Publications by authors named "Priyadharsini Nagarajan"

106 Publications

Mucosal Melanomas of the Anogenital Tract: Clinical and Pathologic Predictors of Patient Survival.

Surg Pathol Clin 2021 Jun 28;14(2):225-235. Epub 2021 Apr 28.

Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, B3-4621, Unit 85, Houston, TX 77030, USA. Electronic address:

Primary anogenital mucosal melanomas (AGMs) are rare aggressive malignancies that are typically diagnosed at an advanced stage. Ulceration is a common feature in AGMs and may not correlate with outcome. Therefore, staging of AGMs similar to primary cutaneous melanomas, based on tumor thickness and ulceration, may not robustly predict outcome. Derivation of site-specific staging systems is essential for prognostication and optimal management of these patients. To this end, recent retrospective studies have revealed tumor thickness (TT) and mitotic rate (MR) as features of most prognostic significance as follows: in anorectal (TT only) and vulvar (TT and MR) melanomas.
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http://dx.doi.org/10.1016/j.path.2021.01.003DOI Listing
June 2021

Immunotherapy combined with high- and low-dose radiation to all sites leads to complete clearance of disease in a patient with metastatic vaginal melanoma.

Gynecol Oncol 2021 Jun 29;161(3):645-652. Epub 2021 Mar 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

A 73-year-old woman with metastatic vaginal mucosal melanoma that had progressed on ipilimumab and nivolumab experienced clinical and radiographic complete response to dual checkpoint inhibitor immunotherapy given in combination with high-dose plus low-dose radiation. General characteristics and treatment options in this disease are highlighted.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.017DOI Listing
June 2021

Metaplasia mimicking malignancy: A challenging case of florid eccrine squamous syringometaplasia.

J Cutan Pathol 2021 Jul 1;48(7):995-998. Epub 2021 Apr 1.

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

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http://dx.doi.org/10.1111/cup.14015DOI Listing
July 2021

Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Virchows Arch 2021 Feb 18. Epub 2021 Feb 18.

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

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.
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http://dx.doi.org/10.1007/s00428-021-03056-yDOI Listing
February 2021

Discordance in Diagnosis of Melanocytic Lesions and Its Impact on Clinical Management.

Arch Pathol Lab Med 2021 Feb 12. Epub 2021 Feb 12.

From the Departments of Pathology (Ronen, Al-Rohil, Keiser, Jour, Nagarajan, Tetzlaff, Curry, Ivan, Middleton, Torres-Cabala, Aung, Prieto).

Context.—: Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management.

Objective.—: To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management.

Design.—: We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not.

Results.—: A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients.

Conclusions.—: Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified; thus, resulting in critical changes in recommendations for clinical management.
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http://dx.doi.org/10.5858/arpa.2020-0620-OADOI Listing
February 2021

Cytotoxic and targeted systemic therapy in patients with advanced cutaneous squamous cell carcinoma in the head and neck.

Head Neck 2021 May 1;43(5):1592-1603. Epub 2021 Feb 1.

Division of Surgery, Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

Background: The outcomes of patients treated with cytotoxic or targeted systemic therapy is not well defined for cutaneous squamous cell carcinoma of the head and neck (cSCCHN).

Methods: Patients with cSCCHN treated with cytotoxic or targeted systemic therapy were included. Patients were divided into two groups based on the presence of distant metastasis (M1 vs. M0) at presentation. A proportional hazards model was used to assess for independent predictors of overall survival.

Results: Of 129 patients with cSCCHN, 20 (16%) were M1 and 109 (84%) were M0. Independent predictors of improved survival were M0 status, treatment of locally advanced disease with radiotherapy, and lower Eastern Cooperative Oncology Group (ECOG) score.

Conclusions: Survival was worse in M1 patients treated with cytotoxic or targeted systemic therapy and poor baseline performance status but improved in those receiving radiotherapy. These data can serve as historical controls for future systemic therapy trials, including immunotherapy.
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http://dx.doi.org/10.1002/hed.26626DOI Listing
May 2021

Tertiary lymphoid structures with overlapping histopathologic features of cutaneous marginal zone lymphoma during neoadjuvant cemiplimab therapy are associated with antitumor response.

J Cutan Pathol 2021 May 13;48(5):674-679. Epub 2021 Jan 13.

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

The development of immune checkpoint inhibitor (ICI) therapy with anti-CTLA-4 and anti-PD-1/L1 monoclonal antibodies has led to a paradigm shift in cancer therapy. ICI neoadjuvant therapy followed by surgery has become the standard of care for several advanced-stage cancers. The pathology associated with ICI therapy is vast and includes neoadjuvant-associated tissue reactions and activation of tertiary lymphoid structures (TLSs) at the site of the tumor bed and off-target immune-related adverse events. TLSs are thought to recapitulate lymph node function and may act as localized immune machinery to mount an antitumor response. B-cell activation in TLSs during neoadjuvant ICI therapy has been correlated with antitumor response. We report a patient with a history of sarcomatoid squamous cell carcinoma treated with neoadjuvant ICI cemiplimab who developed clonal expansion of B-cells in the TLSs of the tumor bed. The TLSs morphologically mimicked a cutaneous marginal zone lymphoma with plasmacytic differentiation. Awareness of clonal expansion of B-cells in TLSs during neoadjuvant ICI therapy is critical to recognize a response to ICI therapy and to avoiding an incorrect diagnosis of low-grade B-cell lymphoma.
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http://dx.doi.org/10.1111/cup.13953DOI Listing
May 2021

Integrating depth of invasion in T classification improves the prognostic performance of the American Joint Committee on Cancer primary tumor staging system for cutaneous squamous cell carcinoma of the head and neck.

Eur J Cancer 2021 Feb 22;144:169-177. Epub 2020 Dec 22.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: The last revision of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual included a specific system for cutaneous squamous cell carcinoma (CSCC) of the head and neck. Here, we assessed the prognostic performance of six candidate modified T-classification models in head and neck CSCC patients.

Methods: Analysis of 916 patients with head and neck CSCC given treatment with curative intent at The University of Texas MD Anderson Cancer Center between 1995 and 2019 was performed. The main outcome was disease-specific survival (DSS), and the impact of depth of invasion (DOI) was analyzed using multivariable regression models. Candidate models were developed using the optimal DOI cut points for each AJCC T classification based on goodness of fit of the model and the simplicity of the model. Staging systems were compared using Harrell's concordance index.

Results: Median age was 70 years (range, 19-97years) and median follow-up time of 22 months (range, 1-250months). The median DOI was 6.0 mm (range, 0.1-70.0 mm). The five-year DSS rate was 80.7% (95%CI, 77.4-83.7%). We found significant association between DOI (hazard ratio, 1.21 [95%CI: 1.01-1.43]) and DSS on multivariable analysis. Based on a low Akaike information criterion score, improvement in the concordance index, and Kaplan-Meier curves, model 6 surpassed the AJCC staging system.

Conclusions: Incorporation of DOI in the current AJCC staging system improves discrimination of T classifications in head and neck CSCC patients.

Lay Summary: The current staging system for head and neck cutaneous squamous cell carcinoma demonstrates wide prognostic variability and provides suboptimal risk stratification. Incorporation of depth of invasion in the T-classification system improves risk prediction and patient counseling.

Precis: We propose improved head and neck cutaneous squamous cell carcinoma T staging that will include depth of invasion and should be considered in future versions of the American Joint Committee on Cancer after external validation.
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http://dx.doi.org/10.1016/j.ejca.2020.11.019DOI Listing
February 2021

Inclusion of extranodal extension in the lymph node classification of cutaneous squamous cell carcinoma of the head and neck.

Cancer 2021 Apr 15;127(8):1238-1245. Epub 2020 Dec 15.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC.

Methods: This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models.

Results: No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195).

Conclusions: The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.
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http://dx.doi.org/10.1002/cncr.33373DOI Listing
April 2021

Prognostic Significance of Subungual Anatomic Site in Acral Lentiginous Melanoma.

Arch Pathol Lab Med 2020 Dec 8. Epub 2020 Dec 8.

From the Department of Pathology (Mejbel, Torres-Cabala, Ivan, Nagarajan, Curry, Prieto, Aung), The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Acral lentiginous melanoma is a rare and aggressive type of cutaneous melanoma that arises on the acral skin and the nail unit. The prognostic significance of subungual anatomic site in acral lentiginous melanoma is not established.

Objective.—: To assess the impact of subungual anatomic site on overall survival and disease-specific survival in acral lentiginous melanoma.

Design.—: Retrospective cohort analysis. Clinicopathologic characteristics of 627 primary acral lentiginous melanomas (45 [7%] subungual and 582 [93%] nonsubungual) were summarized, and the impact of these characteristics on overall survival and disease-specific survival was determined using univariate and multivariable analyses.

Results.—: No significant differences in clinicopathologic features were identified between the subungual and nonsubungual acral lentiginous melanomas. The 1-, 5-, and 10-year overall survival rates were 81%, 40%, and 28%, respectively, for subungual acral lentiginous melanoma and 94%, 59%, and 38%, respectively, for nonsubungual acral lentiginous melanoma (P = .04); risk of death was significantly higher for subungual tumors (hazard ratio [95% confidence interval] = 1.59 [1.02-2.50]; P = .04). The 1-, 5-, and 10-year disease-specific survival rates were 94%, 56%, and 48%, respectively, for subungual acral lentiginous melanoma versus 96%, 69%, and 55%, respectively, for nonsubungual acral lentiginous melanoma (P = .18). By multivariable analysis, independent poor prognostic factors included older age and ulceration for overall survival and greater Breslow thickness and sentinel lymph node positivity for overall survival and disease-specific survival. Subungual anatomic site was not an independent prognostic factor for overall or disease-specific survival.

Conclusions.—: Subungual anatomic site is not an independent prognostic factor for acral lentiginous melanoma.
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http://dx.doi.org/10.5858/arpa.2020-0308-OADOI Listing
December 2020

Male Mammary Paget Disease: A Tale of 2 Contrasting Cases.

Am J Dermatopathol 2020 Dec;42(12):981-985

Departments of Pathology.

Mammary Paget disease (MPD) comprises 1.45% all male breast cancers, compared with only 0.68% of all female breast cancers. Patients usually present in the fifth and sixth decades of life with ulceration, eczematous changes, discharge, bleeding, itching, and induration of the nipple and areola. Typically, there is a delay in definitive diagnosis and treatment from the onset of symptoms because most patients are initially treated for a rash. At the time of diagnosis, about half of the patients may have palpable breast mass, positive lymph nodes, or both. In this article, we present 2 cases of male MPD representing the extremes of clinical, radiologic, and histopathologic spectrum of the disease. One patient presented with a rash of the nipple of several months duration without an underlying lesion, whereas the other presented with sensitivity and pain of the nipple for 1 year and an underlying mass. Biopsies were diagnostic of MPD in both cases, and definitive surgery revealed an underlying ductal carcinoma in situ in the first case and an invasive ductal carcinoma in the second, highlighting the importance of early biopsy to initiate appropriate management.
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http://dx.doi.org/10.1097/DAD.0000000000001799DOI Listing
December 2020

Distant cutaneous metastasis of malignant epithelioid mesothelioma.

J Cutan Pathol 2021 Jul 14;48(7):902-907. Epub 2020 Dec 14.

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

Malignant mesothelioma is a locally aggressive malignancy most commonly arising from the pleural and/or peritoneal cavity. Distant cutaneous metastasis is extremely rare. Here, we describe two cases of mesothelioma metastatic to the head and neck skin. Case 1: A 64-year-old man diagnosed previously with extensive thoracic and abdominal mesothelioma, developed a rapidly growing right upper lip lesion, for which a wedge resection was performed. Case 2: A 77-year-old woman with a history of pleural mesothelioma developed a firm, mobile subcutaneous nodule on the right lateral forehead, clinically thought to represent either an epidermal inclusion cyst or a lipoma. A punch biopsy was performed. In both cases, histopathologic evaluation revealed dermal proliferation of epithelioid cells with moderate cytologic atypia and three mitotic figures per mm and two mitotic figures per mm for Cases 1 and 2, respectively. Immunohistochemical studies revealed the lesional cells to be positive for WT1, mesothelin, D2-40, CK5/6, while being negative for melanocytic and other keratinocytic markers, supporting a diagnosis of metastatic mesothelioma. Awareness of rare instances of cutaneous metastases from malignant mesothelioma is necessary to avoid possible misdiagnosis and ensure appropriate management.
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http://dx.doi.org/10.1111/cup.13927DOI Listing
July 2021

Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer.

Exp Dermatol 2021 Apr 11;30(4):529-545. Epub 2020 Dec 11.

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

The epidermis and skin appendages are maintained by their resident epithelial stem cells, which undergo long-term self-renewal and multilineage differentiation. Upon injury, stem cells are activated to mediate re-epithelialization and restore tissue function. During this process, they often mount lineage plasticity and expand their fates in response to damage signals. Stem cell function is tightly controlled by transcription machineries and signalling transductions, many of which derail in degenerative, inflammatory and malignant dermatologic diseases. Here, by describing both well-characterized and newly emerged pathways, we discuss the transcriptional and signalling mechanisms governing skin epithelial homeostasis, wound repair and squamous cancer. Throughout, we highlight common themes underscoring epithelial stem cell plasticity and tissue-level crosstalk in the context of skin physiology and pathology.
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http://dx.doi.org/10.1111/exd.14247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016706PMC
April 2021

Telomerase Reverse Transcriptase Protein Expression Is More Frequent in Acral Lentiginous Melanoma Than in Other Types of Cutaneous Melanoma.

Arch Pathol Lab Med 2021 Jul;145(7):842-850

From the Departments of Pathology (Cho, Wang, Nagarajan, Curry, Ivan, Lazar, Prieto, Torres-Cabala, Aung), The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Molecularly distinct from cutaneous melanomas arising from sun-exposed sites, acral lentiginous melanomas (ALMs) typically lack ultraviolet-signature mutations, such as telomerase reverse transcriptase (TERT) promoter mutations. Instead, ALMs show a high degree of copy number alterations, often with multiple amplifications of TERT, which are associated with adverse prognosis. The prognostic value of TERT protein expression in acral melanomas, however, is not established.

Objective.—: To evaluate the frequency and pattern of TERT immunoreactivity and assess the potential utility of TERT expression as a prognostic indicator in ALMs.

Design.—: TERT expression by immunohistochemistry was analyzed in a series of 57 acral and nonacral melanocytic lesions, including 24 primary and 6 metastatic ALMs. Clinical outcome in patients with ALMs by TERT expression was assessed.

Results.—: TERT expression was more frequent in ALMs than in nonlentiginous acral melanomas and nonacral cutaneous melanomas, and was absent in acral nevi (P = .01). When present, TERT expression in ALMs was cytoplasmic and more intense than TERT expression in other melanocytic lesions (P = .05) with a higher H-score (P = .01). There was a trend toward decreased overall survival in patients with ALMs with TERT immunoreactivity, but it did not reach statistical significance. Furthermore, no correlation was found between TERT expression and disease-specific survival in patients with ALMs.

Conclusions.—: Although TERT protein expression was frequently detected in both primary and metastatic ALMs, TERT immunoreactivity in ALMs did not correlate with survival in our study. Further studies with larger cohorts are needed to elucidate the prognostic value of TERT expression in ALMs.
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http://dx.doi.org/10.5858/arpa.2020-0330-OADOI Listing
July 2021

High-grade Neuroendocrine Carcinomas of the Vulva: A Clinicopathologic Study of 16 Cases.

Am J Surg Pathol 2021 03;45(3):304-316

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

Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.
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http://dx.doi.org/10.1097/PAS.0000000000001558DOI Listing
March 2021

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Mod Pathol 2021 03 5;34(3):572-583. Epub 2020 Aug 5.

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

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.
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http://dx.doi.org/10.1038/s41379-020-0641-xDOI Listing
March 2021

Langerhans cell sarcoma involving skin and showing epidermotropism: A comprehensive review.

J Cutan Pathol 2021 Apr 7;48(4):547-557. Epub 2020 Sep 7.

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

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.
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http://dx.doi.org/10.1111/cup.13803DOI Listing
April 2021

Cutaneous adnexal carcinosarcoma: Immunohistochemical and molecular evidence of epithelial mesenchymal transition.

J Cutan Pathol 2021 Apr 14;48(4):526-534. Epub 2020 Sep 14.

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

Cutaneous carcinosarcomas are rare biphenotypic tumors that simultaneously show epithelial and mesenchymal differentiation. The most common carcinomatous components in skin carcinosarcomas are basal cell carcinoma and squamous cell carcinoma; adnexal carcinomas are rarely encountered. We report a case of an adnexal carcinoma with ductal and squamous differentiation and spindle cell component, which is interpreted as carcinosarcoma. Loss of immunohistochemical expression of E-cadherin and β-catenin detected in the sarcomatous component suggested epithelial mesenchymal transition (EMT). RNA sequencing analysis identified several gene mutations and alterations such as translocations and upregulations/downregulations, either shared by the two components of the tumor or differentially present in the carcinoma or the sarcoma parts. Thus, mutations in genes, such as TP53, were found in both components of the tumor while mutations in PDGFRA and RB1 (a pathogenic missense mutation) were exclusively present in the sarcomatous areas, further supporting EMT. EMT is a dynamic process by which tumors acquire mesenchymal phenotype while simultaneously losing epithelial properties. Although the pathways involved in EMT have been extensively studied, this phenomenon still needs to be investigated in cutaneous tumors of adnexal origin for a better understanding of their pathogenesis. These molecular changes may represent promising targets for personalized therapies.
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http://dx.doi.org/10.1111/cup.13782DOI Listing
April 2021

Hypertrophic lichenoid dermatitis immune-related adverse event during combined immune checkpoint and exportin inhibitor therapy: A diagnostic pitfall for superficially invasive squamous cell carcinoma.

J Cutan Pathol 2020 Oct 10;47(10):954-959. Epub 2020 Jun 10.

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

Immune checkpoint inhibitors (ICIs) for cancer treatment have revolutionized the field of medicine. However, an unintended but frequent consequence of ICI therapy is the development of cutaneous immune-related adverse events (irAEs), such as lichenoid dermatitis irAEs (LD-irAEs). The hypertrophic variant of LD-irAE may be a diagnostic challenge since it can mimic superficially invasive squamous cell carcinoma (SCC). A 79-year-old woman with metastatic melanoma who began treatment with an ICI-pembrolizumab-plus exportin-1 (XPO1) inhibitor presented after 1 month of therapy with symmetrical violaceous papules coalescing into plaques and with two nodules of the bilateral dorsal hands. Biopsy of the nodules revealed an actinic keratosis and atypical epidermal proliferation concerning for SCC. However, in the ensuing 3 weeks, the patient developed multiple new erythematous, violaceous, and scaly macules and papules, some coalescing into plaques on the extremities. Biopsies of these lesions revealed exuberant irregular epidermal hyperplasia with hypermaturation and lichenoid infiltrate concentrated at the base of the elongated, broadened rete ridges, consistent with hypertrophic LD-irAE. Treatment included topical fluocinonide ointment, intralesional triamcinolone injections and oral acitretin. Distinguishing hypertrophic LD-irAE and SCC can be challenging since both entities share histopathologic features; thus, correlation with clinical presentation is essential for diagnosis and optimal patient management.
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http://dx.doi.org/10.1111/cup.13739DOI Listing
October 2020

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

Am J Dermatopathol 2020 May;42(5):313-321

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

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.
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http://dx.doi.org/10.1097/DAD.0000000000001551DOI Listing
May 2020

T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma.

J Invest Dermatol 2020 11 15;140(11):2146-2156.e4. Epub 2020 Apr 15.

Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3 or CD8 T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3 or CD8 T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3 or CD8 T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3 or CD8 had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.
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http://dx.doi.org/10.1016/j.jid.2020.02.031DOI Listing
November 2020

Lichen planus related to transforming growth factor beta inhibitor in a patient with metastatic chondrosarcoma: a case report.

J Cutan Pathol 2020 May 27;47(5):490-493. Epub 2020 Jan 27.

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

Transforming growth factor-beta1 (TGF-β1) is expressed in normal epidermis. TGF-β1 potently inhibits keratinocyte proliferation and immunomodulatory properties, mainly by suppressing immune responses to self-antigens. Lichen planus (LP) is a form of dermatitis caused by cell-mediated immune dysfunction, but the exact pathogenic pathways are unknown, which poses therapeutic challenges. We report on a 68-year-old man who developed multiple pruritic, discrete, and well-demarcated, flat-topped red-purple papules and macules on the back and upper arms following 4 cycles of treatment with TGF-β receptor I (TGFBR-I) inhibitor, ly3200882, for metastatic chondrosarcoma. The biopsy showed hyperkeratosis, wedge-shaped hypergranulosis, elongation of the rete ridges, and a dense band-like lymphohistiocytic infiltrate admixed with colloid bodies and pigment incontinence, consistent with LP. Temporal correlation suggested that the TGFBR-I inhibitor might be a trigger. Treatment with topical clobetasol and oral metronidazole led to partial resolution of the lesions with postinflammatory hyperpigmentation. We believe this is the first reported case of LP related to TGFBR-I inhibitor therapy. This report expands the list of cutaneous adverse events associated with this novel class of targeted therapy. More importantly, this report supports emerging evidence that failure of TGF-β1 activation/signal transduction is an important mechanism in the pathogenesis of LP and suggests the TGF-β1 pathway as a potential therapeutic target in this disease.
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http://dx.doi.org/10.1111/cup.13645DOI Listing
May 2020

Differentiating keratoacanthoma from squamous cell carcinoma-In quest of the holy grail.

J Cutan Pathol 2020 Apr 14;47(4):418-420. Epub 2020 Jan 14.

Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

To distinguish keratoacanthomas from squamous cell carcinomas remains a diagnostic challenge in dermatopathology. Several immunohistochemical and cytogenetic markers have been evaluated; however, so far there has been no unequivocal evidence supporting practical application of any of these markers. Recent studies have evaluated the composition of tumor-associated immune infiltrate, in particular the number and distribution of CD123-positive plasmacytoid dendritic cells in making this distinction; but these cells also do not appear to be a consistent biomarker in distinguishing keratoacanthoma from squamous cell carcinoma.
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http://dx.doi.org/10.1111/cup.13640DOI Listing
April 2020

Aberrant DNA Methylation Predicts Melanoma-Specific Survival in Patients with Acral Melanoma.

Cancers (Basel) 2019 Dec 16;11(12). Epub 2019 Dec 16.

Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were , , , and . However, when primary AMs (PALM + NALM) were compared with MALM, and were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies.
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http://dx.doi.org/10.3390/cancers11122031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966546PMC
December 2019

Unraveling cancer lineage drivers in squamous cell carcinomas.

Pharmacol Ther 2020 02 11;206:107448. Epub 2019 Dec 11.

Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.
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http://dx.doi.org/10.1016/j.pharmthera.2019.107448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995404PMC
February 2020

Association of Immunosuppression With Outcomes of Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck.

JAMA Otolaryngol Head Neck Surg 2020 02;146(2):128-135

Division of Surgery, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Patients with immunosuppression have a higher incidence of cutaneous squamous cell carcinoma (cSCC) and often present with more aggressive, multifocal disease.

Objectives: To determine the risks for mortality in patients with cSCC and immunosuppression compared with nonimmunosuppression and to compare the difference in mortality risk based on the cause of immunocompromise.

Design, Setting, And Participants: This retrospective cohort study of patients with cSCC of the head and neck recruited participants from a tertiary cancer care center. Patients who underwent no treatment, wide local excision, or biopsy of the lesions were eligible for inclusion from January 1, 1995, to September 30, 2015. Data were analyzed from March 21, 2018, to April 4, 2019.

Exposures: Immunocompromise, defined as having solid organ transplant, stem cell transplant, hematopoetic malignant disease, autoimmune disease requiring treatment with immunosuppressive therapy, type 1 or 2 diabetes treated with insulin, HIV or AIDS, or other hematoproliferative disorder.

Main Outcomes And Measures: Patients were divided into 2 groups according to their immune status (immunosuppression vs no immunosuppression). The primary outcome measure was disease-specific survival. A Cox proportional hazards regression model was used to determine the association of immune status with disease outcome.

Results: A total of 796 patients (680 men [85.4%]; median age, 69 [range, 27-98] years), including 147 with and 649 without immunosuppression (IS and non-IS groups, respectively), constituted the final cohort. In the IS group, 77 (52.4%) had diabetes, 39 (26.5%) had lymphoma or leukemia, 25 (17.0%) had an organ or stem cell transplant, and 3 (2.0%) had HIV. Five-year disease-specific survival was 68.2% in the IS group compared with 84.1% in the non-IS group (difference, 15.9%; 95% CI, 3.5%-27.4%). Immunosuppression was independently associated with worse disease-specific survival (hazard ratio, 2.32; 95% CI, 1.53-3.50).

Conclusions And Relevance: This study's findings suggest that immunosuppression is independently associated with a worse outcome in cSCC, with a 2.32 times increased risk of disease-specific death after adjusting for age, history of skin cancer, recurrent or persistent disease status, disease stage, and treatment.
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http://dx.doi.org/10.1001/jamaoto.2019.3751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902183PMC
February 2020

Immunohistochemical and Molecular Features of Melanomas Exhibiting Intratumor and Intertumor Histomorphologic Heterogeneity.

Cancers (Basel) 2019 Nov 2;11(11). Epub 2019 Nov 2.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to tumor genetic heterogeneity rather than tumor morphology. Therefore, understating the molecular characteristics of such melanomas become indispensable. In this study, DNA was extracted from 11 morphologically distinct regions in eight formalin-fixed, paraffin-embedded melanomas. In each region, mutations in 50 cancer-related genes were tested using next-generation sequencing (NGS). A tumor was considered genetically heterogeneous if at least one non-overlapping mutation was identified either between the histologically distinct regions of the same tumor (intratumor heterogeneity) or among the histologically distinct regions of the paired primary and metastatic tumors within the same patient (intertumor heterogeneity). Our results revealed that genetic heterogeneity existed in all tumors as non-overlapping mutations were detected in every tested tumor ( = 5, 100%; intratumor: = 2, 40%; intertumor: = 3, 60%). Conversely, overlapping mutations were also detected in all the tested regions ( = 11, 100%). Melanomas exhibiting histomorphologic heterogeneity are often associated with genetic heterogeneity, which might contribute to tumor survival and poor response to therapy.
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http://dx.doi.org/10.3390/cancers11111714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896082PMC
November 2019

Unusual cutaneous metastatic carcinoma.

Ann Diagn Pathol 2019 Dec 12;43:151399. Epub 2019 Aug 12.

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

Most of metastatic tumors to the skin are from primary tumors of the breast, lung, or from melanoma; metastases to the skin from primary carcinomas at other sites are rare. Cutaneous metastases of visceral carcinomas most often occur in patients with advanced disease, and are associated with a poor prognosis. We report 6 cases of nonmammary, nonpulmonary carcinoma metastatic to the skin. Most patients were elderly with advanced disease at the time of diagnosis of skin metastasis. The primary tumor sites included the thyroid, esophagus, biliary tract, ovary, and prostate. Awareness of these rare cases of metastasis to the skin will help pathologists and clinicians make the correct diagnosis.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.08.003DOI Listing
December 2019