Publications by authors named "Michelle S Hirsch"

121 Publications

SSX C-Terminus is a Useful Diagnostic Biomarker for Spermatocytic Tumour.

Histopathology 2021 May 7. Epub 2021 May 7.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Aims: Spermatocytic tumour (ST) is a rare testicular germ cell neoplasm that can be challenging to diagnose and for which there are few confirmatory biomarkers. Like normal spermatogonia, STs are known to express SSX proteins. Recently, a novel SSX antibody directed against the C-terminus (SSX_CT) of SSX1, SSX2 and SSX4, has emerged as a reliable biomarker for these SSX proteins and synovial sarcoma. However, SSX_CT immunostaining has not been demonstrated in ST. This study assessed the diagnostic utility of SSX_CT immunohistochemistry in ST and other tumors in the differential diagnosis with ST.

Methods And Results: SSX_CT, OCT3/4 and C-KIT immunohistochemistry was performed on 15 STs, 38 seminomas, 13 embryonal carcinomas, 12 yolk sac tumours, 6 choriocarcinomas, 4 teratomas, 7 Sertoli cell tumors, and 6 lymphomas. Staining was scored as negative, rare, focal or diffuse. SSX_CT was positive in all (15/15) STs; diffusely in 14/15. SSX_CT was positive in 22/38 (58%) seminomas; however, only 2 cases showed diffuse expression. All other tumours were SSX_CT negative. OCT3/4 was negative in all STs, but positive in all seminomas and embryonal carcinomas. C-KIT was frequently positive in both ST (12/15; 80%) and seminoma (33/38; 87%). All other tumours were negative for OCT3/4 and C-KIT.

Conclusions: SSX_CT is a valuable and highly sensitive biomarker that supports the diagnosis of ST. Diffuse expression, observed in 93% of STs (compared to 6% of seminomas), is also highly specific for ST. Nevertheless, SSX_CT is best used in combination with OCT3/4 when ST is in the differential diagnosis.
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http://dx.doi.org/10.1111/his.14398DOI Listing
May 2021

Clinical characterization of radiation-associated muscle-invasive bladder cancer.

Urology 2021 Apr 12. Epub 2021 Apr 12.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.

Objective: To characterize the presentation, patterns of care, and outcomes of radiation-associated muscle-invasive bladder cancer (RA-MIBC) compared to primary (non-radiation associated) MIBC. RA-MIBC has been suggested to represent a more aggressive disease variant and be more difficult to treat compared to primary (non-radiation associated) MIBC.

Methods: We identified 60,090 patients diagnosed with MIBC between 1988-2015 using the Surveillance, Epidemiology, and End Results database and stratified patients based on whether radiation had been administered to a prior pelvic primary cancer. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC compared to primary MIBC.

Results: There were 1,093 patients with RA-MIBC and 58,997 patients with primary MIBC. RA-MIBCs were more likely to be T4 at diagnosis (21.0% vs 17.3%, p<0.001), and less likely to be node-positive (10.3% vs 17.1%, p<0.001). The rate of 5-year BCSM was significantly higher for patients with RA-MIBC vs. primary MIBC (56.1% vs 35.3%, AHR 1.24, p<0.001), even after stratification by other tumor, treatment and patient-specific factors.

Conclusions: RA-MIBCs tended to present with higher grade and T stage disease and were less likely to receive curative treatment. Even when accounting for stage, grade, and receipt of treatment, patients with RA-MIBC had worse survival compared to those with primary MIBC. These findings suggest that RA-MIBC present unique clinical challenges and may also represent a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand the biology of RA-MIBC and develop improved treatment approaches.
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http://dx.doi.org/10.1016/j.urology.2021.03.033DOI Listing
April 2021

Progressive immune dysfunction with advancing disease stage in renal cell carcinoma.

Cancer Cell 2021 May 11;39(5):632-648.e8. Epub 2021 Mar 11.

Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark; Center for Genomic Medicine, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark.

The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8 T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8 T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.
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http://dx.doi.org/10.1016/j.ccell.2021.02.013DOI Listing
May 2021

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Mar 4. Epub 2021 Mar 4.

Department of Pathology MD Anderson Cancer Center, Houston, TX, USA.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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http://dx.doi.org/10.1038/s41379-021-00779-wDOI Listing
March 2021

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Nat Commun 2021 02 5;12(1):808. Epub 2021 Feb 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
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http://dx.doi.org/10.1038/s41467-021-21068-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865061PMC
February 2021

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Feb 1. Epub 2021 Feb 1.

Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
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http://dx.doi.org/10.1038/s41379-021-00737-6DOI Listing
February 2021

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

J Clin Pathol 2021 May 29;74(5):291-299. Epub 2021 Jan 29.

Pathology, University Hospital Center of Martinique, Fort-de-France, Martinique.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.
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http://dx.doi.org/10.1136/jclinpath-2020-207372DOI Listing
May 2021

A Comparison of Genitourinary Pathology Society (GUPS) and International Society of Urological Pathology (ISUP) Prostate Cancer Grading Guidelines.

Am J Surg Pathol 2021 Jan 19. Epub 2021 Jan 19.

Departments of Pathology Oncology Urology, The Johns Hopkins Medical Institutions, Baltimore, MD Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1097/PAS.0000000000001664DOI Listing
January 2021

The Differential Diagnosis of Medullary-Based Renal Masses.

Arch Pathol Lab Med 2021 Jan 7. Epub 2021 Jan 7.

From the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

Context.—: Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between nonneoplastic structures. Although high-grade cortical tumors can rarely exhibit the same growth pattern, the infiltrative morphology should elicit a differential diagnosis to be considered in each case. However, these diagnoses can be challenging to distinguish, especially on small renal biopsy samples.

Objective.—: To provide an overview of the clinical, gross, and microscopic findings; genetic and molecular alterations; and immunohistochemical evaluation of medullary-based renal tumors and other tumor types with overlapping morphologies and growth patterns.

Data Sources.—: Literature review and personal observations were used to compile the information in this review.

Conclusions.—: Collecting duct carcinoma is a prototypical medullary-based tumor, and although diagnostic criteria exist, it remains a diagnosis of exclusion, especially with ancillary techniques aiding the recognition of established as well as more recently described neoplasms. Other medullary-based malignancies included in the differential diagnosis include renal medullary carcinoma/renal cell carcinoma unclassified with medullary phenotype, fumarate hydratase-deficient renal cell carcinoma, and upper tract urothelial carcinoma. Moreover, other rare entities should be excluded, including metastatic carcinoma, lymphoma, and melanoma. In addition to potential prognostic differences, accurate diagnoses can have important surgical and clinical management implications.
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http://dx.doi.org/10.5858/arpa.2020-0464-RADOI Listing
January 2021

Clinicopathological and molecular characteristics of prostate cancer diagnosed in young men aged up to 45 years.

Histopathology 2021 May 16;78(6):857-870. Epub 2021 Mar 16.

Department of Pathology, Genitourinary Pathology Division, Brigham and Women's Hospital, Boston, MA, USA.

Aims: To characterise and compare the poorly understood clinicopathological and molecular characteristics of prostatic adenocarcinoma (PCa) in very young patients.

Methods And Results: We compared the clinicopathological and molecular characteristics of PCa diagnosed in 90 patients aged ≤45 years with those of PCa diagnosed in 200 patients of typical screening age (i.e. 60-65 years). Patients diagnosed at a younger age had a higher frequency of a family history of PCa and lower prostate-specific antigen (PSA) levels than those diagnosed at regular screening age. There were no statistically significant differences in clinical stage or pathological characteristics of the core biopsy specimens between the groups. Young patients had a higher frequency of Grade Group 1 disease at radical prostatectomy. A subset of 13 aggressive PCa cases from young patients underwent successful DNA-based next-generation sequencing. In all, 46.2% (6/13) had TMPRSS2 rearrangements and 23.1% (3/13) had relevant pathogenic variants in DNA damage repair genes, including a mismatch repair-deficient case with biallelic inactivation of MLH1. No statistically significant differences were observed in PCa-specific recurrence/progression between the younger and older patients, including after adjustment for clinical stage, PSA level, and Grade Group.

Conclusions: In this study, the clinicopathological and molecular features of PCa diagnosed in young patients were comparable to those of PCa diagnosed in patients of screening age. Early-onset PCa cases were not enriched in any of the known molecular PCa subtypes in this small series.
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http://dx.doi.org/10.1111/his.14315DOI Listing
May 2021

An Unusual Cause of Secondary Amenorrhea in an Adolescent: Expanding the Differential.

J Endocr Soc 2020 Dec 27;4(12):bvaa159. Epub 2020 Oct 27.

Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.

Secondary amenorrhea is not uncommon in the adolescent female population. There are multiple etiologies to consider, and a comprehensive evaluation is often pursued. Sometimes, however, despite a thorough workup, the diagnosis remains unclear. Here, we report an unusual cause of secondary amenorrhea in a 15-year-old girl. Our patient presented with secondary amenorrhea after a 4-year history of regular menstrual cycles. Her evaluation was notable for very low FSH and low estradiol but normal LH; pregnancy, adrenal, thyroid, prolactin studies, and brain magnetic resonance imaging scan did not reveal a cause of her amenorrhea. Her transabdominal ultrasound showed an enlarged right ovary, initially suggestive of a hemorrhagic cyst. Inhibin A and B were measured because of the persistently low FSH; these were found to be very elevated, concerning for an inhibin-producing tumor. The patient had surgical removal of her right ovary; pathology revealed a juvenile granulosa-cell tumor. Postoperatively, the patient had normalization of serum inhibin A and B and resumption of normal menstrual cycles. This report illustrates that careful consideration of laboratory findings and other studies is essential for correctly identifying the underlying cause of secondary amenorrhea, particularly when the results are not consistent with common causes of this condition.
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http://dx.doi.org/10.1210/jendso/bvaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672807PMC
December 2020

p-120 Catenin is a Useful Diagnostic Biomarker for Distinguishing Plasmacytoid and Sarcomatoid Variants From Conventional Urothelial Carcinoma.

Arch Pathol Lab Med 2020 Nov 25. Epub 2020 Nov 25.

From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Acosta, Barletta, Schnitt, Hirsch).

Context.—: Plasmacytoid urothelial carcinoma (PC-UC) is an aggressive variant of urothelial carcinoma (UC), characterized by loss of E-cadherin (E-Cad)-mediated intercellular adhesion. Loss of E-Cad by immunohistochemistry can help diagnosis PC-UC; however, sensitivity is limited. Expression of other cadherin-catenin adhesion complex members, that is, p-120 catenin (p-120) and β-catenin (B-Cat), which are diagnostically useful for lobular breast carcinoma, remains unknown in UC.

Objective.—: To determine the utility of p-120 and B-Cat in conventional and variant UC.

Design.—: E-cadherin, B-Cat, and p-120 immunohistochemistry was performed in 25 conventional UCs and 33 variant UCs, including 22 PC-UCs, 6 sarcomatoid UCs (SUCs), and 5 micropapillary UCs. Membranous staining for all biomarkers was considered normal; however, any cytoplasmic staining or an absence of staining was considered diagnostically abnormal. Next-generation sequencing was performed on 8 PC-UC cases.

Results.—: E-cadherin, B-Cat, and p-120 showed membranous staining in all conventional and micropapillary UCs. In contrast, most PC-UCs were negative for E-Cad (17 of 22; 77%) with an additional 2 of 22 cases (9%) showing cytoplasmic with partial membranous staining. p-120 catenin demonstrated cytoplasmic or negative staining in 21 of 22 cases (95%). Most SUCs showed an absence of E-Cad (5 of 6; 83%) and cytoplasmic or negative p-120 in 5 of 6 cases (83%). Staining for B-Cat was also abnormal in a subset of PC-UCs and SUCs. Five PC-UC cases that harbored CDH1 gene variants were p-120 cytoplasmic positive.

Conclusions.—: p-120 catenin is a useful adjunct biomarker to E-Cad in the clinically important distinction of PC-UC and SUC from conventional UC. In particular, the combination of cytoplasmic p-120 and loss of E-Cad is strongly supportive of PC-UC and SUC.
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http://dx.doi.org/10.5858/arpa.2020-0262-OADOI Listing
November 2020

Secondary adenocarcinoma of the urinary bladder attributed to metastatic gastroesophageal cancer.

Can J Urol 2020 10;27(5):10415-10417

Division of Urological Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Metastases of advanced gastrointestinal malignancy to the bladder is a rare phenomenon. Few such cases have been reported. Here, we describe the case of a man with recurrent local gastroesophageal adenocarcinoma who presented with acute kidney injury and bilateral ureteral obstruction ultimately found to have de novo metastatic esophageal disease in the urinary bladder.
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October 2020

'Case of the Month' from Brigham and Women's Hospital, Boston, MA, USA: a 70-year-old man with lung cysts and bilateral renal masses.

BJU Int 2020 10;126(4):428-432

Division of Urological Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/bju.15234DOI Listing
October 2020

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
September 2020

Pseudosarcomatous myofibroblastic proliferations of the urinary bladder are neoplasms characterized by recurrent FN1-ALK fusions.

Mod Pathol 2021 02 9;34(2):469-477. Epub 2020 Sep 9.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Pseudosarcomatous myofibroblastic proliferation is a descriptive term that designates a group of clinically indolent genitourinary lesions that most commonly arise in the urinary bladder. Given that pseudosarcomatous myofibroblastic proliferation may show morphologic overlap with inflammatory myofibroblastic tumor, the relationship, if any, between the two entities has been unclear. Moreover, pseudosarcomatous myofibroblastic proliferations are known to be positive for ALK immunohistochemistry in a subset of cases, although an inconsistent association with ALK rearrangement (ranging from 0 to 60%) has been reported. The objectives of this study were to determine the frequency of ALK rearrangement and to identify fusion partners using fluorescence in situ hybridization (FISH) and targeted RNA sequencing studies in a contemporary series of 30 pseudosarcomatous myofibroblastic proliferations of the urinary bladder, as well as to investigate ROS1 status by immunohistochemistry. ALK immunohistochemistry was positive in 70% (21/30) of pseudosarcomatous myofibroblastic proliferations; ROS1 immunohistochemistry was consistently negative (0/28). ALK rearrangements were detected by FISH in 86% (18/21) of cases, correlating with ALK immunohistochemical positivity in all but 3 cases. Of eight cases confirmed to be ALK rearranged by FISH, targeted RNA-sequencing detected FN1-ALK fusions in seven (88%) cases, which involved exons 20-26 of FN1 (5') and exon 18-19 of ALK (3'). In conclusion, ALK rearrangements are frequent in pseudosarcomatous myofibroblastic proliferations, typically involving exon 19, and FN1 appears to be a consistent fusion partner. Given the significant clinicopathologic differences between inflammatory myofibroblastic tumor and pseudosarcomatous myofibroblastic proliferation, our findings provide further support for classification of pseudosarcomatous myofibroblastic proliferation as a distinct clinicopathologic entity, and propose the alternate terminology "pseudosarcomatous myofibroblastic neoplasm of the genitourinary tract."
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http://dx.doi.org/10.1038/s41379-020-00670-0DOI Listing
February 2021

Intestinal metaplasia of the urinary tract harbors potentially oncogenic genetic variants.

Mod Pathol 2021 02 28;34(2):457-468. Epub 2020 Aug 28.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

In the urinary tract, there is an uncertain relationship between intestinal metaplasia (IM), primary adenocarcinoma, and urothelial carcinoma. Although IM is usually found adjacent to concurrent urothelial carcinoma or adenocarcinoma, small retrospective series have shown that most bladder biopsies with only IM do not subsequently develop cancer. However, IM with dysplasia does seem to be associated with a higher risk of concurrent malignancy or progressing to cancer. Since the molecular landscape of these lesions has remained largely unexplored, there are significant uncertainties about the oncogenic potential of IM in the bladder and urethra. This study investigated the presence of potentially oncogenic genetic variants in cases of IM with and without dysplasia. Twenty-three (23) cases of IM (3 urethra, 20 bladder) were sequenced using a solid tumor next-generation sequencing panel. Of these, five contained IM with high-grade dysplasia (including a case with paired IM-adenocarcinoma and another with paired IM-urothelial carcinoma) and 18 lacked dysplasia. Oncogenic genetic variants were found in all cases of IM with high-grade dysplasia and in five non-dysplastic IM cases, including mutations and copy number variants commonly seen in primary adenocarcinoma of the bladder and urothelial carcinoma. This study demonstrates that IM can harbor potentially oncogenic genetic variants, suggesting that it might represent a cancer precursor or a marker of increased cancer risk in a subset of cases.
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http://dx.doi.org/10.1038/s41379-020-00655-zDOI Listing
February 2021

Squamous Cell Carcinoma of the Bladder Is Not Associated With High-risk HPV.

Urology 2020 Oct 16;144:158-163. Epub 2020 Jul 16.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL; O'Neal Comprehensive Cancer Center at UAB, University of Alabama at Birmingham, Birmingham, AL.

Objective: To evaluate the clinical features, pathologic features, and prevalence of human papilloma virus (HPV) in squamous cell carcinoma (SCC) of the bladder. SCC of the bladder is known to be associated with conditions that cause chronic inflammation/irritation. The literature is inconsistent regarding the association of HPV with pure SCC of the bladder.

Methods: A multi-institutional study identified cases of SCC of the bladder. Pure squamous histology and the absence of urothelial carcinoma in situ were required for inclusion. Clinical and pathologic features were collected, and tissues were evaluated for high-risk HPV using p16 immunohistochemistry and in situ hybridization.

Results: We identified 207 cases of SCC of the bladder. Risk factors for bladder cancer included smoking (133/207, 64%) and chronic bladder irritation (83/207, 40%). The majority (155/207, 75%) of patients had > pT2 disease. Mean tumor size was 5.6 ± 3.0 cm and 36/207 (17%) patients had lymph node positive disease. p16 immunohistochemistry was positive in 52/204 (25%) cases but high-risk HPV was identified with in situ hybridization in only 1 (0.5%) case. Tumor size, stage, number of lymph nodes removed, number of positive lymph nodes, lymphovascular invasion, perineural invasion, and positive margins each were associated with cancer-specific mortality when adjusted for demographic factors. A multivariate analysis of variable importance further revealed sex and race as important factors in predicting cancer-specific mortality.

Conclusion: SCC of the bladder is an aggressive histologic subtype. Although bladder SCC can express p16, it is not typically associated with high-risk HPV, although rare cases can occur.
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http://dx.doi.org/10.1016/j.urology.2020.06.065DOI Listing
October 2020

Carbonic anhydrase IX (CA9) expression in multiple renal epithelial tumour subtypes.

Histopathology 2020 Oct 12;77(4):659-666. Epub 2020 Sep 12.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Aims: Renal epithelial neoplasms (RENs) can be difficult to subclassify, owing to overlapping morphological features. Carbonic anhydrase 9 (CA9) is a common biomarker for clear cell renal cell carcinoma (CCRCC); however, the sensitivity and specificity across REN subtypes are less clear. The aim of this study was to investigate CA9 expression in RENs, especially those in the differential diagnosis with CCRCC and less common entities, to determine its reliability as a diagnostic biomarker.

Methods And Results: CA9 immunostaining was performed on 262 RENs, including 119 CCRCCs and 143 non-CCRCC. Immunostaining was evaluated as negative (0%), rare (1+, 1-10%), focal (2+, 11-50%), or diffuse (3+, >50%). CCRCCs were 3+ CA9-positive in 93% of cases; 4% were CA9-negative. Sixty-seven percent of papillary renal cell carcinomas (RCCs) were 1+/2+ CA9-positive, whereas 33% were CA9-negative. Chromophobe RCCs were nearly always CA9-negative (93%), with 7% showing rare cell reactivity. Clear cell tubulopapillary RCCs (CCTPRCCs) were consistently 3+ CA9-positive, but with a cup-like staining pattern. Fifty-three percent of Xp11.2 RCCs were CA9-negative; however, 6% were 3+ CA9-positive and 12% were 2+ CA9-positive. Two of eight fumarate hydratase-deficient RCCs were 3+ CA9-positive. A small subset of the remaining RCCs showed rare to focal CA9 expression. All oncocytomas and eosinophilic solid and cystic RCCs were CA9-negative.

Conclusions: Overall, diffuse CA9 expression was identified in nearly all CCRCCs and in all CCTPRCCs (high sensitivity); however, CA9 was not entirely specific. At least focal CA9 expression can been seen in a subset of many RCCs, and such findings should be taken into consideration with other morphological, immunophenotypic and clinical findings.
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http://dx.doi.org/10.1111/his.14204DOI Listing
October 2020

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2021 Apr;145(4):461-493

Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Maclean).

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
April 2021

Prostatic Metaplasia of the Vagina and Uterine Cervix: An Androgen-associated Glandular Lesion of Surface Squamous Epithelium.

Am J Surg Pathol 2020 08;44(8):1040-1049

Departments of Pathology.

Prostatic-type differentiation in the lower female genital tract is encountered rarely and its causes and clinical associations are not well established. Within the vagina, reports to date have invariably described ectopic prostatic-type differentiation as restricted to the lamina propria. We recently encountered a patient receiving testosterone for gender dysphoria whose vaginectomy specimen showed a prostatic glandular proliferation within the surface epithelium. To elucidate its potential association with androgen exposure, we sought similar lesions, resected over a 26-year period, from patients with exogenous or endogenous androgen excess. Thirteen cases were identified, involving the vagina (n=12) and exocervix (n=1). The most common clinical context was gender dysphoria with long-term testosterone therapy; the lesion was present in 7 of 8 gender-dysphoric patients examined. Four other patients had congenital disorders of sexual development associated with endogenous androgen excess (congenital adrenal hyperplasia, 46,XY disorder of sexual development, and ovotesticular disorder of sexual development). Two had no known exposure to androgen excess. Immunohistochemically, glands stained for NKX3.1 (100% of cases), androgen receptor (100%), CK7 (92%), and prostate-specific antigen (69%). Follow-up (median duration, 11 mo) showed no masses or neoplasia. We propose the designation "androgen-associated prostatic metaplasia" for this form of prostate tissue with distinctive clinical, histologic and immunohistochemical features. It is novel and previously unrecognized within the vagina. It is strikingly prevalent among patients undergoing gender-affirming surgery, an increasingly common procedure. Recognition is important to distinguish it from other potentially neoplastic glandular lesions and facilitate accrual of more follow-up data to better understand its natural history.
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http://dx.doi.org/10.1097/PAS.0000000000001486DOI Listing
August 2020

MRI-targeted prostate biopsy: key considerations for pathologists.

Histopathology 2020 Jul 7;77(1):18-25. Epub 2020 Jun 7.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.

We discuss the role of the pathologist for MRI-targeted prostate biopsy with a focus on specimen processing, reporting of pathological findings and quality assurance in establishing a successful MRI-targeted biopsy programme. The authors discuss the current issues relevant to pathologists regarding MRI-targeted prostate biopsy. In addition, a brief review of the recently published literature was performed using an English literature search on PubMed with a focus on original investigations related to MRI-targeted prostate biopsy. Our search terms included the following: 'prostate cancer', 'pathology', 'histology', 'reporting', 'cores', 'imaging', 'MRI' and 'mpMRI'. Prostate multiparametric magnetic resonance imaging (mp-MRI) and MRI-targeted biopsy has been shown to improve the diagnosis of clinically significant prostatic adenocarcinoma and can affect the management of patients with prostate cancer. The current active surveillance guidelines were based on data from TRUS biopsies and not MRI-targeted biopsies. MRI-targeted biopsy acquires multiple cores of tissue from one or more suspicious lesions found on mp-MRI. The way in which multiple targeted core biopsies obtained from a single image-directed region of interest are analysed and reported can potentially alter the Gleason score and tumour burden as reported on biopsy, which could undoubtedly alter patient management. Pathologists play an important role in the reporting of MRI-targeted prostate biopsies. How we report prostate cancer grade and extent on these biopsies can influence patient management. In addition, the pathologist should be involved in the quality assurance for patients undergoing MRI-targeted prostate biopsy.
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http://dx.doi.org/10.1111/his.14113DOI Listing
July 2020

Volume of Gleason pattern 4 stratifies risk of metastasis and death in patients with Gleason score 3+5=8/5+3=8 positive prostate core biopsies.

Hum Pathol 2020 05 11;99:62-74. Epub 2020 Mar 11.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115 USA. Electronic address:

Implementation of Grade Groups (GrGrs) has been widely accepted for reporting prostate cancer grade since the 2014 International Society of Urological Pathology consensus meeting. Despite their undisputed value for risk stratification, some GrGr are, a priori, quite heterogeneous in that they contain multiple Gleason patterns (GPs). In this regard, the prognostic significance of GP5 in biopsies with highest GrGr4 is uncertain and evaluated in this study. A search of all core biopsies positive for prostate cancer reviewed after 2005 was performed, and 71 cases with highest GrGr4 containing GP5 (i.e., 3 + 5 = 8 or 5 + 3 = 8; referred to as GrGr4/GP5pos) eligible for inclusion were identified. In addition, 95 core biopsy cases with highest GrGr4 and no GP5 (i.e, 4 + 4 = 8; referred to as GrGr4/GP5neg) were selected for comparison. Multiple pathologic parameters, including volume and amount of GP4, and clinical variables were collected to evaluate the influence of GP5 on disease recurrence, development of metastases, and disease-specific death. GrGr4/GP5pos cases did not show, as a group, statistically significant differences in prostatectomy findings, disease recurrence, metastases, and disease-specific mortality when compared with GrGr4/GP5neg cases. In addition, the risk of all outcomes evaluated in the study did not differ between the whole GrGr4/GP5pos and GrGr4/GP5neg groups. However, Kaplan-Meier analysis found that GrGr4/GP5pos cases with a significant amount of GP4 did show a higher risk of prostate cancer-specific death as well as bone and visceral metastases. Univariate Cox regression demonstrated that preoperative prostate specific antigen (PSA), total number of positive cores, and global GrGr5 were also associated with a higher chance of disease-specific death. In a multivariate model, only global GrGr5 and PSA >20 ng/dL remained statistically significant. This study suggests that the mere presence of GP5 in core biopsies with highest GrGr4 disease may not portend a worse prognosis. In these cases, accounting for the case-wide volume of GP4 by reporting a global GrGr appears to be more relevant as it identifies a subset of GrGr4/GP5pos patients with global GrGr5 who have a higher risk of metastases and prostate cancer-specific mortality.
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http://dx.doi.org/10.1016/j.humpath.2020.03.001DOI Listing
May 2020

Results of an abbreviated phase II study of AKT inhibitor MK-2206 in the treatment of recurrent platinum-resistant high grade serous ovarian, fallopian tube, or primary peritoneal carcinoma (NCT 01283035).

Gynecol Oncol Rep 2020 May 3;32:100546. Epub 2020 Feb 3.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.

Platinum-resistant, recurrent, high grade epithelial ovarian carcinoma remains challenging to treat. Chemotherapy produces limited responses with modest survival benefits in the treatment of recurrent disease. In this context, targeted therapies may improve upon conventional therapies. PI3K/AKT pathway alterations are frequently found in several cancer types, including ovarian cancer, and thus AKT inhibition is a rational targeted therapy. Here we report the results of an abbreviated trial of AKT inhibitor MK-2206 in platinum resistant high grade serous ovarian, fallopian tube, and primary peritoneal cancer with PTEN loss.
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http://dx.doi.org/10.1016/j.gore.2020.100546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021536PMC
May 2020

Reporting Practices and Resource Utilization in the Era of Intraductal Carcinoma of the Prostate: A Survey of Genitourinary Subspecialists.

Am J Surg Pathol 2020 05;44(5):673-680

Cleveland Clinic, Cleveland, OH.

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.
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http://dx.doi.org/10.1097/PAS.0000000000001417DOI Listing
May 2020

PNL2: A Useful Adjunct Biomarker to HMB45 in the Diagnosis of Uterine Perivascular Epithelioid Cell Tumor (PEComa).

Int J Gynecol Pathol 2020 Nov;39(6):529-536

Perivascular epithelioid cell tumors (PEComa) are rare neoplasms characterized by co-expression of melanocytic and muscle markers. HMB45 and Melan-A are used to confirm a PEComa diagnosis; however, both are often focally expressed and sensitivity for Melan-A is low. PNL2 is a reliable biomarker for epithelioid melanoma and renal angiomyolipoma/PEComa. The objective of this study was to determine PNL2 utility in diagnosing uterine PEComas as well as distinguishing PEComas from uterine smooth muscle tumors (SMTs). Twenty-one uterine PEComas and 45 SMTs were analyzed for PNL2; a subset was also stained for HMB45, Melan-A, Cathepsin-K, Desmin, and h-Caldesmon. Cases were scored as negative (0), focal (<10% of tumor cells), or patchy to diffusely positive (>10% of tumor cells). PEComas were positive for PNL2, HMB45, and Melan-A in 86%, 100%, and 57% of cases, respectively. In PEComas, PNL2 was patchy to diffusely positive more frequently (10/18, 56%) than Melan-A (4/12, 33%). In contrast, 2 of 45 (4%) SMTs were focally PNL2 positive; HMB45 was focally positive in 4 SMTs (11%) and all were negative for Melan-A. Desmin and h-Caldesmon were positive in 90% and 57% of PEComas, and 91% and 82% of SMTs. Cathepsin-K was positive in 100% of PEComas and 93% of SMTs. PNL2 is a useful biomarker for the diagnosis of uterine PEComa, with comparable sensitivity and specificity to HMB45. In contrast, PNL2 stains more PEComas when compared with Melan-A. Cathepsin-K, Desmin, and h-Caldesmon are of little utility for distinguishing PEComas and SMTs; however, lack of Cathepsin-K argues against PEComa. These results suggest that PNL2 should be used in conjunction with HMB45 in the diagnosis of PEComa of the uterine corpus.
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http://dx.doi.org/10.1097/PGP.0000000000000653DOI Listing
November 2020

Results of a Multicenter Phase II Study of Atezolizumab and Bevacizumab for Patients With Metastatic Renal Cell Carcinoma With Variant Histology and/or Sarcomatoid Features.

J Clin Oncol 2020 01 13;38(1):63-70. Epub 2019 Nov 13.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation.

Patients And Methods: Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory.

Results: Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9) 19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy.

Conclusion: In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.
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http://dx.doi.org/10.1200/JCO.19.01882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051851PMC
January 2020

A Comprehensive Review of Biomarker Use in the Gynecologic Tract Including Differential Diagnoses and Diagnostic Pitfalls.

Adv Anat Pathol 2020 May;27(3):164-192

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.

Morphologic (ie, hematoxylin and eosin) evaluation of the Mullerian tract remains the gold standard for diagnostic evaluation; nevertheless, ancillary/biomarker studies are increasingly utilized in daily practice to assist in the subclassification of gynecologic lesions and tumors. The most frequently utilized "biomarker" technique is immunohistochemistry; however, in situ hybridization (chromogenic and fluorescence), chromosomal evaluation, and molecular analysis can also be utilized to aid in diagnosis. This review focuses on the use of immunohistochemistry in the Mullerian tract, and discusses common antibody panels, sensitivity and specificity of specific antibodies, and points out potential diagnostic pitfalls when using such antibodies.
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http://dx.doi.org/10.1097/PAP.0000000000000238DOI Listing
May 2020

Loss of SMAD4 protein expression in gastrointestinal and extra-gastrointestinal carcinomas.

Histopathology 2019 Oct 13;75(4):546-551. Epub 2019 Aug 13.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Aims: SMAD4 (DPC4) is a tumour suppressor gene that is dysregulated in various tumour types, particularly pancreaticobiliary and gastrointestinal carcinomas. Corresponding loss of protein expression has been reported in approximately 50% of pancreatic and 25% of colonic adenocarcinomas. In the evaluation of carcinoma of unknown primary site, immunohistochemical loss of SMAD4 expression is often used to suggest pancreaticobiliary origin, but there are limited data on the spectrum of SMAD4 expression in carcinomas of other sites. This study evaluates the frequency of SMAD4 loss in a large cohort of carcinomas from diverse anatomical sites.

Methods And Results: Immunohistochemistry for SMAD4 was performed on tissue microarrays or whole tissue sections of 1210 carcinomas from various organs: gastrointestinal tract, liver, pancreas/biliary tract, lung, breast, thyroid, kidney, ovary and uterus. Expression was considered lost when there was complete absence of staining in tumour cell nuclei, in the presence of intact staining in non-neoplastic cells. SMAD4 loss was seen in 58% of pancreatic adenocarcinomas, 27% of appendiceal adenocarcinomas, 19% of colorectal adenocarcinomas, 16% of cholangiocarcinomas, 10% of lung adenocarcinomas and <5% of oesophageal, breast, gastric and mucinous ovarian adenocarcinomas. All papillary thyroid, hepatocellular, non-mucinous ovarian, endometrial and renal cell carcinomas showed intact SMAD4 nuclear expression.

Conclusion: In addition to pancreaticobiliary, appendiceal and colonic tumours, SMAD4 loss is also seen in a small subset of other carcinomas, specifically breast, lung, oesophageal and gastric adenocarcinomas, all of which are typically CK7-positive, similar to pancreaticobiliary carcinoma. Awareness of SMAD4 loss in these other carcinoma types is helpful in the evaluation of carcinomas of unknown or uncertain primary site.
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http://dx.doi.org/10.1111/his.13894DOI Listing
October 2019