Publications by authors named "Meera Mahalingam"

125 Publications

Reforms, Errors, and Dermatopathology Malpractice: Then and Now: A Comprehensive Retrospective.

Authors:
Meera Mahalingam

Adv Anat Pathol 2021 Sep 27. Epub 2021 Sep 27.

*Department of Dermatology, Tufts University School of Medicine, Boston †Dermatopathology Section, VA Consolidated Laboratories, Department of Pathology and Laboratory Medicine, West Roxbury, MA.

Medical malpractice occurs when a hospital, doctor, or other health care professional, through a negligent act or omission, causes an injury to a patient. The negligence might be the result of errors in diagnosis, treatment, aftercare, or health management. To be considered medical malpractice under the law, the claim must violate the standard of care, the injury must be caused by the negligence and, last but most certainly not least, the injury must result in significant damages. This review is an overview of medicolegal issues specific to the practice of Dermatopathology with the caveat that most are likely pertinent to other specialties of pathology as well. The safety of patients remains the priority in pathology as it does in any medical undertaking, and this is no different in the practice of Dermatopathology. The review is broadly divided in 2 parts-we begin with an overview of tort reforms, advocated by physicians to reduce costs associated with malpractice defense. In the second part we address practical issues specific to the practice of pathology and dermatopathology. These include among others, errors-related to the biopsy type, inadequacy of clinical information regarding the lesion that is biopsied, role of interstate dermatopathology as well as examples of select entities commonly misdiagnosed in dermatopathology. In the last decade, artificial intelligence (AI) has moved to the forefront of technology. While research into the uses of AI in pathology is promising, the use of AI in diagnostic practice is still somewhat uncommon. Given that AI is not fully integrated routinely as a diagnostic adjunct, its' impact on pathology-specific medicolegal issues cannot, as yet at least, be defined. Restriction of medical malpractice is of particular relevance in the COVID-19 era, a period that is anything but normal. The response of states with specific pandemic-related guidelines is addressed with the caveat that this particular issue is only covered in select states. Furthermore, given that the COVID pandemic is only a year old, while it does not appear to have had an immediate impact on pathology-specific medicolegal matters, it is possible that the role of COVID on this issue, if any at all, will and can only be fully defined a few years down the line.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAP.0000000000000319DOI Listing
September 2021

Total Margin-Controlled Excision is Superior to Standard Excision for Keratinocyte Carcinoma on the Nose: A Veterans Affairs Nested Cohort Study.

Ann Surg Oncol 2021 Jul 19;28(7):3656-3663. Epub 2021 Mar 19.

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

Background: Keratinocyte carcinoma (KC), including basal and squamous cell carcinoma, is the most common human malignancy. Limited real-world data have compared surgical outcome or cost between total margin-controlled excision (TMCE) and standard excision (SE), the two most common treatments for invasive KC. We compared reconstruction, margin status, and cost between TMCE and SE for KC on the nose at a Veterans Affairs (VA) healthcare system.

Methods: Randomly selected primary KCs on the nose ≤3 cm that were confined to soft tissue, without nerve or lymphovascular invasion, and treated with SE or TMCE between 2000 and 2010, were assessed. Utilization of flap or graft reconstruction and margin status following all surgical attempts were recorded. Costs were based on Current Procedural Terminology codes standardized to 2019 Medicare payments.

Results: Overall, 148 cases were included in each treatment group. Baseline characteristics were similar between groups, although SE tumor median diameter was 1 mm larger. SE was associated with increased utilization of flap or graft reconstruction (odds ratio 2.05, 95% confidence interval 1.16-3.59, p = 0.01). Positive margins were present in 24% of SEs initially and remained positive after the final recorded excision in 9% of cases. No positive final margins were noted in TMCE cases. SE cost per tumor was significantly higher than TMCE ($429.03 ± 143.55; p = 0.003).

Conclusions: Surgical management of KC with SE is associated with increased reconstruction complexity, a significant risk of positive margins, and higher cost compared with TMCE. The 23% risk of positive margins supports National Comprehensive Cancer Network guidelines for the treatment of high-risk KC with TMCE, unless delayed reconstruction is employed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-09604-9DOI Listing
July 2021

Glioblastoma and malignant melanoma: Serendipitous or anticipated association?

Neuropathology 2021 Feb 25;41(1):65-71. Epub 2020 Oct 25.

Tufts University School of Medicine, Boston, Massachusetts, USA.

We describe a patient who had primary glioblastoma (GB) and malignant melanoma (MM). A 78-year-old man presented with several weeks to months of history of gait disturbance, confusion, memory disturbance, and worsening speech. Imaging studies performed on admission revealed a large frontotemporal lobe mass associated with the surrounding zone of vasogenic edema. Given the patient's medical history of incomplete biopsy of a midback tumor performed three weeks before, the presumptive clinical diagnosis was metastatic MM. Pathological examination of frozen sections of fragmented specimens obtained at stereotactic biopsy performed on admission revealed a high-grade malignant neoplasm characterized by discohesive cells in a blue myxoid background and abundant foci of tumor necrosis. Given these features, in conjunction with the abovementioned pathological report, the frozen section diagnosis by the neuropathologist was "neoplasm identified, favor melanoma." Due to the paucity of lesional tissue, a limited immunohistochemistry performed on the permanent sections revealed positive staining of lesional cells for Sox10 alone using a multiplex MART1/Sox10 immunostain and S-100 protein, an immunohistochemical profile supporting the presumptive frozen section diagnosis. A tumor debulk procedure, performed two weeks later, revealed histopathologic features most compatible with GB, IDH wild-type. Thus, additional immunohistochemistry on the permanent sections revealed positive staining of glial fibrillary acidic protein (GFAP), Sox10, and S-100 protein as well as negative staining of gp100, a complex carbohydrate matrix protein in embryonic melanosomes, using a specific antibody HMB45. The concomitant occurrence of MM and GB in our patient underscores the association between these two entities. Our literature review suggests that the sporadic co-occurrence of these two conditions is likely not serendipitous.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/neup.12702DOI Listing
February 2021

Poikilodermatous plaque-like hemangioma: A benign vasoformative entity with reproducible histopathologic and clinical features.

J Cutan Pathol 2020 Oct 30;47(10):950-953. Epub 2020 Jul 30.

Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Consolidated Laboratories, West Roxbury, Massachusetts, USA.

Poikilodermatous plaque-like hemangioma (PPLH) is a recently described benign vasoformative entity with only 16 cases reported to date. We present an additional case of a 90-year-old male who presented with a 2-year history of a relatively large, asymptomatic, atrophic plaque on his left buttock. The lesion was initially smaller and grew before stabilizing in size. The patient denied preceding trauma or injury at this site as well as the presence or history of any similar lesions elsewhere. Physical examination revealed a reniform atrophic pink plaque with peripheral hyperpigmentation and overlying cigarette paper wrinkling. Given this appearance, scar or post-inflammatory changes were favored clinically, but lack of preceding trauma raised clinical concerns for poikilodermatous mycosis fungoides. Given the location and appearance, a broad shave biopsy was performed to rule out mycosis fungoides. Histopathologic examination revealed an increased density of superficial endothelial-cell-lined vessels, telangiectasias with sludging and congestion of superficial dermal vessels and loss of elastic tissue fibers in the lesional area. These findings, in the context of the clinical history, were consistent with this newly described hemangioma. We present this case to increase awareness amongst dermatopathologists of the reproducible clinical and histopathologic findings of this new benign vasoformative entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cup.13734DOI Listing
October 2020

Adherence to the National Comprehensive Cancer Network Criteria of Complete Circumferential Peripheral and Deep Margin Assessment in Treatment of High-Risk Basal and Squamous Cell Carcinoma.

Dermatol Surg 2020 12;46(12):1473-1480

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The National Comprehensive Cancer Network (NCCN) has established guidelines for the treatment of keratinocyte carcinomas (KCs). Complete circumferential peripheral and deep margin assessment (CCPDMA) is recommended for "high-risk" tumors that cannot be closed primarily. If flap or grafts are needed and CCPDMA was not used, it is recommended that reconstruction be delayed until achieving clear margins.

Objective: To measure provider utilization rates of the NCCN guidelines for high-risk KCs and assess barriers that are limiting adherence.

Materials And Methods: A ten-item questionnaire was distributed to NCCN nonmelanoma skin cancer panel members and physicians participating in KC treatment at academic institutions.

Results: Response rate was 49% (57/116). Responses were categorized by practice area: Mohs surgery, pathology, and other specialties: General Dermatology, Otolaryngology, Plastic Surgery, Surgical Oncology, Radiation Oncology, and Oral and Maxillofacial Surgery. Mohs surgeons were most likely to use CCPDMA for tumors meeting NCCN criteria with 14/15 using this technique in a majority of their cases, versus 2/6 pathologists and 10/16 specialists from other fields. Reasons cited for not using CCPDMA included deference to pathologists to determine the appropriate method for margin assessment and logistical difficulty.

Conclusion: Further efforts are needed to increase adherence to NCCN's guidelines regarding CCPDMA in KCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DSS.0000000000002354DOI Listing
December 2020

SOX-10 and S100 Negative Desmoplastic Melanoma: Apropos a Diagnostically Challenging Case.

Am J Dermatopathol 2020 Sep;42(9):697-699

Dermatology Section, Department of Medicine, VA Boston Healthcare System, Boston, MA.

An 83-year-old man presented with a tumor of the neck, clinically consistent with an epidermal inclusion cyst. Excisional biopsy revealed a deeply infiltrating spindled cell tumor. Immunohistochemical markers for S100, SOX-10, Melan-A, HMB-45, and NK1/C3 were negative. Based on the presence of an area of lentigo maligna and the histologic pattern of the spindle cell component, a diagnosis of desmoplastic melanoma was made despite the absence of immunophenotypic evidence for melanocytic differentiation. To the best of our knowledge, the complete lack of both S100 and SOX-10 makes this tumor an unprecedented case. To avoid ruling out the diagnosis of desmoplastic melanoma prematurely, physicians should be made aware of this possible immunohistochemical profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001626DOI Listing
September 2020

Differing biologic behaviors of desmoplastic melanoma subtypes: Insights based on histopathologic, immunohistochemical, and genetic analyses.

J Am Acad Dermatol 2020 Aug 14;83(2):523-531. Epub 2020 Feb 14.

Tufts University School of Medicine, Boston, Massachusetts; Dermatopathology Section, Department of Pathology and Laboratory Medicine, Veterans Adminstration Consolidated Laboratories, West Roxbury. Electronic address:

Desmoplastic melanoma (DM) is an uncommon variant of melanoma that can be challenging to diagnose. Phenotypic variations in terms of the proportion of spindled cells and fibromucinous stroma have led to the subclassification of pure (>90% spindled cells) and mixed (<90% spindled cells admixed with epithelioid cells) histopathologic DM subtypes. This subclassification is not just semantic; several studies have underscored differences in clinical and prognostic behaviors of the subtypes. In this review, we parse the literature on DM subtypes with an emphasis on histopathologic, immunohistochemical, and genetic data to ascertain whether these factors influence and/or affect their differing biological behaviors. Demographics regarding age, location, and clinical behavior of the subtypes are detailed, as is the impact of dermoscopy as a diagnostic adjunct. Despite the plethora of markers used, our findings suggest that few differentiate between the DM subtypes. Differential expression of PD-L1 suggests that patients with the mixed subtype are likely better candidates for anti-PD/PD-L1 therapy. Significant differences between the subtypes in terms of neurofibromin expression and the frequency of TERT promoter mutations suggest that the subtypes have distinct genetic drivers. Thus, immunohistochemical and genetic analyses imply that these likely affect the biological behaviors of the DM subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.02.014DOI Listing
August 2020

Immunohistochemistry as a Genetic Surrogate in Dermatopathology: Pearls and Pitfalls.

Adv Anat Pathol 2019 Nov;26(6):390-420

Dermatopathology Section, Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA-Integrated-Service-Network-1 (VISN1), West Roxbury, MA.

Immunohistochemistry (IHC) is routinely performed in most laboratories, and other than purchase of commercially available antibodies, requires no additional equipment or reagents. As such, IHC is an accessible and relatively inexpensive test and one that can be performed quite quickly. This is in sharp contrast to genomic or mutational testing methodologies that are routinely "send out" tests as they require specialized equipment and reagents as well as individuals with expertise in the performance of the tests and analysis of the results, resulting in a prolonged turn-round-time and enhanced associated costs. However, many open questions remain in a rapidly changing therapeutic and scientific landscape with most obvious one being what exactly is the utility of "good old fashioned" IHC in the age of targeted therapy? For molecular applications, is a negative immunohistochemical result enough as a stand-alone diagnostic or predictive product? Is a positive immunohistochemical result perhaps more suitable for a role in screening for molecular alterations rather than a definitive testing modality? This review is an attempt to answer those very questions. We elucidate the broad range of entities in which IHC is currently used as a molecular surrogate and underscore pearls and pitfalls associated with each. Special attention is given to entities for which targeted therapies are currently available and to entities in which molecular data is of clinical utility as a prognosticator.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAP.0000000000000246DOI Listing
November 2019

PD-L1 Detection-Pearls and Pitfalls Associated With Current Methodologies Focusing on Entities Relevant to Dermatopathology.

Am J Dermatopathol 2019 Aug;41(8):539-565

Professor of Dermatology, Tufts University School of Medicine, Boston, MA.

PD-L1 is a transmembrane glycoprotein with an extracellular as well as an intracellular cytoplasmic domain. Physiologically, it plays a pivotal role in regulating T-cell activation and tolerance. Many tumor cells have exploited this regulatory mechanism by overexpressing PD-L1 in an effort to escape immunologic surveillance. In this review, we parse the literature regarding the prognostic value of tumoral PD-L1 expression before discussing the various methodologies as well as the pearls and pitfalls associated with each for predicting response to anti-PD-1/PD-L1 therapies. Special attention is given to cutaneous entities in which PD-L1 expression has been documented with an emphasis on cutaneous malignancies that have seen the broadest applications of anti-PD-L1/PD-1 therapies. Currently, immunohistochemistry is the method that is most commonly used for detection of PD-L1. However, with the wide array of immunohistochemistry protocols and staining platforms available in the market, there seems to be different cutoffs not just for different entities but also for the same entity. This review is an attempt to address the need for standardization and validation of existing protocols for PD-L1 detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001287DOI Listing
August 2019

Necrotizing Granulomas in a Patient With Psoriasis and Sarcoidosis After Adalimumab-Medication-Induced Reaction or Reactivation of Latent Disease?

Am J Dermatopathol 2019 Sep;41(9):661-666

Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Boston Healthcare System, MA.

In this report, we describe a case of a patient with a clinical history of systemic sarcoidosis and psoriasis who developed biopsy-confirmed perforating and necrotizing cutaneous granulomas after 12 months of treatment with adalimumab, a tumor necrosis factor-alpha-inhibiting, anti-inflammatory, biologic medication, prescribed for the patient's psoriasis. Although rare reports of a "sarcoidosis-like" reaction associated with select tumor necrosis factor-alpha agents exist, to the best of our knowledge, perforating and necrotizing cutaneous granulomas after treatment with adalimumab has not been previously reported. Given the patient's history of systemic sarcoidosis, the differential diagnosis includes reactivation of latent sarcoidosis with adalimumab as a trigger.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001394DOI Listing
September 2019

Demographics, Risk Factors, and Incidence of Melanoma in Patients in the New England VA Healthcare system.

Mil Med 2019 05;184(5-6):e408-e416

Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Integrated Service Network (VISN-1), West Roxbury, MA.

Introduction: A recent study found that the incidence of melanoma and melanoma-related mortality was decreasing in residents of the New England region. However, it is unknown whether this trend is conserved in Veterans of New England who constitute more than 14% of the national Veteran population. Given this, our goal was to analyze the incidence of melanoma in patients of Veteran Integrated Service Network-1 (VISN-1) (geographically consisting of VA health care facilities in Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont) and to calculate an incidence rate ratio (IRR) of melanoma in VISN-1 compared to the general population. Additional goals were to ascertain the risk/susceptibility of this patient population with a view to improve quality of care and outcomes.

Materials And Methods: Data for 523 cases of melanoma [2000-2011] were obtained from the regional branch of the Veterans Affairs Central Cancer Registry (VACCR) within the geographic area comprising VISN-1. A detailed retrospective chart review was conducted on these cases to gather demographic, risk factor, and clinical practice data. Demographic and incidence data from VISN-1 were compared to the general population via data from Surveillance, Epidemiology and End Results Program (SEER) from the same time period. Person-years (PY) were calculated for both populations to measure IRRs which was further standardized for age and gender.

Results: VISN-1 patients were predominantly older (94.26% >50 years), Caucasian (99.43%) males (96.75%). Compared to the general population, VISN-1 patients experienced more invasive lesions defined as stage T1 or greater (4.33% vs. 57.12%, p < 0.001), but reduced melanoma-associated mortality (40.96% vs. 19.05%, p < 0.001) although all-cause mortality was approximately doubled (52.20% vs. 26.14%, p < 0.001). Metastatic disease-rates were similar in both [approximately 4% in both]. IRR of melanoma in VISN-1 patients was 0.36 (95% CI: 0.20-0.67; p = 0.0063) which persisted in all age groups/genders. 60.92% of VISN-1 patients had recreational sun-exposure history and 72.41% of tobacco use. 95.02% of melanomas were located in continuously/intermittently sun-exposed areas, 93.28% were surgically-treated with a median treatment delay of 31 days [range 18-48]. Median lost to follow-up was 0 day [range 0-681 days].

Conclusions: Compared to the general population, melanoma incidence was lower in the VISN-1 cohort, possibly due to decreased UV index in the New England region, protective effects of past tobacco use, improved access to care through the VA and regional public health educational efforts. Yet melanomas were more often invasive in the VISN-1 cohort due to advanced age and male sex both of which are associated with more advanced disease at diagnosis. A strength of this study is the calculation of IRR using PY as this method enhances accuracy of incidence calculations. The data were limited by the fact that the population was from one geographic region and consisted mainly of elderly Caucasian males. Descriptive variable data such as sun-protective habits and risk factors from military service are limited by potential recall bias given the retrospective study design. Further study is necessary to replicate these results and to compare our data to Veteran populations from different geographic regions within the USA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/milmed/usy267DOI Listing
May 2019

Concordance of somatic mutation profiles (BRAF,NRAS, and TERT) and tumoral PD-L1 in matched primary cutaneous and metastatic melanoma samples.

Hum Pathol 2018 12 16;82:206-214. Epub 2018 Aug 16.

Dermatopathology Section, VA Integrated Systems Network (VISN1), Department of Pathology and Laboratory Medicine, West Roxbury, MA 02132, USA. Electronic address:

Despite the efficacy of BRAF-targeted and PD-L1-related immune therapies in tackling metastatic melanoma, a significant number of patients exhibit resistance. Given this, the objective of the current study was to ascertain concordance of somatic mutations in BRAF/NRAS/TERT and immunohistochemical PD-L1 and CD8 in matched primary cutaneous and metastatic melanoma. A total of 43 archival paired samples with sufficient material for genetic and immunohistochemical analyses met the criteria for inclusion in the study. Immunohistochemistry was performed for PD-L1 and CD8 and direct-DNA Sanger sequencing for BRAF/NRAS/TERT promoter mutational analyses. Agreement between paired samples was assessed using Cohen κ. Poor concordance among primary and corresponding metastases was noted in BRAF (9/42 cases discordant, κ = 0.49; 95% confidence interval [CI], 0.21-0.77; P = .0013), TERT promoter mutations (13/41 cases discordant, κ = 0.33; 95% CI, 0.04-0.62; P = .033), tumoral PD-L1 immunoexpression (9/43 cases discordant, κ = 0.39; 95% CI, 0.07-0.72; P = .0099), and immunoexpression of CD8 T lymphocytes (12/43 cases discordant, κ = 0.44; 95% CI, 0.19-0.69; P = .002). Although NRAS1 and NRAS2 were highly concordant (42/43 and 39/43 cases, respectively), discordant NRAS2 mutational status was associated with a median time to metastasis of 90 versus 455 days for pairs with concordant status (P = .07). Although limited by sample size, our findings suggest that consideration be given to mutational analysis of metastatic tissue rather than the primary to guide BRAF-targeted therapy and question the roles of TERT promoter mutations and PD-L1 as predictive biomarkers in malignant melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.08.002DOI Listing
December 2018

Laser Capture Microdissection: Insights into Methods and Applications.

Authors:
Meera Mahalingam

Methods Mol Biol 2018 ;1723:1-17

Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Medical Center, West Roxbury, MA, USA.

Laser capture microdissection is a non-molecular, minimally disruptive method to obtain cytologically and/or phenotypically defined cells or groups of cells from heterogeneous tissues. Its advantages include efficient rapid and precise procurement of cells. The potential disadvantages include time consuming, expensive, and limited by the need for a pathologist for recognition of distinct subpopulations within a specified sample. Overall it is versatile allowing the preparation of homogenous isolates of specific subpopulations of cells from which DNA/RNA or protein can be extracted for RT-PCR, quantitative PCR, next-generation sequencing, immunoblot blot analyses, and mass spectrometry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-7558-7_1DOI Listing
January 2019

Cutaneous Rosai-Dorfman Disease With Linear Lesions and Monoclonal Gammopathy.

Am J Dermatopathol 2017 Oct;39(10):776-781

*Department of Dermatology, Boston University School of Medicine, Boston, MA;†Department of Hematology and Oncology, Boston Medical Center, Boston, MA;‡Massachusetts Area Veterans Epidemiology Research and Information Center (MAVERIC), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA;§Department of Internal Medicine, Boston University School of Medicine, Boston, MA;¶Dermatology Section, Department of Internal Medicine, VA Medical Center, Boston, MA; and‖Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Medical Center, Boston, MA.

Cutaneous Rosai-Dorfman disease (CRDD), a benign histiocytosis of unknown etiology, typically presents as a solitary or clusters of lesions. Although the histopathology is fairly distinctive, the laboratory abnormalities are not; past reports note elevated erythrocyte sedimentation rate, anemia, and polyclonal hyperglobulinemia. We describe a 61-year-old African American diabetic gentleman who presented with nodules in a linear distribution on the flank. Histopathologic examination of a biopsied nodule revealed a pandermal sheet-like infiltrate of plasma cells and histiocytes, some demonstrating elastophagocytosis and emperipolesis. The lesional histiocytes were S100 and CD68 positive and CD1a negative-findings consistent with a diagnosis of CRDD. Additional laboratory work-up performed 12 weeks after the biopsy was taken revealed an elevated serum κ light chain concentration of 37.26 mg/L (reference range: 3.30-19.40 mg/L), which correlated with an M-protein spike identified as IgG κ proteins per serum protein electrophoresis. Given the difficulty in excising a large area and preexisting diabetes, a course of low-dose methotrexate was selected for therapy with a recommendation of close follow-up for the monoclonal gammopathy. To the best of our knowledge, this is the first report of CRDD associated with a linear distribution of lesions and serum protein electrophoresis-confirmed monoclonal gammopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000000875DOI Listing
October 2017

PD-L1 and immune escape: insights from melanoma and other lineage-unrelated malignancies.

Hum Pathol 2017 08 8;66:13-33. Epub 2017 Jul 8.

Dermatopathology Section, Department of Pathology and Laboratory Medicine (113), VA Integrated Systems Network (VISN1), West Roxbury, 02132, MA. Electronic address:

One of the major breakthroughs in oncology in the past decade has been the research and development of immune checkpoint inhibitors. Since the discovery of the PD-1/PD-L1 axis as a key mediator in peripheral self-tolerance and the subsequent discovery of its role promoting immune escape in cancers, the PD-1/PD-L1 pathway has produced considerable excitement from both a scientific and therapeutic standpoint. The past decade has seen an explosion in the number of clinical trials utilizing anti-PD-1/PD-L1 therapy. Notably, pathologists have played a critical role in the development of these trials, and in guiding the use of anti-PD-1/PD-L1 therapies in FDA-approved clinical settings. Analysis of tissue biopsies has been increasingly used to predict patients with which cancers are most likely to benefit from these new therapies. However, many open questions remain in a rapidly changing therapeutic and scientific landscape. In this review, we describe the basic functioning of the PD-1/PD-L1 axis in normal biology, how it is coopted by cancers to promote immune escape, and then review the literature regarding the prognostic value of tumoral PD-L1 expression on its own before discussing recent therapeutic advances, and the emerging role for pathologists in predicting response to anti-PD-1/PD-L1 therapies. Special attention is given to melanoma and non-small cell lung cancer, malignancies that have seen the broadest applications of anti-PD-L1/PD-1 therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2017.06.012DOI Listing
August 2017

An Annular Plaque on the Inner Thigh.

Am J Dermatopathol 2017 Jul;39(7):e85

*Section of Dermatopathology, Department of Dermatology, Boston University School of Medicine, Boston, MA; †Department of Pathology, B.P.Koirala Institute of Health Science, Dharan, Nepal; ‡Department of Dermatology, Boston University School of Medicine, Boston University, Boston, MA; and §Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Medical Center, Boston, MA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000000520DOI Listing
July 2017

Annular Plaque on the Inner Thigh.

Am J Dermatopathol 2017 Jul;39(7):551-552

*Section of Dermatopathology, Department of Dermatology, Boston University School of Medicine, Boston, MA; †Department of Pathology, B.P.Koirala Institute of Health Science, Dharan, Nepal; ‡Department of Dermatology, Boston University, Boston University School of Medicine Boston, MA; and §Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Medical center, Boston, MA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000000521DOI Listing
July 2017

Lack of specificity of cytokeratin-15 loss in scarring alopecias.

Authors:
Meera Mahalingam

J Am Acad Dermatol 2017 04;76(4):e135-e136

Dermatopathology Section, Veterans Affairs Medical Center (VISN1), West Roxbury, Massachusetts. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2016.11.066DOI Listing
April 2017

MSH6, Past and Present and Muir-Torre Syndrome-Connecting the Dots.

Authors:
Meera Mahalingam

Am J Dermatopathol 2017 Apr;39(4):239-249

Dermatopathology Section Chief, Dermatopathology Section, Department of Pathology and Laboratory Medicine (113), VA Consolidated Laboratories, West Roxbury, MA.

Sebaceous neoplasms such as adenoma, sebaceoma, and carcinoma, although sporadic in their occurrence, are clinically significant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous neoplasms and/or keratoacanthomas and visceral malignancies. MTS is usually the result of germline mutations in the DNA mismatch repair genes MSH2 and, albeit less commonly, MLH1. Although less know, MSH6 is yet another key player. Evidence from Lynch syndrome indicates that pathogenic germline mutations in MSH6 are typically microsatellite stable and have a clinical presentation that differs from that associated with germline mutations in MSH2 and/or MLH1. Given this unique mutator phenotype of MSH6, the primary aim of this review was to underscore the clinical manifestations associated with pathogenic mutations in MSH6 in patients with MTS. As the current clinical and laboratory work-up of MTS is geared toward patients harboring a germline mutation in MSH2 and/or MLH1, an additional aim was to provide a scaffolding for the work-up of a patient presenting with an isolated germline mutation in MSH6.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000000633DOI Listing
April 2017

Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant.

Mod Pathol 2017 03 13;30(3):357-369. Epub 2017 Jan 13.

Dermatopathology Section, Department of Pathology and Laboratory Medicine (113), VA Integrated Service Networks (VISN1), West Roxbury, MA, USA.

Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with ⩾5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness >4 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range=3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range=2.04 mm for PD-L1 negatives, P=0.0002) and was linearly associated with increasing depth of invasion (P=0.0003). PD-L1-positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P=0.0047).The presence of CD8+ lymphocytes correlated significantly with depth of invasion >1 mm (P=0.022). On multivariate analysis, PD-L1 was 6.14 × more likely to be expressed in mixed DM than pure DM (P=0.0131), CD8+ staining was 6.22 × more likely in PD-L1 positive cases than in PD-L1 negative (P=0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR=1.61, P=0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2016.210DOI Listing
March 2017

NF1 and Neurofibromin: Emerging Players in the Genetic Landscape of Desmoplastic Melanoma.

Authors:
Meera Mahalingam

Adv Anat Pathol 2017 Jan;24(1):1-14

VA Consolidated Laboratories, Department of Pathology and Laboratory Medicine, Dermatopathology Section, West Roxbury, MA.

Neurofibromatosis type I (NF1), a monogenic disorder with an autosomal dominant mode of inheritance, is caused by alterations in the NF1 gene which codes for the protein neurofibromin. Functionally, NF1 is a tumor suppressor as it is GTPase-activating protein that negatively regulates the MAPK pathway. More recently, much attention has focused on the role of NF1 and neurofibromin in melanoma as mutations in NF1 have been found to constitute 1 of the 4 distinct genomic categories of melanoma, with the other 3 comprising BRAF, NRAS, and "triple-wild-type" subtypes. In this review, we parse the literature on NF1 and neurofibromin with a view to clarifying and gaining a better understanding of their precise role/s in melanomagenesis. We begin with a historic overview, followed by details regarding structure and function and characterization of neural crest development as a model for genetic reversion in neoplasia. Melanogenesis in NF1 sets the stage for the discussion on the roles of NF1 and neurofibromin in neural crest-derived neoplasms including melanoma with particular emphasis on NF1 and neurofibromin as markers of melanocyte dedifferentiation in desmoplastic melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAP.0000000000000131DOI Listing
January 2017

BRAF and epithelial-mesenchymal transition in papillary thyroid carcinoma - challenging the roles of Snail and E-Cadherin?

Am J Transl Res 2016 15;8(11):5076-5086. Epub 2016 Nov 15.

ENT Specialists, Inc. 825 Washington St # 310, Norwood, MA 02062, UK.

Objective: In papillary thyroid carcinoma (PTC), while the role of BRAF is well established, the contribution of BRAF to epithelial-mesenchymal transition is not.

Study Design/setting: To elucidate the relationship between BRAF, surrogates of epithelial-mesenchymal transition (Snail, E-cadherin) and established histopathologic prognosticators in papillary thyroid carcinoma.

Subjects/methods: In this IRB approved cross-sectional study, 50 cases of archived annotated PTC samples were retrieved and immunohistochemically stained for Snail and E-cadherin protein. A semi-quantitative scoring system (incorporating proportion and intensity) was utilized.

Results: Snail and E-cadherin expression were noted in 44% and 84% of BRAF mutant and, in 29% and 95% of BRAFWT samples, respectively. No statistically significant correlations were noted between Snail, E-cadherin and histopathologic prognosticators. However, a trend was noted between Snail expression and tumor size <5 cm (P=0.07). Statistically significant differences between BRAF mutant and BRAFWT samples were noted in the following groups: conventional (68% vs. 5%) and tall cell (32% vs. 0%) histopathologic variants, extrathyroidal extension (32% vs. 5%), infiltrative growth pattern (80% vs. 48%), presence of desmoplasia (72% vs. 29%), psammona bodies (48% vs. 10%), and cystic change (32% vs. 5%). Among follicular variant of papillary thyroid carcinoma compared to BRAF mutant samples, BRAFWT samples were more commonly of the encapsulated variety (52% vs. 4%), and microcarcinomas (29% vs. 0%) (P<0.001 and =0.007, respectively).

Conclusion: Our findings, supporting the utility of BRAF as a putative therapeutic target in PTC, suggest that the interaction between BRAF and epithelial-mesenchymal transition in papillary thyroid carcinoma is not through induction of the Snail/E-cadherin pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126351PMC
November 2016

Ki-67, p53, and p16 expression, and G691S RET polymorphism in desmoplastic melanoma (DM): A clinicopathologic analysis of predictors of outcome.

J Am Acad Dermatol 2016 Sep;75(3):595-602

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: The prognostic role Ki-67, p53, and p16 immunostains and RET (rearranged during transfection) polymorphism in desmoplastic melanoma has not been evaluated.

Objective: We sought to identify potential prognostic markers.

Methods: We performed Ki-67, p53, and p16 immunostains on 66 desmoplastic melanomas, and sequenced RET G691 polymorphism and recurrent mutations of 17 cancer genes in 55 and 20 cases, respectively.

Results: Recurrence and metastasis were documented in 11 of 66 (17%) and 26 of 66 (39%) patients, respectively. Death was noted in 25 of 55 (45%) patients. Ki-67 expression (≥10%, 43%) correlated with male gender (P = .009), ulceration (P = .002), and Breslow depth (P = .009). p53 Expression (≥50%, 28%) correlated with male gender (P = .002) and head and neck location (P = .0228). Using Kaplan-Meier plots, Ki-67 expression (P = .0425) and mitosis (P = .00295) correlated with overall survival, whereas vascular invasion (P = .0292) correlated with disease progression. There was a significant correlation between Ki-67 and p53 expression (P = .003). RET polymorphism was present in 10 of 46 (22%) cases and inversely correlated with Breslow depth (P = .024).

Limitation: Our study is small and lacks power to perform a multivariate analysis.

Conclusion: Although Ki-67 expression correlated with overall survival, additional studies are needed to determine whether Ki-67 would be an independent prognostic marker in addition to the current routine histopathologic assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2016.04.059DOI Listing
September 2016

Frequency of telomerase reverse transcripter promoter mutations in desmoplastic melanoma subtypes: analyses of 76 cases.

Melanoma Res 2016 08;26(4):361-6

aDepartment of Pathology, Boston University of Medicine bBoston University School of Public Health and Ragon Institute of MGH, MIT and Harvard cDepartment of Pathology, Massachusetts General Hospital, Boston dMiraca Life Sciences, Newton Upper Falls eDepartment of Pathology, University of Massachusetts Medical School, Worcester fDermatopathology Section, VA Integrated Systems Network (VISN1), Department of Pathology and Laboratory Medicine, West Roxbury, Massachusetts gCarver College of Medicine, University of Iowa, Iowa City, Iowa hDepartment of Pathology and Dermatology, Icahn School of Medicine Mount Sinai, New York, New York iAurora Diagnostics GPA Laboratories, Greensboro, North Carolina, USA jDepartment of Pathology, Western General Hospital, Edinburgh, Scotland, UK.

Estimates of the frequency of telomerase reverse transcripter (TERT) mutations in desmoplastic melanoma (DM) are limited. DM is categorized into subtypes, pure and mixed, differing in prognosis, suggesting genetic heterogeneity. Given this, our aims were to determine the incidence of TERT promoter mutations in DM subtypes and to evaluate its relationship with established histopathologic prognosticators, BRAF and RETp status, and neurofibromin protein expression. Of the archival annotated samples retrieved, 76 cases of DM (48 pure and 28 mixed) fulfilled the criteria for inclusion. PCR amplification of the TERT promoter region was performed on DNA extracted from formalin-fixed paraffin-embedded tissue using primers5'-GCCGATTCGACCTCTCTCC-3' (forward) and 5'-CAGCGCTGCCTGAAACTC-3' (reverse). For each case, appropriate C>T mutations were identified on the electropherograms. Univariate analysis using χ-test was carried out to identify potential confounders; a nested case-control study of demographic, clinical, histopathological, and genetic determinants was carried out using multiple logistic regression. Significant differences in TERT promoter mutation frequencies were noted in the subtypes (mixed vs. pure; 15/28, 54% vs. 11/48, 23%, respectively, P=0.0066). After adjusting for potential confounding, multivariate analyses indicated a three-fold increase in the odds of the TERT mutation for those with the mixed subtype compared with the pure subtype (P=0.04, adjusted odds ratio =3.32). No other significant associations were noted (sex/junctional component/Breslow depth/ulceration/mitoses/host response/RETp, BRAF status, and neurofibromin protein expression). Our findings, the largest to date investigating TERT promoter mutations in DM, support the hypothesis that the subtypes have distinct genetic drivers and underscore the relevance of telomere integrity in the etiopathogenesis of the mixed variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CMR.0000000000000272DOI Listing
August 2016

BRAF and Epithelial-Mesenchymal Transition: Lessons From Papillary Thyroid Carcinoma and Primary Cutaneous Melanoma.

Adv Anat Pathol 2016 Jul;23(4):244-71

*University of Florida College of Medicine, Gainesville, FL †Department of Otolaryngology, Tufts Medical center, Boston, MA ‡Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Consolidated Laboratories, West Roxbury, MA.

The increased prevalence of BRAF mutations in thyroid carcinoma and primary cutaneous melanoma (PCM) hint that dysregulation of BRAF might contribute to the noted association between PCM and thyroid carcinoma. A recent study evaluating the rate of BRAFV600E mutations among patients who had been diagnosed with primary papillary thyroid carcinoma (PTC) and PCM showed that patients with either PCM or PTC were at an increased risk of developing the other as a second primary malignant neoplasm. Furthermore, the authors noted that samples from patients suffering from both malignancies exhibited a higher rate of incidence of the BRAFV600E mutation, compared with patients not suffering from both malignancies. These studies support the hypothesis that the pathogenesis of these 2 malignancies might share a conserved molecular pattern associated with dysregulation of the BRAF protein. One mechanism through which BRAF might contribute to PCM and thyroid carcinoma progression is through induction of epithelial-mesenchymal transition (EMT). Specifically, the Snail/E-cadherin axis has been demonstrated as a pathway dysregulated by BRAF, leading to EMT in both malignancies. Our analysis focuses on the results of these recent investigations, and through a review of select molecules relevant to EMT, looks to provide a context by which to better understand the relevance and role of stromal-parenchymal signaling and the BRAF mutation in the pathogenesis of PTC and PCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAP.0000000000000113DOI Listing
July 2016

Neurofibromin protein loss in desmoplastic melanoma subtypes: implicating NF1 allelic loss as a distinct genetic driver?

Hum Pathol 2016 07 9;53:82-90. Epub 2016 Mar 9.

Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Consolidated Laboratories, West Roxbury, MA 02132. Electronic address:

Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the proto-oncogene RET (RETp) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET, perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included χ(2) test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P=.02). In DM, significant differences in neurofibromin loss were noted in the following: non-head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp, BRAF status, or PNI. RETp was marginally associated with PNI-positive DM versus PNI-negative DM (36 versus 18%; P=.08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2016.02.012DOI Listing
July 2016

BRAF and epithelial-mesenchymal transition in primary cutaneous melanoma: a role for Snail and E-cadherin?

Hum Pathol 2016 06 1;52:19-27. Epub 2016 Feb 1.

Dermatopathology Section, VA Consolidated Laboratories, Department of Pathology and Laboratory Medicine (113), West Roxbury, MA 02132. Electronic address:

In vitro studies in melanoma indicate that up-regulation of the transcriptional repressor Snail occurs with a concomitant decrease of its target E-cadherin, both hallmarks of epithelial-mesenchymal transition-an association not established in vivo. We sought to elucidate the relationship between BRAF, Snail, E-cadherin, and established histopathologic prognosticators in primary cutaneous melanoma. Archived annotated samples with a diagnosis of primary cutaneous melanoma were retrieved (n = 68 cases; 34 BRAF mutant and 34 BRAF wild type) and immunohistochemically stained for Snail and E-cadherin protein expression. A semiquantitative scoring system was used. Multivariate logistic analysis was used to control confounders of BRAF. Snail expression was significantly associated only with ulceration (42% versus 13%; P = .02). E-cadherin expression was present in 26% of BRAF mutant and 71% of BRAF wild-type cases (P = .0003). Loss of E-cadherin expression was associated with female sex (60% versus 34%; P = .05), BRAF mutation (74% versus 29%; P = .0003), thickness greater than or equal to 1 mm (68% versus 32%; P = .004), mitosis (63% versus 25%; P = .007), and ulceration (75% versus 44%; P = .05). BRAF mutation was associated with male sex (60% versus 30%; P = .02), Breslow thickness (P = .007), thickness greater than or equal to 1 mm (68% versus 29%; P = .002), and ulceration (75% versus 42%; P = .02). Snail expression did not correlate with loss of E-cadherin expression (47% versus 53%; P = .79). After controlling for potential confounding, BRAF mutation was associated with loss of E-cadherin (adjusted odds ratio, 8.332; 95% confidence interval, 2.257-30.757; P = .0015) and Breslow thickness greater than 1 mm (adjusted odds ratio, 7.360; 95% confidence interval, 1.534-35.318; P = .0126). Our findings, indicating that mutant BRAF represses E-cadherin expression, implicating a catalytic role for BRAF in epithelial-mesenchymal transition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2015.12.030DOI Listing
June 2016

Zoledronic Acid-Induced Interface Dermatitis.

Am J Dermatopathol 2015 Dec;37(12):933-5

*Section of Dermatopathology, Department of Dermatology, Boston University School of Medicine, Boston, MA; and †Department of Dermatology, Boston University School of Medicine, Boston, MA.

Zoledronic acid (ZA) is a bisphosphonate given intravenously, most commonly for the treatment of postmenopausal osteoporosis. Increase in usage of ZA because it was FDA-approved has resulted in increasing reports of side effects. For the most part, these are systemic. Cutaneous side effects associated with ZA are infrequent and limited to 2 reports of dermatomyositis to date. In both, patients presented with clinical and laboratory stigmata of dermatomyositis soon after initiation of therapy. In this report, we describe a 62-year-old woman who presented with diffuse, erythematous scaly plaques over the right thigh after 12 hours of infusion of ZA. Histopathologic examination of a skin biopsy from the right thigh revealed patchy scale crust containing neutrophils and inspissated serum, interface change with scattered individually necrotic keratinocytes, and a mild, superficial perivascular lymphocytic infiltrate with scattered eosinophils and pigment incontinence-findings consistent with an interface dermatitis. Given that the patient had no other systemic manifestations or laboratory abnormalities, to the best of our knowledge, ours is the first report of interface dermatitis secondary to ZA with the caveat that longer follow-up is required to definitively exclude the development of drug-induced connective tissue disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000000341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894795PMC
December 2015

Mycosis Fungoides, Then and Now… Have We Travelled?

Adv Anat Pathol 2015 Nov;22(6):376-83

*Department of Pathology and Laboratory Medicine, VA Medical Center, West Roxbury, MA †Department of Pathology, Rush Medical College of Rush University, Chicago, IL.

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma, accounting for almost 50% of all primary cutaneous lymphomas. When initially described, it was believed to be a distinct clinical entity with a pathognomonic histopathologic picture. Through the years we have come to know that, like syphilis, MF is a great masquerader and can present clinically and histopathologically in many ways. This review is an attempt to cover the many faces of MF that have evolved through the years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAP.0000000000000092DOI Listing
November 2015

The HGF-cMET signaling pathway in conferring stromal-induced BRAF-inhibitor resistance in melanoma.

Melanoma Res 2015 Dec;25(6):470-8

aDermatology Section, Dartmouth-Hitchcock Medical Center, Lebanon bDartmouth College, Hanover, NH cDepartment of Pathology and Laboratory Medicine, VA Medical Center, West Roxbury, MA, USA.

Genetic heterogeneity in melanoma is well established. Given this, as well as the complexity of mechanisms involved in cancer in vivo, a more complete understanding of the development of resistance requires a closer look at the tumor ecosystem, including the microenvironment. Echoing this more comprehensive approach, a number of recent studies on BRAF-inhibitor resistance have brought our attention back to the tumor microenvironment, particularly through a focus on HGF-cMET signaling - a known means of stromal-parenchymal communication. Our review focuses on the results of these recent investigations, and through a review of relevant HGF-cMET past literature looks to provide a context by which to better understand the role of stromal-parenchymal signaling in BRAF resistance/melanoma progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CMR.0000000000000194DOI Listing
December 2015
-->