Publications by authors named "Monika Vyas"

24 Publications

  • Page 1 of 1

Incidental secondary findings in hemorrhoidectomy specimens: a 16-year experience from a single academic center.

Hum Pathol 2020 Nov 24;109:12-20. Epub 2020 Nov 24.

Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address:

Hemorrhoidectomy specimens serve as an excellent resource for study of incidental anal pathology. Detection of most incidental findings is quite rare, although diagnosing clinically significant lesions can have profound impact on the clinical follow-ups. While there are many case reports of incidental findings in hemorrhoidectomy specimens, there are few large studies focused on this topic. The aim of this study was to describe the spectrum and likelihood of detecting incidental findings in hemorrhoidectomy specimens. We reviewed all hemorrhoidectomy specimens that showed incidental clinically significant diagnoses over a 16-year period (2003-2019) for this study. Patient's age, sex, and significant clinical history (Human Immunodeficiency Virus (HIV) status, precursor lesions, other malignancy) were recorded from clinical notes. We identified incidental clinically significant findings in 72 of 1612 (4.5%) specimens. We identified 7 incidental malignancies (squamous cell carcinoma, verrucous carcinoma, adenocarcinoma, mixed adenocarcinoma and neuroendocrine carcinoma, poorly differentiated neuroendocrine carcinoma, melanoma), 54 anal intraepithelial neoplasias (AINs), and 11 benign findings (melanocytic lesions, colorectal polyps, angiokeratoma, infectious/inflammatory). Within the AIN group, the detection of low-grade squamous intraepithelial lesions (LSILs) remained steady; there was a recent, sustained rise in detection of high-grade squamous intraepithelial lesions (HSILs), with more cases showing HSILs (2.6%) than only LSILs (0.7%). In 72.2% of patients, the incidental secondary finding represented a first diagnosis for that entity in the anal canal. Thirty seven percent of patients with anal dysplasia in the hemorrhoidectomy specimen had a prior diagnosis of squamous dysplasia in the anogenital tract. Overall, significant incidental findings were detected in 4.5% (72/1612) of hemorrhoidectomies, supporting routine histological examination of these specimens.
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http://dx.doi.org/10.1016/j.humpath.2020.11.008DOI Listing
November 2020

Alterations in Ki67 Labeling Following Treatment of Poorly Differentiated Neuroendocrine Carcinomas: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2021 01;45(1):25-34

Memorial Sloan Kettering Cancer Center, New York, NY.

Assessment of the Ki67 index is critical for grading well-differentiated neuroendocrine tumors (WD-NETs), which can show a broad range of labeling that defines the WHO grade (G1-G3). Poorly differentiated neuroendocrine carcinomas (PD-NECs) have a relatively high Ki67 index, >20% in all cases and commonly exceeding 50%. After anecdotally observing PD-NECs with an unexpectedly low and heterogeneous Ki67 index following chemotherapy in 5 cases, we identified 15 additional cases of treated high-grade neuroendocrine neoplasms (HG-NENs). The study cohort comprised 20 cases; 11 PD-NECs, 8 mixed adenoneuroendocrine carcinomas, and 1 WD-NET, G3 from various anatomic sites (gastrointestinal tract, pancreas, larynx, lung, and breast). The Ki67 index was evaluated on pretreatment (when available) and posttreatment samples. Topographic heterogeneity in the Ki67 index was expressed using a semi-quantitative score of 0 (no heterogeneity) to 5 (>80% difference between maximal Ki67 and minimal Ki67 indices). Relative to the pretreatment group (n=9, mean Ki67 of 86.3%, range 80% to 100%), the neoplasms in the posttreatment group (n=20, mean Ki67 of 47.7%, range 1% to 90%) showed a significantly lower Ki67 index (18/20 cases). Of the 18 cases with a relatively low Ki67 index, 15 showed heterogeneous labeling (mean heterogeneity score of 2.3, range 1 to 5) and in 3 cases it was a homogeneously low. This phenomenon was observed in all subtypes of HG-NENs. In 6 cases, the alterations in Ki67 index following treatment were sufficient to place these HG-NENs in the WHO G1 or G2 grade, erroneously suggesting a diagnosis of WD-NET, and in 9 cases there was sufficient heterogeneity in the Ki67 index to suggest that a limited biopsy may sample an area of low Ki67, even though hotspot regions with a Ki67 index of >20% persisted. In 7 cases, the alterations in the Ki67 index were accompanied by morphologic features resembling a WD-NET. These observations suggest that there is a potential for misinterpretation of previously treated PD-NECs as WD-NETs, or for assigning a lower grade in G3 WD-NETs. While the prognostic significance of treatment-associated alterations in Ki67 index is unknown, awareness of this phenomenon is important to avoid this diagnostic pitfall when evaluating treated NENs.
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http://dx.doi.org/10.1097/PAS.0000000000001602DOI Listing
January 2021

Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies.

Fam Cancer 2020 Oct 9. Epub 2020 Oct 9.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one-and not all-PMS2-LS associated MMR-deficient carcinomas; (3) "compound LS" with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.
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http://dx.doi.org/10.1007/s10689-020-00210-4DOI Listing
October 2020

Hepatocellular Carcinoma: Role of Pathology in the Era of Precision Medicine.

Clin Liver Dis 2020 11 3;24(4):591-610. Epub 2020 Sep 3.

Department of Pathology, Yale School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA. Electronic address:

Hepatocellular carcinoma (HCC) is a morphologically heterogeneous tumor with variable architectural growth patterns and several distinct histologic subtypes. Large-scale attempts have been made over the past decade to identify targetable genomic alterations in HCC; however, its translation into clinical personalized care remains a challenge to precision oncology. The role of pathology is no longer limited to confirmation of diagnosis when radiologic features are atypical. Pathology is now in a position to predict the underlying molecular alteration, prognosis, and behavior of HCC. This review outlines various aspects of histopathologic diagnosis and role of pathology in cutting-edge diagnostics of HCC.
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http://dx.doi.org/10.1016/j.cld.2020.07.010DOI Listing
November 2020

Intestinal metaplasia around the gastroesophageal junction is frequently associated with antral reactive gastropathy: implications for carcinoma at the gastroesophageal junction.

Hum Pathol 2020 Nov 14;105:67-73. Epub 2020 Sep 14.

Department of Surgical Pathology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Increasing evidence suggests that bile reflux (BR) plays a major role in mucosal injury, leading to adenocarcinoma of the proximal stomach and distal esophagus. However, gastric BR is difficult to diagnose and investigate. Reactive gastropathy (RG), in the absence of nonsteroidal anti-inflammatory drugs (NSAIDs) and other known causes, likely represents bile-mediated injury to the gastric mucosa. The goal of this study is to explore the association between antral RG and gastroesophageal junction (GEJ) mucosal inflammation and intestinal metaplasia (IM). The pathology database was searched for patients who had gastric biopsies with a diagnosis of antral RG and concurrent gastric cardia/GEJ/distal esophagus biopsies from 2013 to 2015. Age- and sex-matched patients with normal gastric antral biopsies served as controls. Biopsies from the GEJ region were evaluated for histological changes, including inflammation, antral and pancreatic metaplasia, RG, the type of gastric glands, proton pump inhibitor (PPI) changes, and IM. Detailed clinical history and medication use (including PPIs and NSAIDs) were recorded. IM in the GEJ region was more frequent in patients with antral RG than in controls (33.0% vs. 5.2%, 95% confidence interval [18.3-37.3%]). In addition, inflammation, other mucosal changes around the GEJ (RG and foveolar hyperplasia), antral IM, and PPI-associated mucosal changes were also more frequently seen in patients with antral RG. Our results show that antral RG is associated with mucosal injury and IM around GEJ, suggesting a role of BR. Further studies are needed to study duodenogastric-esophageal BR and its role in development of proximal gastric and distal esophageal adenocarcinoma.
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http://dx.doi.org/10.1016/j.humpath.2020.08.007DOI Listing
November 2020

DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma.

Mod Pathol 2020 04 1;33(4):648-656. Epub 2019 Nov 1.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.
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http://dx.doi.org/10.1038/s41379-019-0398-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125037PMC
April 2020

Adverse Histologic Features in Colorectal Nonpedunculated Malignant Polyps With Nodal Metastasis.

Am J Surg Pathol 2020 02;44(2):241-246

Department of Pathology, Yale School of Medicine, New Haven, CT.

Tumor differentiation, lymphovascular invasion, margin status, polyp shape, and size are important parameters of malignant polyps (pT1) indicating possible node metastasis, which justifies a surgery. However, the size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The aim of the study was to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. A total of 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens from 2005 to 2018 were reviewed. Cases with node metastasis were more often positive for high-grade tumor budding (70.8% vs. 16.7%; P=0.0005), poorly differentiated clusters (54.2% vs. 22.2%; P=0.0369), and both high-grade tumor budding and poorly differentiated clusters (45.8% vs. 11.1%; P=0.0160) compared with controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and combined high-grade tumor budding and poorly differentiated clusters increased the risk of nodal metastasis, with odds ratio of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimen even in completely excised malignant polyps with adverse histologic features. Our findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features in predicting lymph node metastatic potential. These histologic features should be reported and it may warrant a colectomy when they are present.
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http://dx.doi.org/10.1097/PAS.0000000000001369DOI Listing
February 2020

Glucose Metabolic Reprogramming and Cell Proliferation Arrest in Colorectal Micropapillary Carcinoma.

Gastroenterology Res 2019 Jun 7;12(3):128-134. Epub 2019 Jun 7.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Background: Micropapillary carcinoma (MPC) has been reported as an aggressive variant of colorectal carcinoma (CRC) associated with frequent lymphovascular invasion and poor outcome. Altered glycogen metabolism by metabolic reprogramming plays a critical role for cancer cell growth and survival. We aimed to investigate glucose metabolic reprogramming in colorectal MPC.

Methods: Immmunostains for Ki-67 and glucose transporter 1 (GLUT1) were performed on 10 colorectal MPCs. Real-time PCR analysis of expressions of GLUT1 and glycogen metabolizing enzymes: glycogen synthase (GYS1) and glycogen phosphorylase (PYGL) was performed on cultured monolayer and three-dimensional (3D) spheroid HCT116 colon cancer cells.

Results: GLUT1 was strongly expressed in MPC as compared to adjacent conventional glandular component, and was also significantly increased expression in 3D spheroids. Upregulation of GYS1 and PYGL was markedly increased in 3D spheroids. The proliferation rate (Ki-67) of MPC was significantly lower compared to conventional glandular component. The 3D spheroids showed increased cell cycle arrest. Our results demonstrate altered glycogen metabolism in colorectal MPC.

Conclusion: The reprogramming of glycogen metabolism in MPC provides a source of energy contributing to tumor cell survival in a low proliferation state. Targeting glucose-regulated metabolism may warrant consideration as possible MPC therapies.
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http://dx.doi.org/10.14740/gr1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6575135PMC
June 2019

Colorectal carcinoma with double somatic mismatch repair gene inactivation: clinical and pathological characteristics and response to immune checkpoint blockade.

Mod Pathol 2019 10 7;32(10):1551-1562. Epub 2019 Jun 7.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Double somatic mismatch-repair-gene mutation/alteration is a recently recognized molecular mechanism that underlies microsatellite instability-high in some colorectal carcinomas. It remains to be determined whether and how microsatellite instability-high tumors with this molecular defect differ from their counterparts caused by other mechanisms, specifically, Lynch syndrome-associated and MLH1-promoter hypermethylated. In this study, we evaluated the clinical and pathological characteristics of a series of 15 double somatic mutation/alteration-associated microsatellite instability-high colorectal carcinomas identified from our genetics service and 68 such cases reported in the literature. We observed that these cases presented at an age similar to MLH1-promoter hypermethylated (n = 20) and microsatellite-stable (n = 39) cases but older than Lynch syndrome-associated cases (n = 20, p < 0.05). While these tumors simulated other microsatellite instability-high tumors in their prevalent right-sided location, they appeared to differ in TNM stages at presentation (73% stage III/IV versus 25% stage III/IV in other microsatellite instability-high tumors, p = 0.04). Histologically, 40% of them had a dominant solid growth pattern. Inter-tumoral heterogeneity was a striking feature, spanning the spectrum from medullary type (with a tumor-infiltrating-lymphocyte/high-power-field count as high as 59) to conventional-type with only few tumor-infiltrating-lymphocytes (1/high-power-filed). As a group, these tumors seemed less likely to show robustly high lymphocytic infiltration than other microsatellite instability-high tumors (only 20% had ≥10 tumor-infiltrating-lymphocytes/high-power-filed, whereas this rate in Lynch syndrome-associated and MLH1-promoter hypermethylated tumors was 60% and 75%, respectively). Three double somatic mutation/alteration-associated tumors were treated with a PD1/PD-L1 checkpoint inhibitor. While all three had an elevated tumor-mutation-burden (>47 mut/megabase), only one had tumor-infiltrating-lymphocytes >10/high-power-field, yet all three exhibited measurable response. In summary, microsatellite instability-high colorectal carcinomas caused by double somatic mismatch-repair-gene mutation/alteration may have varied clinical and pathological characteristics, and some may have relatively low tumor-infiltrating-lymphocytes; response to immune checkpoint inhibitors can be achieved in this group even when the lymphocytic infiltration is not abundant.
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http://dx.doi.org/10.1038/s41379-019-0289-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849386PMC
October 2019

Acquired resistance to immunotherapy in MMR-D pancreatic cancer.

J Immunother Cancer 2018 11 20;6(1):127. Epub 2018 Nov 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer.

Case Presentation: A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor.

Conclusions: This is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response.
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http://dx.doi.org/10.1186/s40425-018-0448-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247688PMC
November 2018

Cellular localization of PD-L1 expression in mismatch-repair-deficient and proficient colorectal carcinomas.

Mod Pathol 2019 01 30;32(1):110-121. Epub 2018 Aug 30.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Blockade of the interaction between PD-1 and its ligands PD-L1 has shown clinical efficacy across several tumor types, especially in mismatch-repair-deficient colorectal carcinoma. The aim of this study was to examine the pattern and cellular localization of PD-L1 expression in the different molecular subtypes of mismatch-repair-deficient colorectal cancers vs. their mismatch-repair-proficient counterparts. PD-L1/SATB2 double-antibody-immunohistochemistry was utilized to distinguish tumor cell from immune cell staining. We observed in our series of 129 colorectal adenocarcinomas that PD-L1 expression occurred primarily in tumor-associated-immune cells and most prominently at the tumor-stroma-interface of the invasive front. The level of invasive front immune cell staining was significantly higher in mismatch-repair-deficient tumors compared to mismatch-repair-proficient tumors (p < 0.001), but no difference was observed among the different subtypes of mismatch-repair-deficient tumors: Lynch syndrome-associated vs. MLH1-methylated vs. unexplained. While selected mismatch-repair-proficient tumors exhibited unusually high tumor-infiltrating-lymphocytes and had high level immune cell PD-L1 expression, a positive correlation between PD-L1 expression and high lymphocyte count was detected only in mismatch-repair-deficient tumors (r = 0.39, p < 0.001) and not in mismatch-repair-proficient tumors. Notably, true tumor cell PD-L1 expression in colorectal carcinoma was rare, present in only 3 of 129 tumors (2.3%): 2 MLH1-methylated and 1 mismatch-repair-proficient with high tumor-infiltrating-lymphocytes; and the staining in the tumor cells in all 3 was diffuse (>=50% of the tumor). These findings may serve to inform further efforts aiming to evaluate PD-L1 immunohistochemistry vis-à-vis molecular sub-classification as predictive biomarkers in the treatment of colorectal carcinoma.
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http://dx.doi.org/10.1038/s41379-018-0114-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309293PMC
January 2019

Loss of c-KIT expression in breast cancer correlates with malignant transformation of breast epithelium and is mediated by KIT gene promoter DNA hypermethylation.

Exp Mol Pathol 2018 08 28;105(1):41-49. Epub 2018 May 28.

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.

KIT Proto-Oncogene Receptor Tyrosine Kinase (KIT) is a transmembrane receptor tyrosine kinase which plays an important role in regulation of cell proliferation, survival and migration. Interestingly, the role of c-KIT in malignant transformation seems to be highly tissue-specific and it can act either as an oncogene or tumor suppressor gene. Here we analyzed the expression of c-KIT in normal breast tissues and tissues from different stages encompassing major steps of breast tumor development. Our study showed, that the c-KIT protein expression is gradually lost during the process of breast tissue transformation. The analysis of previously published datasets revealed that c-KIT expression in breast malignancies was downregulated at mRNA level. Because sequencing studies did not identify any recurrent mutations or copy number alterations, we proposed a potential epigenetic mechanism for the downregulation of c-KIT expression. In-silico analysis of the KIT promoter revealed the presence of CpG islands, therefore we performed bisulfite sequencing of normal breast epithelial tissues as well as breast tumor samples. We found, that KIT promoter is hypermethylated in breast tumors compared to normal breast tissues. Furthermore, treatment of breast cancer cell lines, that lack the expression of c-KIT, with methyltransferase inhibitor 5-Azacytidine (5Aza-2dC) resulted in increased expression of c-KIT mRNA. Collectively, our studies demonstrate that c-KIT expression is epigenetically downregulated during breast epithelium transformation and cancer development via KIT promoter hypermethylation.
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http://dx.doi.org/10.1016/j.yexmp.2018.05.011DOI Listing
August 2018

A practical diagnostic approach to hepatic masses.

Indian J Pathol Microbiol 2018 Jan-Mar;61(1):2-17

Department of Pathology, Yale School of Medicine, New Haven, CT, USA.

The differential diagnosis of hepatic mass lesions is broad and arriving at the right diagnosis can be challenging, especially on needle biopsies. The differential diagnosis of liver tumors in children is different from adults and is beyond the scope of this review. In adults, the approach varies depending on the age, gender, and presence of background liver disease. The lesions can be divided broadly into primary and metastatic (secondary), and the primary lesions can be further divided into those of hepatocellular origin and nonhepatocellular origin. The first category consists of benign and malignant lesions arising from hepatocytes, while the second category includes biliary, mesenchymal, hematopoietic, and vascular tumors. Discussion of nonepithelial neoplasms is beyond the scope of this review. The hepatocytic lesions comprise dysplastic nodules, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma, and the differential diagnosis can be challenging requiring clinicopathological correlation and application of immunohistochemical (IHC) markers. Liver is a common site for metastasis, sometimes presenting with an unknown primary site, and proper workup is the key to arriving at the correct diagnosis. The correct diagnosis in this setting requires a systematic approach with attention to histologic features, imaging findings, clinical presentation, and judicious use of IHC markers. The list of antibodies that can be used for this purpose keeps on growing continually. It is important for pathologists to be up to date with the sensitivity and specificity of these markers and their diagnostic role and clinical implications. The purpose of this review is to outline the differential diagnosis of hepatic masses in adults and discuss an algorithmic approach to make a right diagnosis.
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http://dx.doi.org/10.4103/IJPM.IJPM_578_17DOI Listing
November 2018

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in a young female athlete at 36 weeks gestation: a case report.

Pathol Res Pract 2017 Oct 25;213(10):1302-1305. Epub 2017 Jul 25.

Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT, 06510, USA. Electronic address:

A 26year old east African professional athlete presented to the obstetric clinic for a routine visit at 36 weeks gestation. She had a history of Right Ventricular Outflow Tract - Ventricular Tachycardia (RVOT-VT) with an episode of cardiac arrest in the past, and had been treated with ablation 4 years earlier. Her current visit was uneventful, her pregnancy progressing normally. Following the visit she went to a local restaurant where she suffered a cardiac arrest that was unresponsive to therapy. Chest compressions were continued from the time of her collapse until an emergency caesarian section was performed, delivering a healthy female infant. At autopsy a focal area of subtle pallor and myocardial thinning was present at the apex of the right ventricle. Histology showed myocyte degeneration and loss with focal full thickness replacement of myocardium by adipose tissue, consistent with the fatty form of arrhythmogenic right ventricular cardiomyopathy (ARVC). Molecular studies revealed a variant of unknown significance in the MYBPC3 gene, but no variant known to be associated with ARVC. In view of the subtlety of the lesion on gross examination this diagnosis could have been easily missed, emphasizing the importance of performing histologic examination of subtle gross cardiac lesions.
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http://dx.doi.org/10.1016/j.prp.2017.07.015DOI Listing
October 2017

Intestinal metaplasia of appendiceal endometriosis is not uncommon and may mimic appendiceal mucinous neoplasm.

Pathol Res Pract 2017 Jan 25;213(1):39-44. Epub 2016 Oct 25.

Department of Pathology, Yale University School of Medicine, New Haven, CT USA. Electronic address:

Endometriosis of the appendix can be an incidental finding or a cause of appendicitis, intussusception, perforation or retention mucocele. Intestinal metaplasia of appendiceal endometriosis may occur, which can lead to a misdiagnosis of low-grade appendiceal mucinous neoplasm. On a retrospective search of the pathology database from 2001 to 2015, we identified 78 appendiceal endometriosis cases and intestinal metaplasia was present in 10/78 (13%) cases. In most of the cases (90%), the foci of intestinal metaplasia were mainly localized close to the mucosa. Intestinal and endometrial hybrid glands were present in 9/10 (90%) cases. These cases were often associated with marked appendiceal distortion, luminal obliteration and mass formation, causing concern for a mucinous neoplasm clinically and pathologically. Our findings indicate that intestinal metaplasia in appendiceal endometriosis is not an uncommon phenomenon, which can be mistaken for a mucinous neoplasm. Endometriosis should be kept in mind when a diagnosis of appendiceal mucinous neoplasm is made, especially in a young woman with a clinical history of endometriosis.
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http://dx.doi.org/10.1016/j.prp.2016.10.011DOI Listing
January 2017

Metastatic tumors in the jaw bones: A retrospective clinicopathological study of 12 cases at Tertiary Cancer Center.

J Oral Maxillofac Pathol 2016 May-Aug;20(2):252-5

Department of Pathology, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India.

Introduction: The metastatic disease of the jaw bones is very uncommon and accounts for approximately 1% of all malignancies of jaw. The most common location is molar region of mandible. Metastasis may go undetected on a routine skeletal survey for assessment of metastasis and rarely includes jaw bones.

Aims And Objective: The aim of the study is to analyze primary malignancies in metastatic jaw tumors.

Materials And Methods: We retrospectively studied clinicopathological features of 12 patients of metastasis to jaw bones diagnosed at tertiary cancer center between 2003 and 2011. All H and E and immunohistochemical slides were reviewed by two pathologists and relevant details were noted.

Results: There were eight female and four male patients, with age range 12-71 years with metastases to jaws. All of them involved mandible with one case also showing the involvement of frontal sinuses. The types of metastatic tumors include adenocarcinoma (six cases), papillary thyroid carcinoma (four cases), carcinoma with neuroendocrine differentiation (one case) and neuroblastoma (one case). The diagnosis was made on biopsies in eight cases and on hemimandibulectomy in four cases. The primary site was known at the time of presentation only in four cases, all of them being thyroid carcinomas. Primary site was determined in seven cases after immunohistochemical workup on metastatic tumor and further investigations, whereas the primary site of carcinoma with neuroendocrine differentiation was unknown.

Conclusion: Metastasis to jaw bones is rare and may be the first manifestation of unknown primary. A lesion predominantly involving bone with unusual morphology should raise a possibility of metastasis.
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http://dx.doi.org/10.4103/0973-029X.185920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989556PMC
September 2016

Metastatic thyroid carcinoma presenting as malignant pleural effusion: A cytologic review of 5 cases.

Diagn Cytopathol 2016 Dec 26;44(12):1085-1089. Epub 2016 Jul 26.

Department of Pathology, Yale New Haven Hospital, New Haven, Connecticut.

Malignant pleural effusion can be a manifestation of many malignancies. Involvement of pleural fluid by metatstatic thyroid carcinoma, though reported, is relatively rare. We present 5 cases of metastatic thyroid carcinoma involving the pleural fluid. The diagnosis of thyroid carcinoma in pleural fluid can be particularly challenging as thyroid transcription factor -1 (TTF-1) which is a marker for carcinoma of thyroid origin is also positive in lung adenocarcinomas (which are more frequently associated with pleural effusions) and thyroglobulin (TG) can often be negative in poorly differentiated/analplastic thyroid carcinomas. In our experience, PAX8 is a particularly useful marker in making the distinction. The diagnosis of metastatic thyroid carcinoma in pleural fluid can be challenging and knowledge of the clinical context and supporting immunohistochemical stains is essential for making the right diagnosis. Diagn. Cytopathol. 2016;44:1085-1089. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/dc.23547DOI Listing
December 2016

Gastric Hamartomatous Polyps-Review and Update.

Clin Med Insights Gastroenterol 2016 7;9:3-10. Epub 2016 Apr 7.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Gastric polyps are frequently encountered on endoscopic examinations. While many of these represent true epithelial lesions, some of the polyps may result from underlying stromal or lymphoid proliferations or even heterotopic tissue. Histologic examination is essential for accurate typing of the polyps to predict malignant potential and underlying possible genetic abnormalities. The focus of this review is on gastric hamartomatous polyps, which are relatively rare and diagnostically challenging. Though most of the gastric hamartomatous polyps are benign, certain types are associated with increased malignant potential. These include certain polyps associated with specific genetic familial polyposis syndromes and gastric inverted hamartomatous polyps. Identification of these polyps can result in the prevention or early diagnosis of gastric carcinoma and also help in the identification of family members with polyposis syndromes. The aim of this review is to categorize gastric hamartomatous polyps and aid in the identification of high-risk categories.
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http://dx.doi.org/10.4137/CGast.S38452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825775PMC
April 2016

NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States.

Cancer 2016 Apr 19;122(7):1097-107. Epub 2016 Jan 19.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background: An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children.

Methods: The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing.

Results: Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAF(V) (600E)) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAF(V) (600E) PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); BRAF(V) (600E) PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1).

Conclusions: Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation.
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http://dx.doi.org/10.1002/cncr.29887DOI Listing
April 2016

Focal hepatic glycogenosis associated with metastatic insulinoma presenting as mass lesions.

Pathol Res Pract 2016 Jan 26;212(1):59-62. Epub 2015 Nov 26.

Department of Pathology, Yale University Medical School and Yale New Haven Hospital, New Haven, CT, United States.

One of the important functions of the liver is glycogen storage. Most processes associated with increased hepatic glycogen, or glycogenoses, are metabolic and affect the entire liver leading to diffuse glycogenosis. We present a case in which the liver contained multiple small pale nodules that on initial assessment were recognized to be composed of glycogenated hepatocytes. Most of the known causes of hepatic glycogenosis were not pertinent to this case. After cutting many deeper levels and obtaining additional sections, small foci of insulinoma were revealed in the center of each of these lesions. The glycogenosis surrounding the foci of insulinoma can be best explained as a local effect of insulin on the hepatocytes, a phenomenon that has been previously described in primate models, but not in human subjects. Here, we report the first case of metastatic insulinoma causing local hepatic glycogenosis.
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http://dx.doi.org/10.1016/j.prp.2015.11.006DOI Listing
January 2016

Myeloid cell nuclear differentiation antigen is expressed in a subset of marginal zone lymphomas and is useful in the differential diagnosis with follicular lymphoma.

Hum Pathol 2014 Aug 24;45(8):1730-6. Epub 2014 Apr 24.

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.

The diagnosis of marginal zone lymphomas (MZL) is challenged by the lack of specific markers that distinguish them from other low-grade non-Hodgkin B-cell lymphomas. Myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein that labels myelomonocytic cells as well as B lymphocytes that localize to the marginal zone areas of splenic white pulp. We evaluated MNDA expression in a large series of B-cell lymphomas to assess the sensitivity and specificity of this antigen for the characterization of MZL. A total of 440 tissue sections containing extramedullary B-cell lymphomas and 216 bone marrow biopsies containing atypical or neoplastic lymphoid infiltrates were stained for MNDA by immunohistochemistry. Among the extramedullary lymphoma cases, approximately 67% of nodal MZL, 61% of extranodal MZL, and 24% of splenic MZL expressed MNDA. MNDA was also infrequently expressed in other B-cell neoplasms including mantle cell lymphoma (6%), chronic lymphocytic leukemia/small lymphocytic lymphoma (13%), follicular lymphoma (FL) (4%), lymphoplasmacytic lymphoma (25%), and diffuse large B-cell lymphoma (3%). In contrast, MNDA was only expressed in 2.3% of all bone marrow biopsies involved by lymphoid infiltrates, including 2 cases of FL and one case of MZL. Collectively, these data support the inclusion of MNDA in the diagnostic evaluation of extramedullary B-cell lymphomas, particularly those in which the differential diagnosis is between low-grade FL and MZL.
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http://dx.doi.org/10.1016/j.humpath.2014.04.004DOI Listing
August 2014

Collision tumor of kidney: A case of renal cell carcinoma with metastases of prostatic adenocarcinoma.

Indian J Med Paediatr Oncol 2013 Jan;34(1):21-3

Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India.

Simultaneous occurrence of prostatic adenocarcinoma and renal cell carcinoma is well documented in the literature. However, metastatic prostatic adenocarcinoma in a kidney harboring a renal cell carcinoma (RCC) is quite rare. Although renal cell carcinoma is the most common tumor that can harbor metastasis, metastatic prostatic adenocarcinoma in a kidney harboring a RCC is quite rare. There are four cases in the literature showing metastasis of prostatic adenocarcinoma to RCC. However, as per our knowledge, this is the first case of a collision between RCC and metastatic prostatic adenocarcinoma.
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http://dx.doi.org/10.4103/0971-5851.113409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715973PMC
January 2013

Splenic angiomatoid nodular transformation in child with inflammatory pseudotumor-like areas.

Indian J Pathol Microbiol 2011 Oct-Dec;54(4):829-31

Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, India.

Reports of sclerosing angiomatoid transformation (SANT) in the pediatric age group are rare. We present a case of SANT in an 11-year-old child with a history of trauma presenting with rapidly growing splenic lesion since 2 months. A partial splenectomy revealed a well-demarcated nodular lesion 5 × 4 × 4 cm with central area of fibrosis. Most part of the lesion showed ill-defined nodules or diffuse areas of plump epithelioid appearing endothelial units that marked with CD31, but the internodular stroma was inflammatory pseudotumor (IPT)-like with a mitotic count of 1-2/10 hpf. The angiomatoid nodules were diffusely positive for CD31, CD163, and CD68; however, they were negative for CD34, CD30, smooth muscle actin, and CD8. Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) was negative. The MIB1 labeling was fairly high in the IPT area but low in the angiomatoid areas. After the diagnosis of SANT, the patient has had an uneventful follow-up for more than 3 years since surgery. The morphologic findings in the case being discussed reaffirm the finding that SANT may have an IPT component and it can be seen even in pediatric age group.
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http://dx.doi.org/10.4103/0377-4929.91543DOI Listing
April 2012

Piggyback mycosis: pulmonary hydatid cyst with a mycotic co-infection.

Mycoses 2010 May 7;53(3):265-8. Epub 2009 Mar 7.

The lungs are common sites for the occurrence of saprophytic or invasive mycosis as well as hydatid cysts. The two diseases seldom coexist, and the manifestation is seen as a fungal ball (usually aspergilloma) formed in the cavity left behind after hydatid cystectomy. Active invasion and proliferation of the fungi in the laminated ectocyst or sometimes the pericyst of the hydatid is very unusual. We report such a unique coexistence identified in two of the six surgically excised pulmonary hydatid cysts in the past 2 years. Both were immunocompetent males, who had presented with non-specific symptoms of cough, haemoptysis and chest pain. The septate slender hyphae of the invading fungus resembled those of Aspergillus.
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http://dx.doi.org/10.1111/j.1439-0507.2009.01693.xDOI Listing
May 2010