Diagnosing liposarcoma on (peri)-renal mass biopsy: A clinicopathological study of 30 cases.

AIMS: Classification of renal neoplasms on small tissue biopsies is in increasing demand, and maintaining broad differential diagnostic considerations in this setting is necessary. When evaluating a renal or perirenal tumour biopsy with sarcomatoid morphology, together with sarcomatoid renal cell carcinoma and sarcomatoid urothelial carcinoma as top diagnostic considerations, it is vital to additionally consider the possibility of well-differentiated and de-differentiated liposarcoma. METHODS AND RESULTS: This study reports a series of 30 biopsy samples from sites in or around the kidney collected from four institutions in which the correct diagnosis was either well-differentiated or de-differentiated liposarcoma. The majority (26 of 30, 87%) of lesions were accurately diagnosed on biopsy sampling, all of which incorporated testing for MDM2 by immunohistochemistry (IHC), fluorescence in-situ hybridisation (FISH) or a combination of the two as part of the diagnostic work-up. Tumour expression of MDM2 by IHC without confirmatory FISH analysis was sometimes (30%) sufficient to reach a diagnosis, but demonstration of MDM2 amplification by FISH was ascertained in the majority (57%) of biopsy samples. A diagnosis of de-differentiated liposarcoma was not definitively established until resection in four (13%) patients, as no MDM2 testing was performed on the corresponding pre-operative biopsies. CONCLUSIONS: When a retroperitoneal tumour is not clinically suspected, histological consideration of a liposarcoma diagnosis may be overlooked. Implementation of ancillary immunohistochemical and cytogenetic testing can ultimately lead to a definitive diagnosis in this potentially misleading anatomical location.

The diagnostic utility of Merkel cell polyoma virus immunohistochemistry in cytology specimens.

OBJECTIVE: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm that predominantly affects elderly and immunocompromised patients. Merkel cell polyoma virus (MCPyV) is clonally integrated into the majority of MCCs and has been linked to patient outcomes, playing a central role in the pathogenesis of the disease. We aimed to assess the utility of MCPyV immunohistochemistry (IHC) in the diagnosis of MCC in cytology cell block specimens and correlating with clinicopathologic features. METHODS: Fifty-three cytology samples of MCC with sufficient cell block material were stained for MCPyV by IHC and scored semi-quantitatively in extent and intensity. Morphologic mimics of MCC including small cell lung carcinoma (n = 10), non-Hodgkin lymphoma (n = 10), basaloid squamous cell carcinoma (n = 6) and other neuroendocrine carcinomas (n = 8) were stained in parallel. Positive staining was defined as >1% of the tumour cells showing at least moderate staining intensity. RESULTS: The cytologic features of MCC were characterized by high nuclear-cytoplasmic ratios, hyperchromatic nuclei with 'salt and pepper' chromatin, and nuclear moulding. MCPyV was detected in 24 of 53 cases (45%). Staining was strong and diffuse in roughly half of the positive samples. Of the morphologic mimics, one follicular lymphoma showed strong and diffuse staining. In contrast to prior studies, we saw no association between MCPyV status and patient outcomes. CONCLUSION: Merkel cell polyoma virus IHC is highly specific (97%) for the diagnosis of MCC in our cohort, and can serve as a useful diagnostic tool for distinguishing MCC for morphologic mimics.

FOXL2: a gene central to ovarian function.

The FOXL2 (forkhead box L2) gene is located on chromosome 3 and encodes for forkhead box (FOX) family of transcription factors which play a critical role in various biological processes. Germline FOXL2 mutations have been identified in blepharophimosis/ptosis/epicanthus inversus syndrome. The somatic missense mutation in FOXL2 (FOXL2 C134W) is now known to be the defining molecular feature of adult-type granulosa cell tumour of the ovary, present in over 90% of cases of this tumour type. Immunohistochemistry for FOXL2 is used as a marker of sex cord-stromal differentiation. However, expression is not restricted to lesions harbouring FOXL2 mutations, and it is positive in a variety of sex cord-stromal proliferations other than adult-type granulosa cell tumour.

An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.

High-fat diet promotes prostate cancer growth through histamine signaling.

Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth.

High-grade Transformation in Adult Granulosa Cell Tumor: Potential Diagnostic Challenges and the Utility of Molecular Testing.

Adult granulosa cell tumor (AGCT) is the most common sex cord-stromal tumor, accounting for about 1% of all ovarian tumors. It has a propensity for recurrences, especially late in the disease course. High-grade or sarcomatoid transformation has been rarely described in AGCT. We present a case of a 65 year old woman who presented with hemodynamic shock and bowel obstruction from a large pelvic mass. Histologic examination revealed predominantly high-grade epithelioid and spindled cells with high mitotic activity and necrosis. A minor component suggestive of AGCT was also identified. Molecular analysis confirmed the diagnosis of AGCT by revealing FOXL2 C134W mutations. Additionally, TP53 mutations were also detected which may contribute to the high-grade transformation. Our case is unique because the high-grade sarcomatous component constituted most of the tumor and the areas of "typical" AGCT were minor. Also, the clinical and operative findings did not suggest a specific site of origin leading to a broad differential diagnosis. High-grade transformation in AGCT is a rarely described phenomenon. The awareness of this presentation is helpful in reaching the correct diagnosis. Molecular analysis may be an extremely helpful adjunct in challenging cases.

Pathologic examination of placenta: a study on 500 live births to assess conformity to College of American Pathologists (CAP) guidelines and clinicopathologic correlation.

PURPOSE: Pathological examination of placenta is vital to understand the pathophysiology of adverse perinatal outcomes, prevention of recurring conditions in subsequent pregnancies and medico-legal risk assessment. The College of American Pathologists (CAP) has published a set of guidelines to help guide the submission of placentas to pathology. However, awareness and conformity to these guidelines are not well established and vary from one institution to the other. We aimed to examine the appropriateness of placental pathologic examination at our institution and their conformity to guidelines in this audit type study to help improve our practices. MATERIALS AND METHODS: Detailed retrospective review of obstetrical records was performed including history and delivery reports for a total of 500 consecutive live births noting whether the placenta was sent for pathologic evaluation according to CAP guidelines. Sensitivity and specificity of placental examination were calculated based on the 2 × 2 contingency table. RESULTS: The sensitivity and specificity of pathologic examination of placenta in conformity to CAP guidelines were 63.4% and 91.6%, respectively. The most common indications for submission were maternal followed by fetal and placental indications. Concordant clinico-pathologic correlation was found in 87/135 placentas submitted. CONCLUSIONS: Placenta has long been ignored with limited understanding of the value of its examination. More awareness of CAP guidelines is needed to appropriately submit placentas for pathologic examination. Each institution needs to develop their own set of guidelines taking guidance from CAP guidelines and tailored to its population. Meaningful communication between obstetricians, neonatologists, and pathologists is key to improving the utility of pathologic examination of placenta and the application of results for better patient care.

Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: Another Provisional Entity Emerging From the Papillary Renal Cell Carcinoma Pandora's Box.

Papillary renal cell carcinoma (especially type 2) is a Pandora's box with many newly described renal cell carcinomas emerging from it as a result of enhanced molecular techniques. Biphasic hyalinizing psammomatous renal cell carcinoma (BHPRCC) is the latest addition, which was first described a few months ago. Here, we report a case of BHPRCC to supplement the very limited literature available about this entity, and to highlight the characteristic morphology as well as the recurring molecular alterations in the neurofibromatosis 2 gene.

Pitfalls in Morphologic Diagnosis of Pathogens: Lessons Learned From the Pseudo-Cystoisospora Epidemic.

Multiple groups have recently reported involvement of the gallbladder mucosa of immunocompetent patients by cystoisospora organisms. However, this has recently been disproved with the support of molecular and ultrastructural studies. Here we present a summary of these events, recounting how this pseudo-Cystoisospora epidemic began and ended. This review also highlights the important role played by ancillary techniques in supplementing the morphologic diagnosis of pathogens.

Ultrastructural Characteristics of Gallbladder Epithelial Inclusions Mimicking Cystoisospora.

OBJECTIVES: There is recently reported increased prevalence of Isospora organisms in cholecystectomy specimens from immunocompetent patients, especially in acalculous cholecystectomies. We performed an ultrastructural and molecular evaluation of these specimens. METHODS: From 28 gallbladders with intraepithelial inclusions, two specimens with diffuse involvement of the gallbladder epithelium were analyzed by electron microscopy. Polymerase chain reaction was performed on five samples for the ITS2 region of C belli and eukaryotic 18S region. The 18S products were sequenced by next-generation sequencing. RESULTS: Electron microscopic analysis showed cytoplasmic condensations leading to vacuole formation. In contrast with true C belli, there were no identifiable organelles or organization. None of these cases showed amplified products other than human on molecular analysis. CONCLUSIONS: Electron microscopic analysis demonstrates that the inclusions are condensed cytoplasmic material and not true organisms.

Post-radiation Mullerian adenosarcoma with sarcomatous overgrowth: rare presentation of an uncommon malignancy.

Mullerian adenosarcoma is an uncommon biphasic malignant uterine tumor. It is composed of benign epithelial and malignant stromal elements. We present a case of a 45-year-old woman who presented with post-menopausal bleeding for three months. She had a significant past medical history of pelvic irradiation for squamous carcinoma of cervix 20 years ago. Pathology revealed adenosarcoma with sarcomatous overgrowth. The patient had a recurrence of pure sarcoma three months later and unfortunately succumbed to her disease. The role of radiation in the pathogenesis of adenosarcoma has been uncommonly described compared to its well established role in the development of carcinosarcoma. Our case fulfils the criteria for a radiation induced sarcoma. We review the salient clinical and pathological features of this uncommon lesion highlighting the importance of sarcomatous overgrowth in these lesions and the possible role of radiation in the development of these tumors.

Prognostic significance of venous invasion in node-negative head and neck squamous cell carcinoma.

BACKGROUND: Venous invasion (VI) is not frequently evaluated on routine histologic examination of head and neck squamous cell carcinoma (HNSCC), and the prognostic significance is largely unknown. Studies have shown that extramural venous invasion is an adverse prognostic factor in colorectal carcinoma. To our knowledge, this is the first study evaluating the prognostic significance of venous invasion in node-negative (without clinical or pathologic evidence of lymph node involvement) HNSCC, utilizing the elastic stain. METHODS: A total of 105 consecutive lymph node-negative (N0) HNSCC were evaluated for the presence of venous channel invasion by tumor utilizing the elastin stain. Clinical, demographic, and follow-up data were recorded. RESULTS: Of 37 patients with venous invasion, 19% had loco-regional recurrence, as opposed to 12% of those without. Univariate analysis revealed statistically significant decreased recurrence-free survival in the presence of venous invasion (log-rank [Mantel-Cox] test P-value .025). CONCLUSION: Identification of VI is greatly aided by elastic stain. In patients with node-negative HNSCC, presence of VI resulted in decreased recurrence-free survival on univariate analysis. The impact of VI as a prognostic marker should be further evaluated.

Prevalence of epithelial abnormalities and high-risk human papilloma virus in cervicovaginal Pap smears of population subgroups as a guide toward evidence-based best practice.

BACKGROUND: The 2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines provide information for managing abnormal cervical cancer screening tests and cancer precursors. According to these guidelines for Pap smear diagnosis of Atypical squamous cells of undetermined significance, reflex high risk (HR) human papilloma virus (HPV) genotyping is required among women 21 years of age or older. Whereas, in women of 30 to 65 years of age, HR-HPV can be ordered by the clinicians as part of co-testing with any diagnosis and every 5 years with a negative Cervico-Vaginal Pap test (CVPT). METHODS: A retrospective review of the CoPath database of the Pathology Department at the University of Florida, College of Medicine Jacksonville, FL, was performed to identify North Florida (NF) women who underwent CVPT and HR-HPV testing between 2006 and 2014. The women were stratified by race and age, respectively. RESULTS: The study included 19,933 CVPTs. Significant differences in the outcomes' distributions were found among age and race groups, respectively. Highest prevalence of HPV positivity was found in African American women, and in 14- to 20-year-old women, respectively. Twenty- to 30-year-old women had the highest percentage (59%) of epithelial abnormality. The most common HR-HPV genotypic distribution was other HR-HPV. CONCLUSIONS: This study underscores the importance of using both HR-HPV and CVPT for screening for cervical cancer, and confirms the need for special focus on managing high-risk populations subgroups, such as African American women, and women of ages 14 to 20 years especially in high-risk populations.

Lymphoma in autopsy cases.

Lymphoproliferative disorders cause significant morbidity and mortality, either related to the disease itself or therapy complications. Some cases of lymphoma may have vague clinical presentation, especially in the absence of lymphadenopathy, and a clinical work up may not be conclusive. Our study focuses on autopsy cases of lymphoma patients, emphasizing clinically unsuspected cases. Autopsy records from the last 20 years at our institution were searched, and the clinical parameters were recorded. Fifteen cases of lymphoma were identified, and 5 cases were diagnosed at the time of autopsy. Most B-cell lymphoma cases were mainly nodal disease, while T-cell lymphoma cases had widespread extra-nodal disease. Most deaths in B-cell lymphoma are due to infection/therapy induced immunosuppression, whereas T-cell lymphoma deaths are due to organ infiltration by lymphoma. Postmortem examination may reveal clinically unsuspected lymphoma, especially in rapidly deteriorating patients with vague presentation such as skin rash, bowel obstruction/bleeding or pacemaker malfunction.

Branched chain in situ hybridization for albumin as a marker of hepatocellular differentiation: evaluation of manual and automated in situ hybridization platforms.

Albumin, widely recognized as a highly sensitive and specific marker of hepatocellular carcinoma (HCC), is currently unavailable in the diagnostic laboratory because of the lack of a robust platform. In a prior study we detected albumin mRNA in the majority of intrahepatic cholangiocarcinomas using a novel branched chain RNA in situ hybridization (ISH) platform. We now explore the utility of albumin ISH as a marker of hepatocellular differentiation in HCCs, and compare its sensitivity with Hep Par 1 and Arginase-1. We evaluated 93 HCCs and its mimics including neuroendocrine tumors of the gastrointestinal tract (n=31), neuroendocrine tumors of the pancreas (n=163), melanoma (n=15), and gallbladder carcinoma (n=34). We performed ISH for albumin and immunohistochemistry for Hep Par 1 and Arginase-1. Five previously uncharacterized hepatic neoplasms from our files were also evaluated. Immunohistochemistry for Arginase-1 was performed on 59 intrahepatic cholangiocarcinomas. In addition, 43 HCCs evaluated on the manual platform were also examined on the automated instrument. Fifty-five percent of HCCs were moderately differentiated and 39% poorly differentiated. The sensitivity of ISH for albumin was 99%, with 92 of 93 HCCs staining positive for albumin. In contrast to ISH, the sensitivity of immunohistochemistry for Hep Par 1 and Arginase-1 was 84% and 83%, respectively. The sensitivity of albumin for poorly differentiated HCCs was 99%, whereas that for Arginase-1 and Hep Par 1 was 71% and 64%, respectively. Ninety-seven percent of the HCCs showed albumin positivity in >50% of tumor cells using the ISH platform, as compared with 76% and 70% for Hep Par 1 and Arginase-1 immunohistochemistry, respectively. Three of the 5 previously uncharacterized neoplasms were positive for albumin ISH. Automated albumin ISH platform performed equivalently to the manual format, with albumin reactivity in >50% of tumor cells in all 43 cases that were tested on both platforms. All non-HCCs were negative for albumin. All 59 intrahepatic cholangiocarcinomas were negative for Arginase-1. In conclusion, branched chain ISH performed on manual and automated mode is a robust assay for detecting albumin with sensitivity for poorly differentiated HCCs superior to Arginase-1 and Hep Par 1. When interpreted in conjunction with Arginase-1, albumin ISH offers a high level of sensitivity and specificity.

Schwannoma of the scrotum: case report and review of the literature.

Schwannomas are benign nerve sheath tumors composed of Schwann cells, which normally produce the insulating myelin sheath covering the peripheral nerves. Common locations include the head, neck, mediastinum, and retroperitoneum. These tumors are usually asymptomatic until they become large and compress the surrounding tissues. Most schwannomas occur during the third and fourth decades of life, with an equal gender distribution. We present the case of a schwannoma that originated in the scrotum.

The role of intraoperative cytology in the diagnostic evaluation of ovarian neoplasms.

OBJECTIVE: To determine the role of intraoperative cytology (IOC) in the diagnostic evaluation of ovarian neoplasms. METHODS: The present study was conducted in the Department of Pathology, Jawaharlal Nehru Medical College, AMU, Aligarh, India, over a time span of 18 months. Depending on the consistency of the lesion, touch, scrape or crush techniques were used to prepare cytological smears. Smears were fixed in 95% ethyl alcohol and then stained with hematoxylin and eosin or Papanicolaou stains. Cytological results were compared with the histological diagnosis taking the latter as the gold standard. RESULTS: Of 50 lesions studied by IOC, 25 lesions were labeled as benign, 24 lesions as malignant and 1 lesion was inconclusive. Final histological diagnoses labeled 25 lesions as benign and 25 lesions as malignant. Comparing the diagnosis of cytology smears with histology sections, 47 of 50 cases were concordant. Sensitivity, specificity and diagnostic accuracy were 95.8, 96.0 and 95.8%, respectively. CONCLUSIONS: IOC is a good complement to histopathology in the study of ovarian neoplasms, particularly in developing countries like ours, where the facility of frozen sections is often not available, since a rapid preliminary diagnosis may help in surgical management planning.

The role of sediment cytology in ovarian neoplasm.

OBJECTIVE: It was our aim to study the role of sediment cytology in a diagnostic evaluation of ovarian neoplasm. METHODS: The present study was conducted in the Department of Pathology, Jawaharlal Nehru Medical College, AMU, Aligarh, India, over a span of 22 months. Cytological smears were prepared by centrifuging the sediment of fluid from the bottom of a container in which surgical specimens were received. Smears were fixed in 95% ethyl alcohol and then stained using hematoxylin-eosin and Papanicolaou stains. The cytological results were compared with histological diagnosis, taking the latter as gold standard. RESULTS: Out of 54 lesions studied by sediment cytology, 22 lesions were labeled as benign, 26 lesions as malignant and 6 lesions were inconclusive. Final histological diagnoses labeled 24 lesions as benign and 30 lesions as malignant. Comparing the diagnosis of the cytology smear with the histological section, 44 out of 54 cases were concordant. A sensitivity, specificity and diagnostic accuracy of 90.3, 92.3 and 90.3% was achieved, respectively. CONCLUSION: Biopsy sediment cytology is a good complementary method to histopathology in the study of ovarian biopsy material. In developing countries like ours, where the facility of frozen section is not available at many centers, this simple and cheap technique can be of much help in rapid diagnosis.