Dermatopathology Database Research Articles

Correlation of eTILs with recurrence free survival (RFS) in stage IIB-IIIA melanoma and use as biomarker for stratification for clinical trials.

9567 Background: Immunotherapy is approved for resected stage IIB-IIIC, but treatment of all patients, particularly those with IIB-IIIA disease, incurs unneeded expense and toxicity. Biomarkers are urgently needed for patient stratification. Time constraints in clinical trial design have led to the adoption of recurrence free survival (RFS) as a primary endpoint in adjuvant melanoma trials. Tumor infiltrating lymphocytes (TILs) are a well-established biomarker in primary melanoma, but quantification is subjective. Electronic TILs (eTILs) are a previously published automated digital pathology tool to quantify TILs. Methods: A retrospective cohort of 194 patients with Stage II-III melanoma from Roswell Park Comprehensive Cancer Center (RPCCC, n=133) and Geisinger Medical Center (GMC, n=61) were evaluated for eTILS by blinded investigators. Patients were included based on a search of dermatopathology databases and tissue availability. Digital images of diagnostic slides were analyzed using quPath, a publicly available software. Briefly, tumor areas were selected to include infiltrating lymphocytes with minimal adjacent stroma. Color variations in H&E images were standardized, and cell types quantified utilizing a machine learning algorithm. A previously published threshold of 16.6% eTILs, calculated as lymphocytes/tumor cells x 100, was used. Patients were staged using American Joint Committee on Cancer (AJCC) guidelines, version 8. Survival was assessed using Kaplan-Meier Curves and correlation of clinic-pathologic features with survival was tested using Cox Proportional Hazards Models. Results: Of 194 patients, 56 were stage IIA, 85 were IIB-IIIA, and 53 were IIIB-D. Median follow up was 47.5 months. 103 patients had eTILs >16.6% of whom 13 (12.6%) died and 84 had eTILS <16.6% of whom 23 (27.4%) died during follow-up. HR for death from melanoma within 5 years for the high eTIL group was 0.53 (CI 0.21-0.90, p=0.024). DSS was significantly longer in the high eTIL group than the low eTIL group (p=0.0095). Among 85 stage IIB-IIIA patients, local and distant recurrence data was available for the RPCCC cohort of 68 patients. 46 of these patients had high eTILs of whom 9(19.6%) recurred and 22 had low eTILS of whom 10 (45.95%) recurred. HR for recurrence within 5 years for the high eTIL group was 0.44 (CI0.23-0.83, p=0.012). RFS was significantly longer in the high TIL group (p=0.016) as was distant metastatic recurrent survival (p= 0.0063). eTIL score correlated with RFS in a univariable Cox model (p=0.033) and added to stage and depth in a multivariable Cox model (p=0.018). Conclusions: eTILs, readily evaluable at low cost using diagnostic slides, correlate with clinical outcome in a retrospective cohort of 194 patients. eTILS should be prospectively evaluated as a biomarker to stratify early-stage melanoma patients for adjuvant clinical trials.

Refining the application of PRAME-a useful marker in high CSD and acral melanoma subtypes.

Pathologic discordance affecting patient management may approach 20% in melanocytic cases following specialist review. The diagnostic utility of PRAME has been highlighted in several studies but interpretative challenges exist including its use in severely dysplastic compound nevi showing progression to melanoma in situ, nevoid melanoma, and coexisting nevi with melanoma. We examine the PRAME status of a broad spectrum of melanocytic lesions including challenging, dysplastic nevi with severe atypia from a large Irish patient cohort. Retrospective review of the dermatopathology database was conducted to evaluate the PRAME staining characteristics of two hundred and twenty-one melanocytic lesions using a commercially available PRAME antibody (EPR20330). The proportion of nuclear labeling and intensity of staining was recorded. The sensitivity and specificity of PRAME for in situ and malignant melanocytic lesions was 77% and 100%, respectively. Virtually all of our melanoma in situ from high-cumulative sun damaged (CSD) skin (22/23) and all acral lentiginous melanoma (5/5) were PRAME positive while 80% (8/10) of our lentigo maligna melanoma showed diffuse expression. None of our benign subgroup showed diffuse immunoexpression (0/82), including thirty-seven moderate or severely dysplastic nevi. In all cases of melanoma in situ arising in association with a dysplastic compound nevus (0/10), no immunoexpression was observed in the nevic component while in five cases of melanoma in situ with coexistent, intradermal nevus immunostaining was confined to the in situ component. A total of 100% (2/2) of desmoplastic melanomas and 50% (4/8) of nodular melanomas were PRAME positive. PRAME is a sensitive and highly specific immunostain in the diagnosis of in situ and invasive melanoma and we emphasize its application in the evaluation of high CSD and acral melanoma subtypes as well as in challenging threshold cases.

IL17A mRNA Staining Distinguishes Palmoplantar Psoriasis from Hyperkeratotic Palmoplantar Eczema in Diagnostic Skin Biopsies

Acral dermatoses, including hyperkeratotic palmoplantar eczema (HPE), palmoplantar psoriasis (PP), and mycosis fungoides palmaris et plantaris (MFPP), can be challenging to diagnose clinically and histopathologically. In this setting, cytokine biomarkers may be able to help provide diagnostic clarity. Therefore, we evaluated IL-17A, IFN-γ, and IL-13 expression in PP, HPE, and MFPP and compared their expression profiles with nonacral sites. We used biopsy specimens from the Yale Dermatopathology database, selecting cases of HPE (n= 12), PP (n= 8), MFPP (n= 8), normal acral skin (n= 9), nonacral eczema (n= 10), and nonacral psoriasis (n= 10) with classic clinical and histopathologic features. IL17A mRNA expression by RNA in situ hybridization differentiated PP (median score 63.1 [interquartile range 9.4-104.1]) from HPE (0.8 [0-6.0]; P= 0.003), MFPP (0.6 [0-2.6]; P= 0.003), and normal acral skin (0 [0-0]; P < 0.001). Unexpectedly, both PP and HPE showed co-expression of IFNG and IL13 mRNA. In contrast, nonacral psoriasis and eczema showed divergent patterns of IFNG and IL13 mRNA expression. Taken together, we show that IL17A mRNA expression may be a useful biomarker of PP, and we further show that acral dermatoses exhibit distinct immunology compared to nonacral sites, with implications for clinical management.

Next-generation Sequencing as a Potential Diagnostic Adjunct in Distinguishing Between Desmoplastic Melanocytic Neoplasms.

Desmoplastic melanomas (DMs) are often challenging to diagnose and ancillary tests, such as immunohistochemistry, have limitations. One challenge is distinguishing DM from benign desmoplastic melanocytic neoplasms. In this study, we explored the utility of next-generation sequencing data in the diagnosis of DMs versus desmoplastic Spitz nevi (DSN) and desmoplastic nevi (DN). We sequenced 47 cases and retrieved 12 additional previously sequenced clinical cases from our dermatopathology database. The 59 total cases were comprised of 21 DMs, 25 DSN, and 13 DN. The DMs had the highest tumor mutation burden at 22 mutations/megabase (m/Mb) versus the DSN (6m/Mb) and DN (8m/Mb). Truncating mutations in NF1 resulting in a loss-of-function were exclusive to the DM cohort, identified in 8/21 (38%) cases. Importantly, missense mutations in NF1 were nonspecific and seen with similar frequency in the different cohorts. Other mutations exclusive to the DMs included truncating mutations in TP53 , CDKN2A , and ARID2 . Among the DSN, 17/25 (68%) had an HRAS mutation or receptor tyrosine kinase fusion consistent with other Spitz tumors. Two cases in the DN cohort had missense mutations in BRAF without additional progression mutations and 2 other cases had mutations in GNAQ , supporting a diagnosis of a sclerosing blue nevus. The remainder of the DN had nonspecific mutations in various signaling pathways with few progression mutations. Overall, our study provides preliminary data that next-generation sequencing data may have the potential to serve as an ancillary diagnostic tool to help differentiate malignant and benign desmoplastic melanocytic neoplasms.

An Examination of Melanoma Detection and Characteristics at a Nova Scotia Tertiary Care Centre, From 2015-2019.

Melanoma is one of the most common cancers in Canada,1 with the highest incidence in Nova Scotia (NS). To describe the demographics, lesion characteristics, and diagnostic accuracy of suspected melanomas excised at the largest center in NS. The dermatopathology database was interrogated for cases of possible melanoma from 2015 through 2019. Age, gender, site of lesion, pathologic diagnosis, Breslow depth, and equivocal pathology were assessed. 984 lesions had a clinical diagnosis of possible melanoma, identifying 301 melanomas. Of these, 142 (47%) were melanoma in situ (MIS) which in females occurred mostly on the extremities, while in males the head predominated. For invasive melanoma (IM), the extremities remained predominant for women, while the back was most common in men. Lower extremity lesions were more likely to be invasive and female patients were more likely to present with them at a younger age compared to males. The pathology was challenging for 23.94% of MIS, and 16.18% of IM. A mean of 3.1 lesions were excised for every melanoma identified. Early diagnosis of melanoma is challenging clinically and pathologically. Our melanoma detection rate was 31%, with an increasing trend in the proportion of MIS, and decreasing trend in the proportion of IM over the years. Almost 50% of melanomas were detected in early stages, supporting positive outcomes. Melanomas were more common on extremities in females and the back in males. Melanomas on the lower limbs were more likely to be invasive regardless of gender.

Impact of COVID-19 on melanoma diagnosis.

Impact of COVID-19 on melanoma diagnosis.

Association of a Proposed New Staging System for Folliculotropic Mycosis Fungoides With Prognostic Variables in a US Cohort

A new cutaneous staging system for folliculotropic mycosis fungoides (FMF) has been purported to better estimate survival compared with the staging system for conventional mycosis fungoides. To analyze predictive variables associated with survival and evaluate the effectiveness of the newly proposed staging system for estimating overall survival and disease-specific survival (DSS) in a US cohort. This cohort study assessed 195 patients with FMF in the dermatopathology database of the University of California, San Francisco from January 1, 1990, to April 31, 2012, for eligibility. A total of 153 patients were excluded for the following reasons: (1) alternative diagnoses were favored ranging from benign dermatitides to other forms of cutaneous lymphoma; (2) technical problems with slides; and (3) lack of follow-up information. Data were analyzed from January 1, 2018, to August 31, 2020. Kaplan-Meier curves were used to estimate overall survival and DSS for the entire cohort. Possible predictive variables associated with survival were evaluated using Cox proportional hazards regression modeling. Each variable was examined separately, followed by a multiple-variable model. Kaplan-Meier curves were used to estimate overall survival and DSS by subdividing the cohort into early- and advanced-stage cutaneous disease. Forty-two patients were included in the analysis (mean age at diagnosis, 55 [range, 8-89] years; 31 men [74%]). For the entire cohort, the estimated 5-year overall survival rate was 89% (95% CI, 79%-99%); 10-year rate, 78% (95% CI, 63%-92%); and 15-year rate, 58% (95% CI, 31%-85%). Estimated 5- and 10-year DSS rates were 89% (95% CI, 79%-99%); 15-year rate, 80% (95% CI, 61%-99%). For overall survival in the multiple-variable Cox proportional hazards regression model, only age was statistically significant (hazard ratio [HR] per 10-year age increase, 3.1; 95% CI, 1.4-7.2; P = .008), whereas for DSS, only cutaneous disease was statistically significant (HR, 11.4; 95% CI, 1.3-103.0; P = .03). When stage stratified, the 5-year estimated overall survival rate for early-stage disease was 96% (95% CI, 89%-103%); 10-year rate, 82% (95% CI, 65%-98%); and 15-year rate, 65% (95% CI, 33%-97%). For advanced-stage disease, the estimated 5- and 10-year overall survival rates were 70% (95% CI, 41%-98%); the 15-year rate, 53% (95% CI, 16%-89%). For early-stage cutaneous disease, the estimated 5-, 10- and 15-year DSS rates were all 96% (95% CI, 89%-103%). For advanced-stage cutaneous disease, the estimated 5- and 10-year DSS rates were 70% (95% CI, 41%-98%); the 15-year rate, 53% (95% CI, 16%-89%). Cox proportional hazards regression modeling demonstrated cutaneous stage to be the only statistically significant predictive variable associated with DSS. Subdividing FMF into early and advanced cutaneous stages was associated with effective estimation of survival in this cohort. Thus, findings suggest that FMF is a heterogeneous disease with early and advanced cutaneous stages; that the new staging system is effective in estimating survival in a US cohort; and that the poor prognosis initially associated with FMF only applies to the advanced cutaneous stage.

Multiple epidermolytic acanthomas mimicking condyloma: a retrospective study of 8 cases.

Epidermolytic acanthoma (EA) is an uncommon benign cutaneous lesion. Multiple epidermolytic acanthomas (multiple EAs) are rarely reported. We retrospectively identified patients diagnosed with multiple EAs between 2005 and 2017 from our dermatopathology database and analyzed their clinical, pathological, and immunohistochemical features. We also evaluated the association of multiple EAs with human papillomavirus (HPV) infection. In total, eight patients (average age 51years; 3:1 male predominance) with multiple EAs were found. All patients had lesions on the genitocrural area. The two most common clinical diagnoses were condyloma (5/8) and soft fibroma (3/8), which were predominantly skin-colored (5/8) or whitish (2/8). The lesions were less than 1cm in diameter, and most (6/8) appeared to have a smooth surface. No molecular evidence suggesting HPV infection was found. Immunohistochemical staining showed low mitotic activity. The lesions were removed in one of two patients via cryotherapy, and one patient was treated with electrocauterization. The other five patients were followed without treatment. The genital area was the most common location for multiple EAs, which was commonly misdiagnosed clinically as condyloma. Patients presenting with uniformly small-sized, skin-colored to whitish, smooth papular lesions in the genitalia should be carefully evaluated. The specific pathological features of epidermolytic hyperkeratosis are diagnostic, and the lesions can be observed without aggressive treatment after confirmed diagnosis.

The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential.

FISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma. 73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010-2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6. The study was composed of 50 females and 23 males with an age range of 1-73 and a mean age of 35years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis. Despite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4-probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome.

Abstract A50: Impact of indoor tanning and MC1R genotype on basal cell carcinoma risk in young people

Abstract Background: The incidence of basal cell carcinoma (BCC), which accounts for the majority of non-melanoma skin cancer (NMSC), is increasing, particularly in young people. While BCC is treatable, it can be associated with significant morbidity and health care costs. The ability to identify individuals at the highest risk of early-onset BCC could help focus public health efforts and mitigate the increasing incidence. However, to date, few risk prediction models exist for BCC. To identify individuals at risk of BCC at young ages, we assessed the utility of existing skin cancer risk prediction models (for melanoma or overall skin cancer) in the setting of early-onset BCC and built a novel risk prediction model, with a focus on indoor tanning and melanocortin 1 receptor (MC1R) genotype. Methods: We evaluated unconditional multivariate logistic regression models among 759 (376 cases, 383 controls) non-Hispanic whites from the Yale Study of Skin Health, a case-control study of early-onset BCC conducted in Connecticut among individuals under age 40. BCC cases and randomly sampled controls with minor benign skin conditions diagnosed between July 2006 and September 2010 were identified through Yale University's Dermatopathology database. Participants completed a structured in-person interview, self-administered questionnaires, and provided a saliva sample. We gathered self-reported eye color, skin color (inner upper arm), hair color (natural color), freckling on the arms (based on images), number of moles on the back ≥ 5 mm (clear acetate size template), mole removal, skin reaction to sunlight for the first time in the summer for one hour without sunscreen, skin reaction after repeated and prolonged exposure to sunlight, family history of melanoma and NMSC, and indoor and outdoor ultraviolet (UV) radiation exposure. We assessed the predictive performance of our novel risk prediction model and two models in the literature via summary measures of calibration, misclassification, and discrimination. We employed bootstrapping to better reflect the area under the receiver operating characteristic curve (AUC) expected when the model is tested on an independent, but similar set of patients. To investigate if indoor tanning and MC1R improved prediction performance over our early-onset BCC base model, we evaluated the regression coefficients for the markers in the expanded risk model and the corresponding likelihood ratio test statistic. All statistical tests were two-sided and analyses were performed in the statistical software R (Version 3.0.2). Results: An existing model by Han et al. (2006) included seven MC1R variants and in our data the bootstrapped AUC for this model was 0.72 (95% CI, 0.66-0.78). Another existing model by Smith et al. (2012) with MC1R and indoor tanning resulted in a bootstrapped AUC of 0.69 (95% CI 0.63-0.75) in our population. Our base model, which included hair color, skin color, skin reaction with prolonged sun exposure, education, freckles on arm, family history of NMSC, and outdoor sun exposure in warm months, had greater predictive ability (bootstrapped AUC=0.75, 95% CI=0.72-0.79) than the existing models we evaluated. We also found that our model was significantly improved when we added ever indoor tanning, burns from indoor tanning, and the R151C MC1R variant (bootstrapped AUC=0.77, 95% CI, 0.74-0.81). Conclusions: Our risk prediction model incorporating both MC1R and indoor tanning in the risk of early-onset BCC, validates and extends the work of other skin cancer risk prediction models and emphasizes the value of considering both genotype and indoor tanning in skin cancer risk prediction in young people. Therefore, in addition to the typical skin cancer characteristics clinicians rely on, assessing and counseling young people to reduce both indoor and outdoor UV exposure is needed to reduce BCC risk. Citation Format: Annette M. Molinaro, Leah M. Ferrucci, Brenda Cartmel, Erikka Loftfield, David J. Leffell, Allen E. Bale, Susan T. Mayne. Impact of indoor tanning and MC1R genotype on basal cell carcinoma risk in young people. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A50.

Basal cell carcinomas in a tertiary referral centre: a systematic analysis.

Basal cell carcinoma (BCC) is the most frequent skin cancer with increasing incidence and generally high cure rates. BCC can be quite aggressive and is difficult to treat. To investigate BCCs with a focus on histological subtypes, treatment procedures and correlation to clinical progress to collect further information on complex BCC cases. In this retrospective single-centre analysis the dermatopathology database, a network of cooperating dermatological surgeons, was queried for BCC cases between January 2007 and December 2011. Of 14,423 samples from a total of 9652 patients initially identified, 2938 patients were treated at the University Hospital Zurich and had corresponding local electronic patient records. Patients (n = 2938) (with 4769 diagnoses, 2006 re-excisions with 1180 microscopically controlled surgeries) were classified based on severity estimations into 2240 simple, 640 moderate, and 58 severe cases, including one BCC-treatment-associated death and 11 patients with subsequent participation in a clinical trial. In moderate and severe cases (n = 698), there were significantly higher rates of unique histological diagnoses (n = 2·5; P < 0·0001), higher association with basosquamous carcinoma [odds ratio (OR) 3·6; P < 0·0001] and sclerosing BCC (OR 2·48; P < 0·0001). Of the patients with basosquamous carcinoma 82·6% had a previous history of BCC. This is the first study that analyses the frequency of complicated BCCs in a tertiary referral centre. There were 6·6% moderate (640 of 9652) and 0·6% (58 of 9652) severe cases. We found significantly more varying histological diagnoses and significant association with aggressive subtypes in moderate and severe cases. These patients might especially benefit from new therapeutic options.

Prurigo Pigmentosa

Prurigo pigmentosa (PP) is a rare inflammatory dermatosis originally reported in Japan. Since then, most reports have originated from Asia, and to a lesser extent from Europe. Although the pathogenesis remains unclear, it is now established that PP is linked to ketoacidotic states. Four patients diagnosed with PP were identified from the dermatopathology database at the American University of Beirut Medical Center between January 2009 and December 2013. Clinicopathologic findings in the 4 patients were similar to those previously reported in the literature. The patients were all female with a mean age of 23.5 years. They all presented with itchy erythematous reticulated papulovesicles/plaques leaving variable reticulated brownish patches. Two patients had, in addition, annular lesions arranged en cocarde and pustules, respectively. In 3 patients, the rash was associated with fasting or dieting. The rash had a predilection to the trunk and proximal part of the upper extremities. One patient had intergluteal area involvement. Two biopsy specimens revealed psoriasiform hyperplasia and neutrophilic exocytosis mimicking psoriasis or an impetiginized spongiotic dermatitis. One biopsy specimen exhibited a mild superficial perivascular lymphocytic infiltrate with ballooning and reticular degeneration, a picture mimicking a viral exanthema. Another biopsy specimen exhibited a picture similar to chronic spongiotic dermatitis. Although mostly described in Japan, PP has been described much less frequently in the Middle East region likely due to mis/underdiagnosis. Therefore, increased awareness is necessary especially because fasting is a common religious practice among Arab countries. Further investigations are necessary to better understand the etiopathogenesis of this rare entity.

Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case-control study.

Tea and coffee are hypothesized to play a protective role in skin carcinogenesis through bioactive components, such as caffeine, yet the epidemiologic evidence is mixed. Existing data support an inverse association with basal cell carcinoma (BCC), more so than for melanoma or squamous cell carcinoma. To understand whether tea, coffee, and caffeine are related to early-onset BCC, we evaluated data from 767 non-Hispanic Whites under age 40 in a case-control study in Connecticut. BCC cases (n=377) were identified through Yale's Dermatopathology database. Controls (n=390) were randomly sampled from individuals in the same database with benign skin diagnoses and frequency matched to cases on age, sex, and biopsy site. Participants completed an in-person interview including assessment of caffeinated coffee and hot tea. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression for regular consumption and frequency and duration measures. Combined regular consumption of caffeinated coffee plus hot tea was inversely associated with early-onset BCC (OR=0.60, 95% CI=0.38-0.96). Those in the highest category of caffeine from these sources had a 43% reduced risk of BCC compared with nonconsumers (OR=0.57, 95% CI=0.34-0.95, P-trend=0.037). Our findings suggest a modest protective effect for caffeinated coffee plus tea in relation to early-onset BCC that may, in part, be due to caffeine. This study adds to the growing body of literature suggesting potential health benefits from these beverages.

Hypopigmented interface T-cell dyscrasia: a form of cutaneous T-cell dyscrasia distinct from hypopigmented mycosis fungoides.

Hypopigmentation in cutaneous T-cell lymphoproliferative disease should not always be equated with hypopigmented mycosis fungoides (MF). A form of hypopigmented pre-lymphomatous T-cell dyscrasia falling under the designation of the so-called hypopigmented interface variant of T-cell dyscrasia has recently been proposed. The aim of the present study was to establish hypopigmented interface T-cell dyscrasia as its own entity apart from other T-cell dyscrasias and MF using a patient case series. Twenty four cases of hypopigmented interface T-cell dyscrasia were identified in the dermatopathology database of Weill Medical College of Cornell University. There were 17 females and seven males (mean age, 36years). In children and adolescents, the patients were most commonly of African American extraction. Truncal photo-protected areas manifesting as large solitary patches or multiple smaller macules were characteristic; disease progression to MF occurred in only one patient. The lesions responded to topical steroids and light therapy. The pathology was defined by a cell poor interface associated with degeneration of keratinocytes and melanocytes, and by lymphocytes whose nuclei showed low-grade cerebriform atypia, and which expressed a significant reduction in CD7 and CD62L expression. In 50% of the cases, the implicated cell type was of the CD8 subset. Clonality was not identified. Hypopigmented interface T-cell dyscrasia is a distinct entity separate from and rarely progressive to MF.

Defining the role of CD2 in disease progression and overall survival among patients with completely resected stage-II to -III cutaneous melanoma

Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor immunity, but its role in melanoma progression warrants further investigation. We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. Primary tumors from patients who developed recurrent disease had fewer CD2(+) cells (P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence (P = .008) and overall survival (P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes (P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence (P = .0006) and overall survival (P = .0318). Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.

The MPATH-Dx reporting schema for melanocytic proliferations and melanoma

The histologic diagnosis of melanoma and nevi can be subject to discordance and errors, potentially leading to inappropriate treatment and harm. Diagnostic terminology is not standardized, creating confusion for providers and patients and challenges for investigators. We sought to describe the development of a pathology reporting form for more precise research on melanoma and a diagnostic-treatment mapping tool for improved patient care and consistency in treatment. Three dermatopathologists independently reviewed melanocytic lesions randomly selected from a dermatopathology database. Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) reporting schema evolved from iterative case review and form revision. Differences in diagnostic thresholds, interpretation, and nomenclature contributed to development of the MPATH-Dx histology reporting form, which groups lesions by similarities in histogenesis and degrees of atypia. Because preliminary results indicate greater agreement regarding suggested treatments than for specific diagnoses, the diverse terminologies of the MPATH-Dx histology reporting form were stratified by commonalities of treatments in the MPATH-Dx diagnostic-treatment mapping scheme. Without transformative advances in diagnostic paradigms, the interpretation of melanocytic lesions frequently remains subjective. The MPATH-Dx diagnostic-treatment mapping scheme could diminish confusion for those receiving reports by categorizing diverse nomenclature into a hierarchy stratified by suggested management interventions.

Dermatopathology of the Female Breast

To better define the spectrum of neoplastic and inflammatory diseases that affect female breast skin and the nipple-areola complex, we searched an institutional dermatopathology database and identified 500 specimens of female "breast" (from consecutive records accessioned January 2009-March 2011), 143 specimens of "areola," 124 specimens of "nipple" (records from the latter 2 groups were from patients evaluated June 1992-March 2011), and 500 control specimens of "abdomen" (accessioned January 2010-March 2011). Most specimens obtained from breast skin (76%) represented melanocytic or epithelial proliferations (eg, nevi, seborrheic keratoses, and cysts), as did those from the abdomen, whereas many from the nipple (41%) and areola (60%) were of inflammatory dermatoses. A striking finding was eosinophilic spongiosis (ES) in most areola specimens with spongiotic dermatitis (78%); in contrast, ES was identified in 50% and 31% of spongiotic dermatitis specimens from nipple and breast skin, respectively. ES was associated with a clinical diagnosis of dermatitis in all patients except one (who had pemphigus). Metastatic breast cancer was identified in 28 of 767 specimens (4%), including 6 of 124 (5%) from the nipple. Five of 124 specimens from the nipple (4%) and 1 of 143 from the areola (1%) showed Paget disease. All but one patient with Paget disease showed acantholytic features and none had tissue eosinophils. Abnormalities categorized as complications of radiotherapy, including mild fibrosis and vascular ectasias, morphea, and angiosarcoma, constituted a minority of cases. Our data and the literature indicate that few disorders specifically affect breast skin, but the nipple-areola complex should be approached with a different set of diagnostic considerations.

A retrospective study of squamous cell carcinoma of the nail unit diagnosed in a Belgian general hospital over a 15-year period

Squamous cell carcinoma (SCC) is the most common malignant tumor at the nail unit. It mainly affects middle-aged men, with a peak incidence between 50 and 69 years of age. Diagnosis is often delayed because of the slow evolution of the lesion and multiple clinical features. We sought to characterize the different clinical and histopathological patterns of SCC of the nail unit and evaluate their therapeutic outcome. Records for 58 patients were retrieved from our department's dermatopathology database over a period of 15 years (1995-2011) and the patients recontacted. Of the 58 patients, 51 were eligible for follow-up. There was a male predominance (72.5%). The fingers were most commonly affected (98%), the right index and long fingers being most commonly affected (20.8% each). The nail bed was mainly affected. The commonest clinical signs were, in decreasing order, subungual hyperkeratosis, onycholysis, oozing, and nail plate destruction. The majority of SCC of the nail unit was in situ (63%). The recurrence rate of all treatments taken together was 30.6%. Retrospective study design is a limitation. SCC of the nail unit mostly affects men aged 50 to 69 years. Most cases were the warty type, with oozing being an underrecognized clinical sign. Contrary to prior studies, most lesions were in situ, and bone involvement was uncommon. Conservative surgical resection should be the first-line treatment when the bone is not involved. Recurrence rate is high when a procedure other than Mohs micrographic surgery is performed.

Evaluation of AJCC Tumor Staging for Cutaneous Squamous Cell Carcinoma and a Proposed Alternative Tumor Staging System

This study proposes an alternative tumor staging system for cutaneous squamous cell carcinoma (CSCC) that more precisely defines the small subset of tumors with a high risk of metastasis and death. To identify risk factors for poor outcomes in CSCC and evaluate the 2010 American Joint Committee on Cancer (AJCC) tumor (T) staging system's ability to stratify occurrence of these outcomes. Retrospective cohort study. A single academic hospital. Study participants were identified via a pathology and dermatopathology database search for patients diagnosed as having high-risk CSCC. Two hundred fifty-six primary high-risk CSCCs were included. Outcomes for AJCC tumor stages T2 to T4 were statistically indistinguishable because only 4 cases (<2% of the cohort) were AJCC stages T3 or T4, which require bone invasion. Subsequently, the bulk of poor outcomes (83% of nodal metastases, 92% of deaths from CSCC) occurred in AJCC stage T2 cases. An alternative tumor staging system was developed with the aim of better stratifying this stage T2 group. Four risk factors were found to be statistically independent prognostic factors for at least 2 outcomes of interest in multivariate modeling. These factors (poor differentiation, perineural invasion, tumor diameter ≥2 cm, invasion beyond subcutaneous fat) were incorporated in the alternative staging with 0 factors indicating T1, 1 factor indicating T2a; 2 to 3 factors, T2b; and 4 factors or bone invasion, T3. Stages T2a and T2b significantly differed in incidences of all 4 end points. Stage T2b tumors comprised only 19% of the cohort but accounted for 72% of nodal metastases and 83% of deaths from CSCC. The proposed alternative tumor staging system offers improved prognostic discrimination via stratification of stage T2 tumors. Validation in other cohorts is needed. Meanwhile, stage T2b tumors are responsible for most poor outcomes and may be a focus of high-risk CSCC study.

Host Phenotype Characteristics and MC1R in Relation to Early-Onset Basal Cell Carcinoma

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under age 40. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype-genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under age 40 were identified through Yale’s Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for one hour [severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08–36.94] and skin color (very fair vs. olive OR=11.06, 95% CI=5.90–20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37–5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC cases status (37% of cases) than single BCC case status. MC1R, number of moles, skin reaction to first summer sun for one hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low-risk of skin cancer.