Melanocytic lesions with borderline features are diagnostically challenging. Single nucleotide po... more Melanocytic lesions with borderline features are diagnostically challenging. Single nucleotide polymorphism (SNP) arrays, which detect genomic copy number alterations (CNAs), can be helpful in distinguishing between nevi and melanoma. Fluorescence in situ hybridization (FISH) has been used as a more rapid, less expensive alternative to SNP array, employing a panel of probes that are often gained or lost in melanoma. We used SNP array data from 63 borderline cutaneous melanocytic lesions and 44 definitive melanomas to predict the performance of FISH testing. Lesions were considered positive by "virtual FISH" if one or more of the 5 FISH-probed loci demonstrated appropriate CNAs by SNP array. Cases were classified as positive by SNP array if ≥ 3 CNAs were present, based on internal validation studies, or if FISH criteria were met. Conventional FISH was performed in 33 cases (17 borderline lesions, 16 melanomas). Of the 63 borderline cases, 44 (70%) were positive by SNP array and 30 (48%) were positive by virtual FISH. A higher proportion of melanomas were positive by SNP array (41/44, 93% sensitivity) and virtual FISH (36/44, 82% sensitivity). Virtual FISH had 61% sensitivity in the borderline group, using SNP array as the gold standard, while specificity was 84%. There was good correlation between conventional and virtual FISH, with agreement in 30/33 (91%) cases. While FISH is highly effective in distinguishing between nevi and melanoma in cases where the histological diagnosis is straightforward, it is not nearly as sensitive or specific as SNP array when applied to borderline lesions.
Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To thi... more Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.
(A) Percentage of positive cells in MCPyV-positive tumors by RNA-ISH (n=42). (B) Photomicrograph ... more (A) Percentage of positive cells in MCPyV-positive tumors by RNA-ISH (n=42). (B) Photomicrograph of MCC/25 (Patient 12) with positive MCPyV RNA-ISH. The tumor (lymph node metastasis) was composed of a focal area of tumor cells surrounded by lymphocytes (green arrow). Tumor cells stain positively (red arrows) with punctate brown staining (400X magnification). (C) Comparison of percentage of positive cells by RNA-ISH and LTAg copy number by qPCR.
Representative microphotographs of samples showing different MCPyV RNA in situ hybridization (RNA... more Representative microphotographs of samples showing different MCPyV RNA in situ hybridization (RNA-ISH) intensity (400X magnification)
Read depth histograms across the Merkel cell polyomavirus (MCPyV) genome for two Merkel cell carc... more Read depth histograms across the Merkel cell polyomavirus (MCPyV) genome for two Merkel cell carcinoma (MCC) tumors.
Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can... more Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer diseasespecific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.
Morpheaform basal cell carcinoma (BCC) is a variant of BCC characterized by narrow strands and ne... more Morpheaform basal cell carcinoma (BCC) is a variant of BCC characterized by narrow strands and nests of basaloid cells with dense sclerotic stroma. The histologic extent often exceeds the clinical impression, leading to high recurrence rates after standard excision. The authors encountered a case with single-cell invasion distant from the main tumor. To date a systematic review of single-cell infiltration in morpheaform BCC has yet to be performed. Ten morpheaform BCCs, 10 nonmorpheaform aggressive BCCs, 5 desmoplastic trichoepitheliomas, and 2 microcystic adnexal carcinomas were identified by database search and confirmed on hematoxylin and eosin. Cases were evaluated by hematoxylin and eosin, immunohistochemical staining for p63, and (in a subset) broad-spectrum cytokeratin. Single-cell pattern was defined as individual cells, 2-cell clusters, or single-file invasion. Three types of single-cell pattern were identified: intratumoral (single cells within the main tumor mass), peripheral, and distant. Single cells were typically a minor component relative to larger tumor nodules and strands. Eight of the 10 cases of morpheaform BCC demonstrated areas of single-cell pattern: 3 intratumoral, 3 peripheral, and 2 with distant spread (0.75 and 1.0 mm from the main tumor). Eight of the 10 aggressive BCC demonstrated a peripheral single-cell pattern. Rare intratumoral single cells were identified in 3/5 desmoplastic trichoepitheliomas and 1/2 microcystic adnexal carcinomas. Single-cell pattern is frequently a component of morpheaform BCC. Tumor cells at a significant distance from the main component were unique to morpheaform BCC. Thus, when evaluating margins for morpheaform BCC, increased caution is recommended, and immunohistochemical stains for p63 or cytokeratins may be helpful.
Sentinel lymph node (SLN) status currently represents the single most important prognostic factor... more Sentinel lymph node (SLN) status currently represents the single most important prognostic factor in clinically localized melanoma and is widely used in patients with melanoma at significant risk for nodal micrometastasis. Although several studies have looked at the rates and implications of inaccuracies in the histopathologic diagnosis of melanocytic lesions, accuracy in the histologic interpretation of the SLN in melanoma has not been addressed. The goal of this study was to determine the rates of discordance in the histopathologic evaluation of the SLN and the potential clinical impact on patients referred to a comprehensive melanoma center. A prospectively collected database was queried for melanoma patients who had SLN biopsies performed at outside institutions before referral to the University of Michigan Multidisciplinary Melanoma Program between 2006 and 2009. These cases were reviewed and clinical follow-up obtained. After internal review of the SLN material, 13 (8 %) of 167 cases had major discrepancies in diagnosis that impacted patient management and prognosis. The disease of five patients was subsequently downstaged and the disease of eight patients was upstaged after internal review of the SLNs and reversal in diagnoses. There appears to be a small yet significant rate of discordance in diagnosis of the SLN for melanoma after expert histopathologic review. The implications of this discordance and revision of diagnosis is substantial. Expert histopathologic review of the SLN warrants consideration to provide the most accurate prognostic information and optimal patient care.
Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epit... more Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epithelioid or spindled cytomorphology that typically grow around blood vessels. These tumors are phenotypically and immunohistochemically distinct, expressing markers of both melanocytic and smooth muscle differentiation. Herein, we describe a case of histopathologically malignant cutaneous PEComa without metastatic spread, with review of the pertinent literature. Telescoping punch biopsy demonstrated an epithelioid neoplasm with marked atypia, hypercellularity, and increased mitotic activity. Immunohistochemical stains for HMB‐45, NK1‐C3, PGP9.5, MiTF, CD10, and CD68 were positive within tumor cells. In addition, there was diffuse expression of caldesmon and focal cytoplasmic staining for smooth muscle actin on the excision specimen. The patient underwent treatment with surgical excision with adjuvant radiation and surveillance computed tomography (CT). The patient remains free of recurren...
Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can... more Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized onc...
Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its ... more Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (<8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.
Melanocytic lesions with borderline features are diagnostically challenging. Single nucleotide po... more Melanocytic lesions with borderline features are diagnostically challenging. Single nucleotide polymorphism (SNP) arrays, which detect genomic copy number alterations (CNAs), can be helpful in distinguishing between nevi and melanoma. Fluorescence in situ hybridization (FISH) has been used as a more rapid, less expensive alternative to SNP array, employing a panel of probes that are often gained or lost in melanoma. We used SNP array data from 63 borderline cutaneous melanocytic lesions and 44 definitive melanomas to predict the performance of FISH testing. Lesions were considered positive by "virtual FISH" if one or more of the 5 FISH-probed loci demonstrated appropriate CNAs by SNP array. Cases were classified as positive by SNP array if ≥ 3 CNAs were present, based on internal validation studies, or if FISH criteria were met. Conventional FISH was performed in 33 cases (17 borderline lesions, 16 melanomas). Of the 63 borderline cases, 44 (70%) were positive by SNP array and 30 (48%) were positive by virtual FISH. A higher proportion of melanomas were positive by SNP array (41/44, 93% sensitivity) and virtual FISH (36/44, 82% sensitivity). Virtual FISH had 61% sensitivity in the borderline group, using SNP array as the gold standard, while specificity was 84%. There was good correlation between conventional and virtual FISH, with agreement in 30/33 (91%) cases. While FISH is highly effective in distinguishing between nevi and melanoma in cases where the histological diagnosis is straightforward, it is not nearly as sensitive or specific as SNP array when applied to borderline lesions.
Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To thi... more Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.
(A) Percentage of positive cells in MCPyV-positive tumors by RNA-ISH (n=42). (B) Photomicrograph ... more (A) Percentage of positive cells in MCPyV-positive tumors by RNA-ISH (n=42). (B) Photomicrograph of MCC/25 (Patient 12) with positive MCPyV RNA-ISH. The tumor (lymph node metastasis) was composed of a focal area of tumor cells surrounded by lymphocytes (green arrow). Tumor cells stain positively (red arrows) with punctate brown staining (400X magnification). (C) Comparison of percentage of positive cells by RNA-ISH and LTAg copy number by qPCR.
Representative microphotographs of samples showing different MCPyV RNA in situ hybridization (RNA... more Representative microphotographs of samples showing different MCPyV RNA in situ hybridization (RNA-ISH) intensity (400X magnification)
Read depth histograms across the Merkel cell polyomavirus (MCPyV) genome for two Merkel cell carc... more Read depth histograms across the Merkel cell polyomavirus (MCPyV) genome for two Merkel cell carcinoma (MCC) tumors.
Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can... more Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer diseasespecific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.
Morpheaform basal cell carcinoma (BCC) is a variant of BCC characterized by narrow strands and ne... more Morpheaform basal cell carcinoma (BCC) is a variant of BCC characterized by narrow strands and nests of basaloid cells with dense sclerotic stroma. The histologic extent often exceeds the clinical impression, leading to high recurrence rates after standard excision. The authors encountered a case with single-cell invasion distant from the main tumor. To date a systematic review of single-cell infiltration in morpheaform BCC has yet to be performed. Ten morpheaform BCCs, 10 nonmorpheaform aggressive BCCs, 5 desmoplastic trichoepitheliomas, and 2 microcystic adnexal carcinomas were identified by database search and confirmed on hematoxylin and eosin. Cases were evaluated by hematoxylin and eosin, immunohistochemical staining for p63, and (in a subset) broad-spectrum cytokeratin. Single-cell pattern was defined as individual cells, 2-cell clusters, or single-file invasion. Three types of single-cell pattern were identified: intratumoral (single cells within the main tumor mass), peripheral, and distant. Single cells were typically a minor component relative to larger tumor nodules and strands. Eight of the 10 cases of morpheaform BCC demonstrated areas of single-cell pattern: 3 intratumoral, 3 peripheral, and 2 with distant spread (0.75 and 1.0 mm from the main tumor). Eight of the 10 aggressive BCC demonstrated a peripheral single-cell pattern. Rare intratumoral single cells were identified in 3/5 desmoplastic trichoepitheliomas and 1/2 microcystic adnexal carcinomas. Single-cell pattern is frequently a component of morpheaform BCC. Tumor cells at a significant distance from the main component were unique to morpheaform BCC. Thus, when evaluating margins for morpheaform BCC, increased caution is recommended, and immunohistochemical stains for p63 or cytokeratins may be helpful.
Sentinel lymph node (SLN) status currently represents the single most important prognostic factor... more Sentinel lymph node (SLN) status currently represents the single most important prognostic factor in clinically localized melanoma and is widely used in patients with melanoma at significant risk for nodal micrometastasis. Although several studies have looked at the rates and implications of inaccuracies in the histopathologic diagnosis of melanocytic lesions, accuracy in the histologic interpretation of the SLN in melanoma has not been addressed. The goal of this study was to determine the rates of discordance in the histopathologic evaluation of the SLN and the potential clinical impact on patients referred to a comprehensive melanoma center. A prospectively collected database was queried for melanoma patients who had SLN biopsies performed at outside institutions before referral to the University of Michigan Multidisciplinary Melanoma Program between 2006 and 2009. These cases were reviewed and clinical follow-up obtained. After internal review of the SLN material, 13 (8 %) of 167 cases had major discrepancies in diagnosis that impacted patient management and prognosis. The disease of five patients was subsequently downstaged and the disease of eight patients was upstaged after internal review of the SLNs and reversal in diagnoses. There appears to be a small yet significant rate of discordance in diagnosis of the SLN for melanoma after expert histopathologic review. The implications of this discordance and revision of diagnosis is substantial. Expert histopathologic review of the SLN warrants consideration to provide the most accurate prognostic information and optimal patient care.
Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epit... more Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epithelioid or spindled cytomorphology that typically grow around blood vessels. These tumors are phenotypically and immunohistochemically distinct, expressing markers of both melanocytic and smooth muscle differentiation. Herein, we describe a case of histopathologically malignant cutaneous PEComa without metastatic spread, with review of the pertinent literature. Telescoping punch biopsy demonstrated an epithelioid neoplasm with marked atypia, hypercellularity, and increased mitotic activity. Immunohistochemical stains for HMB‐45, NK1‐C3, PGP9.5, MiTF, CD10, and CD68 were positive within tumor cells. In addition, there was diffuse expression of caldesmon and focal cytoplasmic staining for smooth muscle actin on the excision specimen. The patient underwent treatment with surgical excision with adjuvant radiation and surveillance computed tomography (CT). The patient remains free of recurren...
Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can... more Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized onc...
Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its ... more Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (<8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.
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Papers by Rajiv Patel