Androgen Receptor Immunohistochemical Expression in Undifferentiated/Dedifferentiated Endometrial Carcinoma.

Uterine undifferentiated (UC)/dedifferentiated (DEAC) carcinomas are rare malignant neoplasms. They tend to pursue an aggressive clinical course with an advanced stage at presentation. It has been found that androgen receptor (AR) might play a role as a prognostic and therapeutic marker in endometrial carcinoma. However, its expression in UC/DEAC has not been investigated. Herein, the aim of this study was to evaluate the expression of AR along with estrogen receptor (ER), progestin receptor (PR), and HER2 in UC/DEAC and also in other subtypes of high-grade endometrial carcinomas. Review of our pathology database over the period of 2011 to 2019 identified 16 UC/DEAC cases (N=16). We also randomly selected other high-grade endometrial carcinomas including FIGO 3 endometrioid carcinoma (N=9), serous carcinoma (N=8), clear cell carcinoma (N=12) and carcinosarcoma (N=10) for comparison. Immunohistochemical stains for AR, ER, PR, and HER2 were performed on all 55 cases. The protein expression was evaluated both quantitatively and qualitatively. In DEAC cases both the undifferentiated component and the well-differentiated component were recorded separately. Overall, variable degrees of AR reactivity (by Allred scoring method) was present in 63% of UC/DEACs(10/16), 67% of FIGO 3 endometrioid carcinomas (6/9), 88% of serous carcinomas (7/8), 80% of carcinosarcomas (8/10), and 9% of clear cell carcinoma (1/12). AR expression was most often seen with PR (70%) or ER (60%) staining in UC/DEACs. Thirteen cases of UC/DEACs were positive for at least 1 hormone receptor. HER2 was negative in all UC/DEACs. Almost all other high-grade carcinoma cases were negative for HER2 except 20% of carcinosarcoma (2/10) and 13% of serous carcinoma (1/8) which showed 3+ HER2. Loss of AR appears to be associated with worse clinicopathologic parameters in UC/DEAC. AR is highly expressed in UC/DEAC, and in the majority of FIGO 3 endometrioid carcinomas, serous carcinomas, and carcinosarcoma. These findings suggest a potential role for androgen inhibitors in the management of patients with these tumors.

Human Papillomavirus (HPV) Detection by Chromogenic In Situ Hybridization (CISH) and p16 Immunohistochemistry (IHC) in Breast Intraductal Papilloma and Breast Carcinoma.

PURPOSE: This study explored human papillomavirus (HPV) amplification in breast benign and malignant lesions by chromogenic in situ hybridization (CISH) and the concordance of p16 expression by immunohistochemistry. PATIENTS AND METHODS: The presence of HPV6/11 and HPV16/18 in 33 cases of intraductal papilloma, 34 cases of ductal carcinoma in situ (DCIS), and 56 cases of invasive breast carcinoma (IBC) was evaluated using matched-background breast parenchyma and breast reduction as control groups. Association with clinicopathologic factors including prognosis was assessed. RESULTS: HPV 6/11 was observed in 0 cases (0%) of breast reduction, one case (3%) of intraductal papilloma, 11 cases (32.4%) of DCIS, and eight cases (14.3%) of IBC. HPV 16/18 was detected in three cases of (9.1%) breast reduction, six cases (18.8%) of intraductal papillomas, 14 cases (41.2%) of DCIS, and 25 cases (44.6%) of IBC. There was no difference in the HPV status between intraductal papilloma and breast reduction. HPV amplification in intraductal papilloma did not associate with developing atypia or carcinoma after long-term follow-up. However, HPV 6/11 and HPV 16/18 amplification was significantly higher in both DCIS and IBC when compared with breast reduction (P < .05). Compared with background breast parenchyma, HPV 16/18 amplification was significantly higher in both DCIS and IBC (P = .003 and P = .013, respectively). No correlation between p16 immunohistochemical staining and either of the HPV CISH testing was found (P > .05). CONCLUSION: HPV infection was detected in both breast lesions and background parenchyma. HPV infection may play a role in the pathogenesis of breast cancer but is not associated with intraductal papilloma. Immunohistochemical stain for p16 is not a good surrogate marker for HPV infection in breast lesions.

GATA binding protein 3 (GATA3) as a marker for metaplastic spindle cell carcinoma of the breast.

Spindle cell lesions of the breast comprise a diverse set of tumors; harboring significant histological and immunohistochemical (IHC) overlap. Accurate diagnosis and classification of spindle cell lesions in the breast remains challenging, especially in core biopsies. In the current study, we evaluated a spectrum of spindle cell lesion of the breast with a panel of IHC antibodies in an effort to differentiate metaplastic spindle cell carcinoma from its benign and malignant mimickers. Our study included 92 patients who underwent breast core biopsies or breast resections at Northwell Health who were diagnosed with benign and malignant tumor/tumor-like spindle cell lesions. Tumors subtypes in this the study included: angiosarcoma, nodular fasciitis, fibromatosis, myofibroblastoma, phyllodes tumors (benign, borderline and malignant), primary sarcomas and metaplastic spindle cell carcinoma. Our biomarker panel included high molecular weight keratin (HMWK), CAM5.2, AE1/AE3, p63, CD34 and GATA3. GATA3 expression was significantly higher in metaplastic carcinomas (88.9 % vs 4.1 %, p < 0.001), when compared to other spindle cell lesions. The sensitivity and specificity for detecting metaplastic carcinomas reached 84.2 % and 97.3 %, respectively. Regarding cytokeratin panels, none of the three individual markers were as sensitive or specific for metaplastic breast carcinoma. GATA3 is the most specific and sensitive marker forfor the identification of metaplastic spindle cell carcinoma of the breast.

MaTAR25 lncRNA regulates the Tensin1 gene to impact breast cancer progression.

Misregulation of long non-coding RNA (lncRNA) genes has been linked to a wide variety of cancer types. Here we report on Mammary Tumor Associated RNA 25 (MaTAR25), a nuclear enriched and chromatin associated lncRNA that plays a role in mammary tumor cell proliferation, migration, and invasion, both in vitro and in vivo. MaTAR25 functions by interacting with purine rich element binding protein B (PURB), and associating with a major downstream target gene Tensin1 (Tns1) to regulate its expression in trans. The Tns1 protein product is a critical component of focal adhesions linking signaling between the extracellular matrix and the actin cytoskeleton. Knockout of MaTAR25 results in down-regulation of Tns1 leading to a reorganization of the actin cytoskeleton, and a reduction of focal adhesions and microvilli. We identify LINC01271 as the human ortholog of MaTAR25, and importantly, increased expression of LINC01271 is associated with poor patient prognosis and metastasis. Our findings demonstrate that LINC01271 represents a potential therapeutic target to alter breast cancer progression.

COVID-19 in recent heart transplant recipients: Clinicopathologic features and early outcomes.

BACKGROUND: The impact of COVID-19 on heart transplant (HTx) recipients remains unclear, particularly in the early post-transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID-19 (three within 2 months post-transplant) from our institution at the epicenter of the pandemic. RESULTS: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID-19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C-reactive protein, procalcitonin, and ferritin. All had bilateral ground-glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID-19 appears to negatively impact outcomes early after heart transplantation.

Correction: Identification of grade and origin specific cell populations in serous epithelial ovarian cancer by single cell RNA-seq.

[This corrects the article DOI: 10.1371/journal.pone.0206785.].

Identification of grade and origin specific cell populations in serous epithelial ovarian cancer by single cell RNA-seq.

Here we investigated different cell populations within ovarian cancer using single-cell RNA seq: fourteen samples from nine patients with differing grades (high grade, low grade and benign) as well as different origin sites (primary and metastatic tumor site, ovarian in origin and fallopian in origin). We were able to identify sixteen distinct cell populations with specific cells correlated to high grade tumors, low grade tumors, benign and one population unique to a patient with a breast cancer relapse. Furthermore the proportion of these populations changes from primary to metastatic in a shift from mainly epithelial cells to leukocytes with few cancer epithelial cells in the metastases. Differential gene expression shows myeloid lineage cells are the primary cell group expressing soluble factors in primary samples while fibroblasts do so in metastatic samples. The leukocytes that were captured did not seem to be suppressed through known pro-tumor cytokines from any of the cell populations. Single cell RNA-seq is necessary to de-tangle cellular heterogeneity for better understanding of ovarian cancer progression.

Mucinous Cystadenocarcinoma of the Breast: Report of 2 Cases Including One With Long-Term Local Recurrence.

Primary mucinous cystadenocarcinoma (MCA) of breast is an exceedingly rare tumor with histologic resemblance to MCA arising in ovary, pancreas, and gastrointestinal tract. In this article, we present 2 additional cases of MCA of breast, one highlighting the diagnostic challenges of a rare entity that may potentially lead to unnecessary chemotherapy and the second case presenting with recurrence after 8 years of primary surgical excision defying the indolent behavior reported in the literature. To our knowledge, this is the first reported instance of such behavior.

Routine Pathologic Evaluation of Plastic Surgery Specimens: Are We Wasting Time and Money?

BACKGROUND: Recent health care changes have encouraged efforts to decrease costs. In plastic surgery, an area of potential cost savings includes appropriate use of pathologic examination. Specimens are frequently sent because of hospital policy, insurance request, or habit, even when clinically unnecessary. This is an area where evidence-based guidelines are lacking and significant cost-savings can be achieved. METHODS: All specimen submitted for pathologic examination at two hospitals between January and December of 2015 were queried for tissue expanders, breast implants, fat, skin, abdominal pannus, implant capsule, hardware, rib, bone, cartilage, scar, and keloid. Specimens not related to plastic surgery procedures were excluded. Pathologic diagnosis and cost data were obtained. RESULTS: A total of 759 specimens were identified. Of these, 161 were sent with a specific request for gross examination only. There were no clinically significant findings in any of the specimens. There was one incidental finding of a seborrheic keratosis on breast skin. The total amount billed in 2015 was $430,095. CONCLUSIONS: The infrequency of clinically significant pathologic examination results does not support routine pathologic examination of all plastic surgery specimens. Instead, the authors justify select submission only when there is clinical suspicion or medical history that warrants evaluation. By eliminating unnecessary histologic or macroscopic examination, significant cost savings may be achieved.

Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer.

MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival.

Aberrant Expression of Napsin A in Breast Carcinoma With Apocrine Features.

An incidental finding of napsin A-positive breast carcinoma with apocrine features during workup for metastatic cancer in an axillary lymph node led to our investigation of the incidence of napsin A expression in breast carcinomas, focusing on those with apocrine features. We included 97 cases of breast carcinomas and performed immunohistochemistry with napsin A, GATA-3, thyroid transcription factor-1, and GCDFP-15. There was a statistically significant difference between apocrine and nonapocrine cases with respect to polyclonal napsin A H-scores (P < .00152), monoclonal napsin A H-scores (P < .00631), GATA-3 H-scores (P < .00029), and GCDFP-15 H-scores (P < .00251). Of the 49 cases of apocrine carcinoma, monoclonal napsin A antibody was positive in 66.7% of cases, including in 7 (14.6%) that showed 3+ staining. The majority of nonapocrine cases were negative (62.5%) or weakly (1+) positive (29.2%), with none exhibiting 3+ strength. It is important for pathologists to be aware that breast carcinomas with apocrine features can express napsin A.

Young investigator challenge: Cadherin-17 and SATB2 in cytology specimens: Do these new immunostains help in differentiating metastatic colorectal adenocarcinoma from adenocarcinomas of other origins?

BACKGROUND: Cadherin-17 (intestinal peptide-associated transporter) and SATB2 (SATB homeobox 2) immunoexpression has recently been described in surgical pathology to have value in establishing the colorectal origin of metastatic adenocarcinoma. However, to the authors' knowledge, the role of these markers in metastatic colorectal adenocarcinoma (MCA) in cytology has not been addressed to date. In the current study, the authors evaluated the contribution of cadherin-17 and SATB2 to the diagnosis of MCA in cytology specimens and compared these two novel markers with the standard gastrointestinal immunohistochemistry panel in an attempt to identify the optimal panel. METHODS: A total of 43 MCA cytology cases and 68 metastatic noncolorectal adenocarcinoma (non-MCA) cytology controls were stained for SATB2; cadherin-17; and the standard panel of cytokeratin (CK) 7, CK20, and Caudal-Type Homeobox Transcription Factor 2 (CDX2). Staining intensity and percentage of positive cells were recorded. Sensitivity and specificity values for immunostains individually and in combination were computed and compared. RESULTS: Despite specificities of 83.8% and 91.2%, respectively, for cadherin-17 and SATB2, when critically examining the new immunostains together with the standard panel, there was no significant difference noted with regard to prediction of MCA (vs non-MCA) compared with the standard panel alone (P < .6). CONCLUSIONS: The results of the current study reinforce that the standard gastrointestinal immunohistochemistry panel remains the gold standard for distinguishing MCA from non-MCA in cytology.

Utility of telepathology as a consultation tool between an off-site surgical pathology suite and affiliated hospitals in the frozen section diagnosis of lung neoplasms.

BACKGROUND: Increasingly, as in our institution, operating rooms are located in hospitals and the pathology suite is located at a distant location because of off-site consolidation of pathology services. Telepathology is a technology which bridges the gap between pathologists and offers a means to obtain a consultation remotely. We aimed to evaluate the utility of telepathology as a means to assist the pathologist at the time of intraoperative consultation of lung nodules when a subspecialty pathologist is not available to directly review the slide. METHODS: Cases of lung nodules suspicious for a neoplasm were included. Frozen sections were prepared in the usual manner. The pathologists on the intraoperative consultation service at two of our system hospitals notified the thoracic pathologist of each case after rendering a preliminary diagnosis. The consultation was performed utilizing a Nikon™ Digital Sight camera and web-based Remote Medical Technologies™ software with live video streaming directed by the host pathologist. The thoracic pathologist rendered a diagnosis without knowledge of the preliminary interpretation then discussed the interpretation with the frozen section pathologist. The interpretations were compared with the final diagnosis rendered after sign-out. RESULTS: One hundred and three consecutive cases were included. The frozen section pathologist and a thoracic pathologist had concordant diagnoses in 93 cases (90.2%), discordant diagnoses in nine cases (8.7%), and one case in which both deferred. There was an agreement between the thoracic pathologist's diagnosis and the final diagnosis in 98% of total cases including 8/9 (88.9%) of the total discordant cases. In two cases, if the thoracic pathologist had not been consulted, the patient would have been undertreated. CONCLUSIONS: We have shown that telepathology is an excellent consultation tool in the frozen section diagnosis of lung nodules.

Periductal Stromal Sarcoma of the Breast With Liposarcomatous Differentiation: A Case Report With 10-Year Follow-up and Literature Review.

A biphasic tumor with features of benign ductal elements and a malignant stromal component that lacks the architecture of a phylloides tumor represents a diagnostic challenge. A 35-year-old woman presented with a painful mass located in the upper inner quadrant of the right breast. A biopsy revealed histologically that the tumor had a multinodular architecture with malignant spindle cells forming cuffs around multiple open benign ducts. No leaf-like architecture was present. In addition, liposarcomatous differentiation was seen in focal areas. Immunohistochemical staining showed positive for CD34, vimentin and CDK4, and negative for ER, PR, Her2/neu, CD10, CD117, p63, bcl-2, cytokeratin, and MDM2. A diagnosis of periductal stromal sarcoma with liposarcomatous differentiation was established. Following excision with mastectomy and adjuvant chemotherapy, the patient was disease-free for 10 years. To our knowledge, this is the first case report of periductal stromal sarcoma showing liposarcomatous differentiation.

Retrospective blinded review of interpretational diagnostic discrepancies in surgical pathology: 18 years of experience at a tertiary care facility.

We evaluated our quality assurance (QA) methods and QA consensus conference model for assessing the rate of interpretational diagnostic errors and trend of errors. Using monthly QA reports from review of frozen section- permanent section correlation and amended reports, all cases with interpretational diagnostic errors were identified. Retrospective blinded review of study cases were independently performed by all staff pathologist and subsequently discussed in QA conference sessions. 277 (.07%) interpretational errors were identified from 1993-2010. Errors with patient consequences comprised 15% of all errors, 4% of which were major errors. More than half (57%) of the errors were identified on review of frozen section- permanent section correlation and accounted for 64 % of all errors with patient consequence and 45% of major errors. Comparison of errors between two equally divided time periods (1993-2001 and 2002-2010) showed significant error reduction (p< 0.05). 64% of all errors, 61% of errors with patient consequence and 73% of major errors were a consequence of incorrect interpretation of the biologic behavior of the neoplasm. To conclude, we propose this quality assurance model as an effective tool for assessing interpretational errors, particularly those with significant patient consequences, enhancing participation of pathologists and reducing errors.

Localized crystal-storing histiocytosis presenting as a breast nodule: an unusual presentation of a rare entity.

Crystal-storing histiocytosis (CSH) is a rare disorder associated with crystalline immunoglobulin deposition in the cytoplasm of histiocytes and is usually associated with lymphoproliferative or plasma cell disorders (LP-PCD) that express monoclonal immunoglobulin. Localized CSH without underlying LP-PCD are extremely rare. We report a case of localized CSH in breast which was an unexpected difficult diagnosis. The awareness of this entity is of importance to delineate it morphologically from other common differential diagnosis and enable appropriate management. To date, this is the first case of localized CSH reported in breast in a patient with no known history of LP-PCD.

Ossifying fibromyxoid tumor of the breast mimicking fibroadenoma: a case report and differential diagnoses.

An 80-year-old woman presented with a palpable mass in the right breast. Mammographic findings were consistent with calcified fibroadenoma. An ultrasound was performed that showed a solid nodule with peripheral calcification. A core biopsy was obtained that revealed a spindle cell proliferation with a shell of mature bone. The histologic features, in combination with immunohistochemical studies, were those of an ossifying fibromyxoid tumor. Complete excision of the specimen further confirmed the diagnosis. To the best of our knowledge, this is the first reported case of ossifying fibromyxoid tumor occurring in the breast. We review the current literature on ossifying fibromyxoid tumor and discuss the differential diagnoses when confronted with bland spindle cells on a core biopsy of the breast.

Usefulness of GATA3 and p40 immunostains in the diagnosis of metastatic urothelial carcinoma in cytology specimens.

BACKGROUND: GATA3 (GATA-binding protein 3) expression in urothelial carcinoma (UC) and mammary carcinomas has been recently reported. However, to the authors' knowledge, studies examining GATA3 staining of metastatic UC (MUC) in cytology specimens are lacking. Delta Np63 (p40) has been shown to be expressed highly selectively in squamous cell carcinomas (SCCs) but the literature concerning the expression of p40 in UC is limited and controversial. In the current study, the authors evaluated the usefulness of GATA3 and p40 in the diagnosis of MUC in cytology specimens. METHODS: Thirty-two MUC cytology cases and 44 controls (22 UC cases and 22 SCC cases) were stained for GATA3, p40, and p63 and nuclear staining intensity and the percentage of positive cells were recorded and compared. RESULTS: MUC cytology cases stained positive for GATA3, p40, and p63 in 78.13%, 80.65%, and 61.29% of cases, respectively, with moderate/strong staining intensity. MUC cases had a significantly higher percentage of GATA3 positivity compared with SCC controls (P<.001), but GATA3 positivity was not found to be significantly different from UC controls (90.91%) (P = .28). For p40 positivity, there was no significant difference observed between MUC cases, UC controls (95.45%), and SCC controls (90.91%) (P=.29). p63 positivity was found to be significantly lower in MUC cases compared with UC controls (95.45%) and SCC controls (95.45%) (P<.01). CONCLUSIONS: The results of the current study demonstrate that GATA3 is useful in confirming the diagnosis of MUC in cytology specimens and in distinguishing between MUC and SCC. p40 is a valuable adjunct to GATA3 in the diagnosis of MUC in cytology specimens, especially when SCC is not part of the clinical differential diagnosis.

Role of PAX-8, CD5, and CD117 in distinguishing thymic carcinoma from poorly differentiated lung carcinoma.

AIM: To determine if PAX-8, CD5, and CD117 can differentiate thymic carcinoma from poorly differentiated lung carcinoma. DESIGN: Archived cases of thymic (n=13) and poorly differentiated lung (n=15) carcinoma were analyzed for intensity and proportion of expression of PAX-8, CD117, and CD5. RESULTS: PAX-8 was positive in 69.2% of thymic and 5.8% of lung carcinomas. CD117 was positive in 84% of thymic and 26.6% of lung carcinomas. A total of 53% of thymic and none of the lung carcinomas were positive for CD5. Forty-six percent, 53%, and 69% of thymic carcinomas were dual positive for combinations of CD5/PAX-8, CD117/CD5, and CD117/PAX-8, respectively. None of the lung carcinomas were dual positive. Positivity for any 2 of the 3 markers was seen in 84% of thymic and none of the lung carcinomas. Triple positivity was seen in 53% of thymic carcinomas. CONCLUSION: Adding PAX-8 to CD117 and CD5 increases the diagnostic yield for thymic carcinoma.

Classic lobular neoplasia on core biopsy: a clinical and radio-pathologic correlation study with follow-up excision biopsy.

There are no consensus guidelines for the management of lobular neoplasia diagnosed on core biopsy as the highest risk factor for cancer. This study aimed to assess the risk of upgrade (invasive carcinoma or ductal carcinoma in situ) at the site of the lobular neoplasia and any clinical, radiological or pathologic factors associated with the upgrade. We reviewed all cases with a diagnosis of lobular neoplasia on core biopsy from June 2006 to June 2011. Any cases with radio-pathologic discordance, coexistent lesion that required excision (atypical ductal hyperplasia, flat epithelial atypia, duct papilloma or radial scar) or non-classic variant of lobular carcinoma in situ (pleomorphic, mixed ductal and lobular, lobular carcinoma in situ with necrosis) were excluded from the study. Core biopsy indications included calcification in 35 (40%), non-mass like enhancement in 19 (22%), mass lesion in 31 (36%) and mass as well as calcification in two cases (2%). Follow-up excisions were studied for the presence of upgrade. The study cohort included 87 cases and showed an upgrade of 3.4% (95% confidence interval: 1-10%). Three cases showed an upgrade (one ductal carcinoma in situ and two invasive cancers). All upgraded cases were breast imaging-reporting and data system score ≥4 and associated with atypical duct hyperplasia or in situ or invasive cancer in prior or concurrent biopsies in either breast. The number of cores and lobules involved, pagetoid duct involvement, presence of microcalcification in lobular neoplasia, needle gauge and number of cores obtained showed no correlation with the upgrade. Our results suggest that with radio-pathologic concordance and no prior biopsy proven risk for breast cancer, core biopsy finding of lobular neoplasia as the highest risk lesion can be appropriately and safely managed with clinical and radiologic follow-up as an alternative to surgical excision.