. Polysomy of chromosomes 10, 21, and 22 was found in 4/14 cases each, of which one case displayed polysomy for all these three chromosomes. No pathogenic mutations were found in the VHL, c-kit, PDGFR, and folliculin (FLCN) genes. (1) We have shown that hybrid oncocytic/chromophobe tumors of the kidney do occur, albeit rarely, outside the Birt-Hogg-Dubé syndrome and without associated renal oncocytosis. (2) These tumors constitute a relatively homogenous group with histomorphologic features of both chromophobe renal cell carcinoma and renal oncocytoma. (3) Sporadic hybrid oncocytic/chromophobe renal tumors are characterized by multiple numerical aberrations (both mono- and polysomies) of chromosomes 1, 2, 6, 9, 10, 13, 17, 21, and 22 and lack of mutations in the VHL, c-kit, PDGFRA, and FLCN genes. (4) The tumors seem to behave indolently as no evidence of malignant behavior was documented in our series, although admittedly, the follow-up was too short to fully elucidate the biological nature of this rare neoplasm. At worst, these tumors could have a low malignant potential, which only can be found out with longer follow-up.

The spectrum of histologic changes in thyroid hyperplasia: a clinicopathologic study of 300 cases.

Thyroid hyperplasia is a physiologic response of follicular epithelium to hormonal changes that result in disturbances in the feedback mechanism of thyrotropin-releasing hormone and thyroid-stimulating hormone. The most common manifestation of this process is the so-called sporadic goiter (diffuse or nodular hyperplasia), a condition that may be associated with a variety of stimuli. Some of the histologic changes that can be observed in hyperplasia of the thyroid can sometimes lead to an incorrect diagnosis of malignancy. We studied 300 consecutive cases of hyperplasia of the thyroid to evaluate morphologic features that could potentially be mistaken for neoplastic conditions. Florid papillary hyperplasia of follicular epithelium was observed in 13% of cases, in several instances closely resembling the papillary structures of papillary thyroid carcinoma. Foci displaying nuclear clearing closely resembling "Orphan-Annie" nuclei were present in 15% of cases. Nuclear grooves and pseudonuclear inclusions were also identified focally in 8% of cases. Cytologic atypia was observed in 7% of cases, including nuclear enlargement, multinucleation, and nuclear pleomorphism with prominent nucleoli. Mitoses were observed in 6% of cases and averaged 1 to 2 per 20 high-power fields. This finding was usually seen in the more cellular areas in cases characterized by a solid, microfollicular pattern of growth. Psammoma bodies were observed focally in 4 cases (1.3%). Infiltration of adjacent skeletal muscle by benign hyperplastic follicles was seen in 3 cases (1%). Another unexpected finding in 2 cases was the identification of small clusters of normal thyroid follicles within the sinuses of lymph nodes located adjacent to the gland (>1%). The present study confirms that thyroid hyperplasia can sometimes display features that may be confused for a malignant neoplastic process. Awareness of such features and their recognition are of importance to avoid a misdiagnosis of malignancy.

Differential expression of smooth muscle myosin, smooth muscle actin, h-caldesmon, and calponin in the diagnosis of myofibroblastic and smooth muscle lesions of skin and soft tissue.

The diagnosis of low-grade and pseudosarcomatous spindle cell lesions of skin and soft tissue can sometimes be problematic; in particular, distinction between fibroblastic, myofibroblastic, and smooth muscle proliferations can occasionally pose difficulties on routine histologic examination. We have applied a panel of immunohistochemical markers to a series of spindle cell lesions of skin and soft tissue to assess the utility of the differential expression of smooth muscle and myofibroblastic-associated markers. Twenty-eight cases of nodular fasciitis, 42 cases of fibromatosis, and 3 cases of myofibroblastic sarcoma were stained with antibodies against smooth muscle actin (SMA), smooth muscle myosin (SMMS), calponin, and high-molecular weight caldesmon (h-caldesmon). For comparison, 12 cases of cutaneous leiomyoma and 8 cases of leiomyosarcomas involving superficial soft tissues and fascia were studied with the same panel of antibodies. Thirty-eight of 42 cases of fibromatosis were positive for SMA, 42/42 cases were positive for calponin, 39/42 cases were negative for SMMS, and all cases were negative for h-caldesmon. All cases of nodular fasciitis were positive for SMA and calponin, and all were negative for h-caldesmon and SMMS. All cases of myofibroblastic sarcoma were positive for SMA and 2/3 cases for calponin, and were negative for SMMS and h-caldesmon. All cases of cutaneous leiomyoma and leiomyosarcoma were positive for all 4 markers tested. Our results demonstrate a remarkably consistent pattern of reactivity of muscle and myofibroblastic-associated markers in lesions predominantly composed of myofibroblastic spindle cells, characterized by positive staining for SMA and calponin and absence of reactivity for SMMS and h-caldesmon. Application of this panel of stains may be of aid in the differential diagnosis of low-grade myofibroblastic lesions such as nodular fasciitis and fibromatosis from smooth muscle tumors of skin and soft tissue. This panel may additionally be of assistance in the diagnosis of myofibroblastic sarcoma.