Meera Mahalingam

Boston University, Boston, Massachusetts, United States

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Publications (106)322.03 Total impact

  • Sowmya Varada, Meera Mahalingam
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    ABSTRACT: Despite the efficacy and success of targeted therapies, a significant number of patients with melanoma exhibit either intrinsic or acquired resistance to these drugs. Numerous mechanisms for the development of resistance have been postulated, but the precise reason for this is not known. In this review, we examine the incidence of mutations in select genes (BRAF, NRAS, C-KIT, and GNAQ) known to occur in melanoma, specifically in primary tumors and their paired metastases, to understand the significance of intratumoral heterogeneity by assessing how changes in mutation status alters the process of metastatic spread. Our data revealed a small yet consistent degree of discordance of mutations in the MAPK pathway commonly occurring in melanoma indicating that failed targeted therapy may be a consequence of this.
    Histology and histopathology 01/2015; · 2.24 Impact Factor
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    ABSTRACT: The relationship between microvessel density (MVD), lymphovascular density (LVD), and lymphovascular invasion (LVI) in primary cutaneous melanoma (PCM) remains unclear. Given this, a total of 102 PCMs were assessed for MVD (vascular endothelial growth factor receptor 2 and Endocan), LVD (D2-40), and LVI (immunostaining with D2-40/S-100 and hematoxylin and eosin); tumoral S-100A13, vascular endothelial growth factor receptor 2, and Endocan; and BRAF status. LVD was associated with MVD (P = .01). MVD was higher in PCMs with depth greater than or equal to 2 mm and ulceration (P = .04, .05), whereas LVD was higher in PCMs with depth greater than or equal to 2 mm and mitoses (P = .03, .02). After adjusting for MVD and LVD, only ulceration was associated with LVI (P < .02). A BRAF mutation was seen in 30.4% cases, and when present, both LVD and host response (P = .0008 and .04, respectively) were significantly associated with MVD. Immunostaining with S-100A13 was noted in 99% of cases and a significant association noted only with ulceration (P = .05). Immunostaining increased LVI positivity (46.5% versus 4.9% by hematoxylin and eosin, P < .0001). MVD and LVD are not associated with LVI, appear to be closely related with each other, and are associated with select markers of poor prognosticative value. The association between a host response and LVD and MVD in PCMs with a BRAF mutation suggests that they exhibit potential for strategizing immunotherapies. Copyright © 2014 Elsevier Inc. All rights reserved.
    Human pathology 11/2014; · 2.81 Impact Factor
  • Phyu P Aung, Meera Mahalingam
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    ABSTRACT: : The progressive calcification and fragmentation of elastic fibers, primarily affecting the skin, are histopathologic features typically associated with pseudoxanthoma elasticum (PXE), pseudo-pseudo PXE, or even acquired PXE. We present a case of a 65-year-old woman, with a known history of breast carcinoma, status after wide excision (T1N0Mx) in 2010, who presented with a 0.6 × 0.5-cm, nontender pink nodule in the right inferior axilla of 1 week duration on the same side as her mastectomy. Histopathologically, the lesion revealed a circumscribed, nonencapsulated bland dermal tumor with poroid and clear cells and foci of ductal differentiation-features diagnostic for hidradenoma. Of note, immediately adjacent to the hidradenoma, the specimen also exhibited short, frayed elastic tissue fibers (positive for EVG and Von Kossa stains)-features reminiscent of PXE. With this case, we expand the spectrum of reaction patterns observed in the skin to include a PXE-like change, a reaction pattern that, to the best of our knowledge, has not been previously reported in association with a benign cutaneous tumor.
    The American Journal of dermatopathology. 10/2014;
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    ABSTRACT: Dysregulation of the CXCR4/CXCL12 axis, relevant in melanoma progression, activates cell cycle progression and migration via stimulation of the MAPK-pathway. We sought to ascertain the cooperativity of the CXCR4/CXCL12 axis with established prognosticators and BRAF status in melanoma. Samples (n=107) of primary cutaneous melanoma were assessed for protein expression of CXCR4 and CXCL12 and molecular analyses were performed to ascertain BRAF status. Univariate analyses of CXCR4 protein showed that the proportion of CXCR4 positives was greater in melanomas with absence of mitoses (p<0.0001), absence of ulceration (p=0.0008) and absence of regression (p=0.02). Patients presenting at shallower stages (AJCC 1-2) exhibited a larger proportion of CXCR4 positives (76.9%, p<0.0001 and 69.0%, p=0.008), while those at deeper stages (AJCC 3-4) exhibited a larger proportion of negatives (75.0%, p=0.004 and 66.7%, p=0.22). In a multivariable analysis, lower odds of CXCR4 protein expression were associated with AJCC stage-3 (OR=0.16, p=0.01), stage-4 (OR=0.17, p=0.04), and mitoses (OR=0.21, p=0.01). Univariate analyses of CXCL12 protein showed that the proportion of CXCL12 negatives was significantly smaller in melanomas with: depth ≥1 mm, absence of ulceration and absence of vascular invasion (p<0.0001 for all). CXCR4 and CXCL12 appear to be biomarkers associated with established prognosticators of good and poor clinical outcome respectively in primary cutaneous melanoma. A BRAF mutation does not appear to be associated with CXCR4/CXCL12 axis upregulation in primary cutaneous melanoma.
    Human pathology 10/2014; · 2.81 Impact Factor
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    ABSTRACT: Dysregulation of the chemokine receptor CXCR4 is relevant in melanoma progression, and the CXCR4/CXCL12 axis has been shown to activate cell cycle progression and malignant cell migration through stimulation of the mitogen-activated protein kinase pathway. Studies ascertaining the potential utility of CXCR4 mRNA as a prognosticator in melanoma have focused mainly on metastatic melanoma with conflicting results. In the light of this, we sought to explore the potential relationship between CXCR4 mRNA expression with established histopathologic prognosticators and BRAF status in melanoma. Archived consecutive samples (n=107) of primary cutaneous melanoma were retrieved and assessed for the following: CXCR4 mRNA (semiquantitative RT-PCR) and BRAF exon 15 status (DNA Sanger sequencing). Statistical analyses included correlation between CXCR4 mRNA levels and established histopathologic prognosticators as well as the BRAF status using univariate and multiple linear methods. Multivariable analyses revealed a significant correlation between elevated CXCR4 mRNA (low ΔCt value) and the presence of BRAF mutation (P=0.02). Absence of a brisk host response was associated with elevated CXCR4 mRNA expression (P=0.04). CXCR4 mRNA was significantly lower in AJCC stage 2 compared with stage 1 after controlling for significant clinical prognosticators (P=0.02). The association between elevated CXCR4 mRNA and absence of a brisk host response suggests that CXCR4 may be involved in regulation of the host immune response in melanoma and is a molecule of potential utility as a biomarker for recruiting melanoma patients for immunotherapy. Higher CXCR4 mRNA in patients with a BRAF mutation suggests its utility as a putative therapeutic target.
    Melanoma Research 09/2014; · 2.10 Impact Factor
  • Journal of the American Academy of Dermatology 09/2014; 71(3):586. · 5.00 Impact Factor
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    ABSTRACT: Huntington interacting protein 1 (HIP1), an antiapoptotic protein normally expressed in the brain, is highly expressed in Merkel cell carcinomas (MCCs). Given this, the aim of the current study was to ascertain the value of HIP1 as a histopathologic adjunct in the diagnosis of MCC.
    International journal of dermatology 07/2014; · 1.23 Impact Factor
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    ABSTRACT: : The authors describe a patient with a lesion on the right forearm. Her past medical history was significant for ulcerative colitis (UC, status post-colectomy six months prior). Eleven months earlier, she was diagnosed with myelodysplastic syndrome (MDS), a finding confirmed by bone marrow biopsy showing refractory anemia with excess blasts. The forearm lesion was biopsied. Within 2 weeks, the lesions spread to involve both arms. A month later, another lesion on the left elbow was biopsied. Histopathologic findings of both the biopsies revealed similar findings of multiple, superficial and deep, noncaseating granulomas. Including our case, the total number of reported cases of noninterstitial granulomatous dermatitis in a setting of MDS with impending leukemic transformation totals two. In contrast to the other, a confounding variable in ours was the history of UC. However, the development of the lesions after colectomy argued against them being a manifestation of UC. The authors present this case to increase awareness of the noninterstitial granulomatous dermatitis granulomatous reaction pattern as a possible histopathologic clue to the preleukemic state in a patient with MDS.
    American Journal of Dermatopathology 07/2014; 36(7):e117-20. · 1.43 Impact Factor
  • B Mitchell, M Mahalingam
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    ABSTRACT: The highly metastatic and variable behavior of melanoma has accentuated the need for early detection and targeted therapy. Putative targets identified include those belonging to the extensive network of chemokines and their receptors. One such target is the chemokine receptor CXCR4, a G protein-coupled receptor with a 34 amino acid extracellular N-terminus, the primary ligand of which is CXCL12 (SDF-1, stromal derived factor-1). The ligand uniquely utilizes the N-terminus of CXCR4 for signal transduction and stimulates the protein kinase B (AKT)/mitogen activated protein kinase (MAPK) pathway. Functionally, the CXCR4/CXCL12 axis is believed to play a key role in cell migration and proliferation. Upregulation of CXCR4 and consequently dysregulation of the CXCR4/CXCL12 axis has been implicated in the progression of several lineage-unrelated malignancies including melanoma. The contributions of the CXCR4/CXCL12 axis in melanomagenesis are well documented. More recently, the potential cooperativity between the mutational status of BRAF and the CXCR4/CXCL12 axis has been shown, lending credence to the concept that both CXCR4 and CXCL12 may be putative targets for therapy in melanoma. In this review, we summarize the role of the CXCR4/CXCL12 axis in cancer progression and metastasis, with an emphasis on cutaneous malignancy, melanoma in particular. Furthermore, we discuss the effects of CXCL12 on CXCR4 expressing malignant cells in vitro and the potential prognostic utility of both CXCR4 and CXCL12 expressions. Lastly, we highlight the therapeutic potential of targeting this axis and the unique response of CXCR4 expression to anti-cancer treatments with an emphasis on melanoma.
    Histology and histopathology 05/2014; · 2.24 Impact Factor
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    ABSTRACT: The histopathologic distinction between primary adnexal carcinomas and metastatic adenocarcinoma to the skin from sites such as the breast, lung, and others often presents a diagnostic dilemma. Current markers of diagnostic utility include p63 and cytokeratin 5/6; however, their expression has been demonstrated in 11%-22% and 27% of cutaneous metastases, respectively. Furthermore, the immunoreactivity of p40 and GATA3 in various cutaneous adnexal carcinomas has not been previously reported. In the present study, we compared the expression of p40, p63, cytokeratin 5/6, and GATA3 in a total of 143 cases, including 67 primary adnexal carcinomas and 76 cutaneous metastases. p40, p63, cytokeratin 5/6, and GATA3 expression was observed in 80%, 84%, 86% and 47% of primary adnexal carcinoma, respectively; and in 8%, 17%, 26% and 40% of cutaneous metastases, respectively. Chi-square analysis revealed statistically significant p-values (<0.0001) for p40, p63, and cytokeratin 5/6 in distinguishing primary adnexal carcinoma from cutaneous metastases. In summary, while p63 and cytokeratin 5/6 have similar sensitivity (84% and 86%, respectively) in detecting primary adnexal carcinomas, p40 appeared to be the most specific marker (92%) with the best positive predictive value (90%). Since breast and lung are the most common sites of origin for cutaneous metastases, p40 is the best distinguishing marker in these settings. None of the four studied markers (p40, p63, cytokeratin 5/6, and GATA3) are helpful in distinguishing between primary adnexal carcinomas from cutaneous metastases of salivary gland or bladder malignancies.
    Human pathology 05/2014; · 2.81 Impact Factor
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    ABSTRACT: Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI:
    eLife Sciences 02/2014; 3:e01460. · 8.52 Impact Factor
  • Hye Jin Chung, Meera Mahalingam
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    ABSTRACT: Angiogenesis, defined as new vessel growth from a pre-existing vessel, has been shown to be crucial for tumor survival and growth in several lineage-unrelated malignancies including melanoma. The concept of vasculogenic mimicry, a highly patterned microcirculation independent of angiogenesis, has also been described in melanoma. The prognostic value of vascular invasion, characterized by the presence of tumor cells within vascular channels, in melanoma remains controversial as in the current American Joint Committee on Cancer-staging system for melanoma vascular invasion is not included for microscopic staging purposes. This review summarizes contemporary understanding of these three processes i.e. angiogenesis, vasculogenic mimicry, and vascular invasion in an effort to uncover putative targets as therapeutic strategies in melanoma.
    Expert Review of Anti-infective Therapy 02/2014; · 3.06 Impact Factor
  • Meera Mahalingam
    Expert Review of Dermatology 01/2014; 8(6).
  • Meenakshi Batrani, Meera Mahalingam
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    ABSTRACT: The majority of cutaneous human papillomaviruses (HPVs) belong to the α, β and γ genera. High-risk mucosal HPVs belonging to α-papillomaviruses are strongly implicated in squamous cell carcinoma of the cervix, prompting many to speculate about the oncogenic potential of β-papillomavirus in cutaneous squamous cell carcinoma. In this review, evidence favoring, as well as disputing, the putative role of HPV in cutaneous squamous cell carcinoma is presented. Specific questions pertaining to HPV and cutaneous squamous cell carcinoma that this review attempts to answer include the following: is the presence of HPV the cause of the cutaneous squamous cell carcinoma or an epiphenomenon?; is HPV involved in the initiation or promotion of squamous cell carcinoma?; and last, but not least, what really is the oncogenic potential of β-papillomavirus?
    Expert Review of Dermatology 01/2014; 7(2).
  • Stephanie D Gan, Meera Mahalingam, Daniel D Miller
    JAMA dermatology. 12/2013;
  • Journal of the American Academy of Dermatology 12/2013; 69(6):e310-2. · 5.00 Impact Factor
  • Phyu P Aung, Leomar Y Ballester, Meera Mahalingam
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    ABSTRACT: Background/Aims. Given the defining histopathologic architecture of keratoacanthoma (KA), the aim of this study was to measure the crateriform orifice ("orificial size") in histopathologically crateriform lesions to ascertain its utility as an objective diagnostic histopathologic adjunct. Methods. This cross-sectional, retrospective study included 97 cases with a histopathologic diagnosis of KA. We measured the "orificial size" using the ocular micrometer in a BH-2 Olympus microscope at 4× magnification, in a blinded manner with respect to information. Frequency of histopathologic features observed was also recorded. Results. The average orificial size for different groups was as follows: 2.3 ± 0.2 mm for cases with a clinical presentation of KA/keratotic papule (KP) (n = 30) versus 2.9 ± 0.3 mm for other (n = 67), P = .18. Histopathologic findings in the 2 groups were as follows: crateriform architecture/epithelial lip and sharp demarcation of tumor from stroma (100% in both groups), fibrosis (29/30 vs 64/67), apoptotic keratinocytes (27/30 vs 56/67), dermal islands of "glassy" keratinocytes (26/30 vs 54/67), entrapped elastic fibers (26/30 vs 49/67), and neutrophilic abscesses (11/30 vs 21/670 [P = not significant for all]. Conclusion. Our findings indicate that, in the appropriate clinical setting, a smaller orificial size, although predictive of a KA, in itself is not sufficient for a definitive diagnosis. Given that a major limitation is that this is a function of age of the lesion as orificial size depends on the evolution stage of the neoplasm with the largest diameter often evident in lesions at early stages of regression, for now correlation with histopathologic features such as presence of an epithelial lip, sharp demarcation of tumor from stroma, and fibrosis (present in >95% of cases of KAs) is required.
    International Journal of Surgical Pathology 11/2013; · 0.96 Impact Factor
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    ABSTRACT: Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.Oncogene advance online publication, 21 October 2013; doi:10.1038/onc.2013.409.
    Oncogene 10/2013; · 8.56 Impact Factor
  • Dan C Filitis, Meera Mahalingam
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    ABSTRACT: The treatment of malignant melanoma with inhibitors targeting the BRAF V600E mutation has demonstrated dramatic clinical and radiographic response with improved progression-free and overall survival in the majority of patients receiving treatment. However, cutaneous adverse effects-from proliferative processes to more classic drug side effects-are increasingly being reported in patients on BRAF inhibitors. In this comprehensive literature review we provide (1) an all-inclusive list of cutaneous adverse effects associated with selective class I RAF inhibitors, (2) specific adverse effects associated with each inhibitor, and (3) the therapeutic time interval associated with the onset of all reported lesion types. Twenty-two studies reporting cutaneous adverse reactions with selective class I RAF inhibitor therapy were retrieved from PubMed and sourced from relevant articles referenced by other papers. We identified over 45 differently described lesion types, corresponding to close to 2,000 cases. The most commonly reported lesion types in order of decreasing frequency include inflammatory dermatoses, benign lesions, malignant lesions, and hair/nail-related abnormalities. For the most part, the terminologies used in the original studies were retained. Case totals and time-to-lesion onset are presented for every group, and where available, for individual lesion types, by associated BRAF inhibitor.
    American Journal of Clinical Dermatology 09/2013; · 2.52 Impact Factor
  • A Halawi, O Abbas, M Mahalingam
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    ABSTRACT: The structurally related, low-molecular weight S100 proteins constitute a family of proteins that possess a common basic structure allowing them to carry out a range of intracellular and extracellular functions. Unifying intracellular functions relate to regulation of proliferation, energy metabolism, calcium homeostasis, enzyme activities, cell growth and differentiation. Extracellular tasks, however, appear somewhat specific to select S100 members and include participation in innate and adaptive immune responses, tissue development and repair, and/or cell migration and chemotaxis. This review is an attempt to comprehensively summarize the function and expression of S100 proteins selectively expressed in normal skin and/or involved in diseased skin.
    Journal of the European Academy of Dermatology and Venereology 08/2013; · 2.69 Impact Factor

Publication Stats

994 Citations
322.03 Total Impact Points


  • 2009–2014
    • Boston University
      • Department of Dermatology
      Boston, Massachusetts, United States
  • 2008–2014
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 2001–2014
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2012–2013
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2009–2013
    • American University of Beirut
      • Department of Dermatology
      Beirut, Mohafazat Beyrouth, Lebanon
  • 2011
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2007–2009
    • University of Massachusetts Medical School
      • • Department of Pathology
      • • Department of Medicine
      Worcester, MA, United States
  • 2001–2006
    • Quest Diagnostics Incorporated
      Madison, New Jersey, United States