Elisabete Rios

Oncocytic Lesions of the Thyroid, Kidney, Salivary Glands, Adrenal Cortex, and Parathyroid Glands

Oncocytic cell represents a special phenotype of neoplastic cells reflecting a unique biologic process characterized by the huge proliferation of morphologically abnormal mitochondria in the cytoplasm of neoplastic cells. This phenotype is driven by quite specific molecular mechanisms that interfere with mitochondrial function and metabolism. The oncocytic phenotype is more common in tumors arising in tissues presenting low proliferative rate, such as thyroid, kidney, salivary glands, adrenal cortex, and parathyroid glands, and it is superimposed on the genotypic and conventional histologic features of the tumors. In this short review, we address the similarity of the molecular alterations and of the biological features of the neoplastic cells in the oncocytic tumors of the different organs. We also discuss the differential diagnosis of benign and malignant oncocytic tumors as well as the prognosis of the malignant ones. We conclude that this rather unique phenotype, which is observed in tumors from different organs, indicates common metabolic alterations that may represent a useful target for therapeutic purposes.

Genotypes and prevalence of HPV single and multiple concurrent infections in women with HSIL

The contribution of human papillomavirus (HPV) types to the carcinogenesis of cervical cancer has been established for a long time. However, the role of phylogenetically related and rare variants remains uncertain, as well as the influence of concurrent multiple HPV genotypes infection. We aimed at studying the prevalence of several HPV genotypes infecting women with single versus concurrent multiple HPV genotypes infection with a HSIL diagnosis in a cervical cytology. We conducted a cross‐sectional study using Thin‐Prep® liquid‐based cervical cytology specimens with the diagnosis of high‐grade squamous intraepithelial lesion (HSIL), in which HPV genotype was sequentially tested. Genotypes were determined with a PapilloCheck® system, a DNA‐Chip for the type‐specific identification of 18 high‐risk and six low‐risk types of HPV. Of the total study population, 176 cases had a diagnosis of HSIL and positive HPV genotyping result, being HPV16 the most prevalent genotype (48.86%; 95%CI: 41.58–56.19) followed by HPV31 (14.20%; 95%CI: 9.75–20.18). Concurrent multiple HPV genotypes were detected in 36.93% (95%CI: 30.15–44.27) of the patients. The prevalence of the 10 most common HPV genotypes detected varied significantly according to the presence of single vs. concurrent multiple HPV genotypes (P = 0.022). Moreover, women with concurrent multiple HPV genotypes were on average 3.53 (95%CI: 0.43–6.64) years younger than women with single genotype infection. Our results suggest that women with multiple genotype HPV infection differ in terms of age and distribution of the most prevalent HPV genotypes. Additionally, we provide further evidence of the predominance of HPV16 in HSIL lesions of the uterine cervix. Diagn. Cytopathol. 2014;42:919–923.

Osteopontin-a splice variant is overexpressed in papillary thyroid carcinoma and modulates invasive behavior

Osteopontin (OPN) is a matricellular protein overexpressed in cancer cells and modulates tumorigenesis and metastasis, including in thyroid cancer (TC). The contribution of each OPN splice variant (OPN-SV), named OPNa, OPNb and OPNc, in TC is currently unknown. This study evaluates the expression of total OPN (tOPN) and OPN-SV in TC tissues and cell lines, their correlation with clinicopathological, molecular features and their functional roles. We showed that tOPN and OPNa are overexpressed in classic papillary thyroid carcinoma (cPTC) in relation to adjacent thyroid, adenoma and follicular variant of papillary thyroid carcinoma (fvPTC) tissues. In cPTC, OPNa overexpression is associated with larger tumor size, vascular invasion, extrathyroid extension and BRAFV600E mutation. We found that TC cell lines overexpressing OPNa exhibited increased proliferation, migration, motility and in vivo invasion. Conditioned medium secreted from cells overexpressing OPNa induce MMP2 and MMP9 metalloproteinases activity. In summary, we described the expression pattern of OPN-SV in cPTC samples and the key role of OPNa expression on activating TC tumor progression features. Our findings highlight OPNa variant as TC biomarker, besides being a putative target for cPTC therapeutic approaches.

Morphological features and mucin expression profile of breast carcinomas with signet-ring cell differentiation.

Signet-ring cells are relatively common in breast cancers but are frequently overlooked. Although previously defined as a subtype of mucin producing carcinomas, breast carcinomas with signet-ring cell (SRC) differentiation nowadays are not considered a distinct entity. The objective of the present study was to characterize the morphological features and mucin expression profile of breast carcinomas with SRC differentiation. All breast carcinomas diagnosed at Centro Hospitalar S. Joao between 1996 and 2006 in which the pathology report mentioned the presence of SRCs (n=11) and four mucinous carcinomas were included in the study. The frequency of SRCs and immunohistochemistry expression of MUC1/MUC2/MUC5AC/MUC6 were evaluated. We confirmed that SRC differentiation can occur in different histological types, including ductal, lobular, mucinous and metaplastic carcinomas. The proportion of SRCs was highly variable (range: 8-70%). Tumors encompassed SRCs of intracytoplasmic lumina and goblet-cell type. A higher percentage of SRCs was associated with lymphovascular invasion (p=0.047). All tumors expressed cytoplasmic and membranous MUC1. Secretory mucins were more frequent in mucinous carcinomas and in carcinomas with extensive SRC differentiation. We conclude that besides the usefulness of mucin immunodetection for the differential diagnosis of carcinomas with SRC differentiation of breast origin, it is important to report SRC differentiation regardless of histological type because of its intrinsic prognostic value.

p16 immunostaining in histological grading of anal squamous intraepithelial lesions: a systematic review and meta-analysis

Abstractp16 is the most widely studied biomarker in lower anogenital tract squamous intraepithelial lesions and, currently the only recommended biomarker for histological grade assessment. The aim of this systematic review and meta-analysis was to evaluate p16-positive rates according to anal squamous intraepithelial lesions/anal intraepithelial neoplasia (AIN) grade. Two investigators independently searched four electronic databases: PubMed, Web of Sciences, Scopus, and Embase from inception until August 2017. Studies that evaluated p16 immunostaining in histological samples of anal and/or perianal squamous intraepithelial lesions and defined a p16-positive result as diffuse block staining with nuclear or nuclear plus cytoplasmic staining were included. A meta-analysis was performed using a random effects model. Fifteen studies consisting of 790 samples were included. The proportion of p16 expression increased with the severity of histological grade. p16 positivity was 2% (95% CI: 0.2–5%) in normal histology, 12% (95% CI: 2–27%) in low-grade squamous intraepithelial lesions (LSILs)/AIN1 (excluding condylomas), 7% (95% CI: 2–13%) in all LSIL (AIN1/LSIL/condyloma), 76% (95% CI: 61–88%) in AIN2, and 90% (95% CI: 82–95%) in AIN3. For anal high-grade squamous intraepithelial lesions (HSILs), in studies using a two-tiered nomenclature, p16 positivity was 84% (95% CI: 66–96%) and for all HSIL (AIN2, AIN3, HSIL combined) it was 82% (95% CI: 72–91%). In summary, p16 positivity in anal squamous intraepithelial lesions appears to be in a similar range to the commonly described cervical squamous intraepithelial lesions, however, for anal low-grade lesions positivity seems to be lower.

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression.

OPNa Overexpression Is Associated with Matrix Calcification in Thyroid Cancer Cell Lines

Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia and dystrophic calcification, including psammoma bodies (PB). This work aimed to investigate total OPN (tOPN) and OPN-SV expression and their association with the presence of PB in the PTC classical variants (cPTC), as well as the involvement of OPN-SV in matrix calcification of TC cell lines. We found that cPTC samples presenting PB showed higher OPN expression levels. In TC cell lines, OPNa overexpression promotes higher matrix calcification and collagen synthesis when compared to that of clones overexpressing OPNb or OPNc. In response to OPN knockdown, calcification was inhibited, paralleled with the downregulation of calcification markers. In conclusion, our data evidenced that OPN expression is associated with the presence of PB in cPTC samples. Among the OPN-SV, OPNa is the main contributor to matrix calcification in tested TC cells, providing clues to a better understanding on the biology and ethiopathogenesis of the calcification process in TC cells.

Pseudolymphomatous nodular lymphoid hyperplasia of small bowel

A 41-year-old woman was referred to the Gastroenterology outpatient clinic due to non-bloody chronic diarrhea with associated iron-deficiency anemia (hemoglobin 8 g/dL). Initial work-up laboratory study revealed marked deficit of all immunoglobulins, especially Ig A (< 8 mg/dL for a normal value of 78—312 mg/dL), consistent with common variable immunodeficiency (CVID). Viral serologies and anti-transglutaminase antibodies were negative. Upper endoscopy revealed multiple small nodules in the duodenal bulb and the second part of duodenum (Fig. 1A). Biopsies showed nodular lymphoid hyperplasia (NLH) with associated duodenitis and presence in the epithelium surface of trophozoites compatible with Giardia lamblia (Fig. 1B).

Large myocardial infarction with myocardium calcium deposits associated with reperfusion injury

The clinical and autopsy findings of a 66-year-old man with myocardial infarction complicated by reperfusion injury are described, highlighting the presence of large myocardium calcium deposits.

Gastrointestinal: Anal Buschke Loewenstein tumor

A 33 year-old male was diagnosed with Human immunodeficiency virus (HIV) infection in 2009, CD4 count of <200 cells/mL and HIV RNA 756000 cps/ml. Antiretroviral therapy (ART) was started. In 2010, a mass involving the rectum and bladder was diagnosed as a pelvic non-Hodgkin′s lymphoma (diffuse large B-cell lymphoma) and initially submitted to six cycles of chemotherapy—CHOP (Cyclophosphamide, doxorubicin, vincristine and prednisolone) and followed by radiotherapy (45 Gy), due to the persistence of the pelvic lesion. Six months later, a painful and progressively larger perianal lesion appeared complicating evacuation. A 15 cm ¥ 10 cm exophytic mass of the perianal region was observed (Figures 1 and 2). Laboratory tests showed normal hemoglobin level (15 g/dl), white blood cells count (4.68 ¥ 10/L), platelets (232 ¥ 10/L), CD4 count >200 cells/mL, and HIV RNA not detected. Endoscopic ultrasound (EUS) revealed an external anal sphincter defect. This HIV patient had a large, vegetative, cauliflower-like tumor in the perianal region, with local invasion revealed by EUS and histology confirming a condyloma acuminata (Figure 3). Anal Buschke Loewenstein Tumor (Giant Condyloma Acuminata) was diagnosed. This is a rare disease with a potentially fatal course, due to human papillomavirus (HPV) infection, most commonly HPV types 6 and 11 and occasionally types 16 and 18. It is characterized by its size, capability of local infiltration, and high recurrence rate. There seems to be a trend towards younger age at presentation and male predominance. Perianal mass, pain, abscess, fistula and bleeding are the most common presenting symptoms. It most often affects the glans penis, but has also been reported in the scrotum, vulva, perianal region, and bladder. Local invasion and local recurrence are the major sources of morbidity in this disease. Despite the benign histological pattern in most cases, transformations into verrucous carcinoma and squamous-cell carcinoma have been described. Wide surgical excision, radiochemotherapy, topical and intralesional chemotherapy, carbon dioxide laser therapy, and photodynamic therapy have been used as treatment. Wide local excision remains the mainstay of therapy. The high recurrence rate after wide local excision has prompted the employment of therapy adjuncts. Both radiation and chemotherapy have been used as the most common preoperative regimen. This patient refused surgery and abandoned follow up.