Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases.

ABSTRACT: Information regarding the genetic alterations in extramammary Paget disease (EMPD) is scarce. This study investigated the significance of CDKN2A and MTAP alterations in EMPD progression using immunohistochemistry and panel DNA sequencing. In total, 24 invasive/metastatic EMPD cases were included in this study. The immunoexpression of p16 and MTAP in the primary in situ, primary invasive, and metastatic tumor components was evaluated. Panel DNA sequencing was performed for metastatic tumor components in 5 of the 24 cases. Immunoexpression of p16 in the in situ tumor component was at least partially preserved in all 19 tested cases (100%). By contrast, the invasive tumor component was diffusely or partially lost in 18 (81.8%) of 22 tested cases. Regarding the foci of lymph node metastasis, 13 (81.2%) of the 16 patients showed a significant loss of p16 expression. Loss of MTAP immunoexpression was observed less frequently compared with the loss of p16 expression. CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.

Bowen disease with sebaceous differentiation arising from clonal seborrheic keratosis.

We present a rare case of clonal seborrheic keratosis (SK) with focal Bowen disease (BD) (squamous cell carcinoma in situ) accompanied by sebaceous differentiation. An 89-year-old woman presented with a pale reddish-brown plaque on the left buttock. Histopathological examination of the excisional specimen revealed hyperkeratosis, acanthosis, and intraepidermal epithelioma. In some areas of the tumor, we observed proliferation of basaloid keratinocytes within the intraepidermal nests and pseudohorn cysts. This area was diagnosed as clonal SK. However, in other areas, the tumor cells within the intraepidermal nests showed nuclear pleomorphism, abnormal mitoses, dyskeratotic cells, and clumping cells, consistent with BD with a nested/clonal pattern (clonal BD). The SK and BD areas were contiguous with the transitional zone. Some nests within the BD area contained vacuolated cells with bubbly cytoplasm and scalloped nuclei, suggestive of sebaceous differentiation. Therefore, we made the diagnosis of clonal BD with sebaceous differentiation arising from clonal SK. All areas contained intraepidermal nests, which revealed that the lesions were not the result of accidental collision, but that the neoplastic cells in the intraepidermal nests of the SK transformed into BD and underwent sebaceous differentiation.

Recurrent GATA3 P409Afs*99 Frameshift Extension Mutations in Sweat-gland Carcinoma With Neuroendocrine Differentiation.

Sweat-gland carcinoma with neuroendocrine differentiation (SCAND) was recently proposed as a new cutaneous adnexal neoplasm with neuroendocrine differentiation; however, its genetics are not well known. Herein, we performed clinicopathologic and genetic analyses of 13 SCAND cases and 5 control cases of endocrine mucin-producing sweat gland carcinoma (EMPSGC). The SCAND group included 11 males and 2 females with a median age of 68 years (range, 50 to 80 y). All SCAND lesions occurred in the ventral trunk or genital area. Of the 13 SCAND cases, 9 and 5 exhibited lymph node and distant metastases, respectively. Three (23.1%) patients with SCAND died of the disease. In contrast, neither metastasis nor mortality was confirmed in the EMPSGC cases. Immunoexpression of the androgen receptor, c-Myb, and MUC2 was limited in SCAND, whereas EMPSGC frequently expressed these immunomarkers. GATA3 P409Afs*99 extension mutations were detected in 7 (53.8%) of the 13 SCAND cases, using Sanger or panel sequencing. All 7 SCAND cases with GATA3 mutations were located in the genital, inguinal, or lower abdominal regions, whereas 5 of the other 6 SCAND cases were located in the anterior upper to mid-trunk. No GATA3 mutations were detected in the EMPSGC cases (0/5, 0%). These clinicopathologic and genetic findings support SCAND as a tumor entity distinguishable from EMPSGC. In addition, the characteristic frameshift extension mutations in GATA3 contribute to the establishment of the tumor-type concept of SCAND.

Clinicopathologic and genetic characterization of invasive melanoma with BRAF V600K mutation: A study of 16 cases.

BACKGROUND: The clinicopathologic and genetic features of cutaneous melanoma with a BRAF V600K mutation are not well-known. We aimed to evaluate these characteristics in comparison with those associated with BRAF V600E. METHODS: Real-time polymerase chain reaction (PCR) and/or the MassARRAY® system were used to detect BRAF V600K in 16 invasive melanomas and confirm BRAF V600E in another 60 cases. Immunohistochemistry and panel next-generation sequencing were used to evaluate protein expression and tumor mutation burden, respectively. RESULTS: The median age of melanoma patients harboring the BRAF V600K mutation (72.5 years) was higher than those with the BRAF V600E (58.5 years). The two groups also differed in sex (13/16 [81.3%] male in the V600K group vs. 23/60 [38.3%] in V600E) and in the frequency of scalp involvement (8/16 [50.0%] in V600K vs. 1/60 [1.6%] in V600E). The clinical appearance was similar to a superficial spreading melanoma. Histopathologically, non-nested lentiginous intraepidermal spread and subtle solar elastosis were observed. One patient (1/13, 7.7%) had a pre-existing intradermal nevus. Diffuse PRAME immunoexpression was seen in only one (14.3%) of seven tested cases. Loss of p16 expression was observed in all 12 cases (100%) analyzed. The tumor mutation burden was 8 and 6 mutations/Mb in the two tested cases. CONCLUSIONS: Melanoma carrying the BRAF V600K mutation showed the predominance on the scalp of elderly men, lentiginous intraepidermal growth, subtle solar elastosis, possible existence of intradermal nevus component, frequent loss of p16 immunoexpression, limited immunoreactivity for PRAME, and intermediate tumor mutation burden.

Skin rash associated with combined cytotoxic chemotherapy and immunotherapy for cancer: A retrospective single-center case series.

In recent years, the development of combination therapies with immune checkpoint inhibitors (ICIs) and cytotoxic anticancer drugs has radically changed the management of diverse malignancies and significantly improved patient outcomes. Several clinical trials have shown that skin rash caused by combination therapy with ICIs and cytotoxic drugs may be more frequent and severe than that developing after administration of ICIs alone or cytotoxic drug monotherapy. However, most reports provide little information on severity, treatment, post-diagnosis course, and recurrence of rashes on drug rechallenges. We aimed to describe the experience of skin rashes developing within 2 weeks from the first administration of combination therapy with ICIs and cytotoxic drugs in 11 patients visiting our dermatology department. This study included seven men and four women, and the patients' median age was 52 years. The primary disease was non-small-cell lung cancer in eight patients, cervical cancer in two patients, and esophageal cancer in one patient. Nine patients had a maculopapular rash and two patients developed erythema multiforme-like eruptions. The skin rash was often accompanied by extracutaneous symptoms, such as fever (n = 9), mucositis (n = 4), and liver dysfunction (n = 2). In all cases, the symptoms improved with topical steroid therapy alone, with no patients exhibiting severe symptoms requiring systemic steroids or immunosuppressive agents. In addition, when the causative drugs were re-administered after recovery from the rash, only two patients relapsed with accompanying systemic symptoms, and all patients except one were able to continue treatment using the same drug regimen. Although it was suggested that the rash caused by the combination therapy of ICIs and cytotoxic drugs may be more prominent than that caused by each agent alone, comprehensive judgment, including histopathological examination, may indicate the feasibility of continuing the treatment regimen for cancer.

Erythema multiforme associated with cancer radiotherapy: A single-institution case series and literature review.

Radiation dermatitis, limited to the irradiated site, is the most common cutaneous adverse reaction due to radiotherapy. There are scattered reports of erythema multiforme-like rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis associated with radiotherapy. Some of these reports include cases without remarkable drug history, which suggests rashes induced by radiotherapy. The lack of a large cohort study, however, makes it difficult to ascertain the time course, severity, and outcome of the cases. We aimed to evaluate the potential association between radiotherapy and erythema multiforme-like rash in a larger sample of patients. We examined the records of patients at our institute who received radiotherapy and developed a rash from 2010 to 2021. We present 30 patients with erythema multiforme-like rash, which arose during or after radiotherapy. We describe the background, details of radiotherapy, and clinical course of the patients including the cutaneous and extracutaneous symptoms. Radiotherapy was the most likely cause of rash, and in most cases, the rash was relieved by conservative management and radiation could be continued. When erythema multiforme-like rash arises in patients under cancer treatment, radiotherapy should be considered a potential trigger.

Trichilemmal cysts with proteinaceous material: A potential diagnostic pitfall.

BACKGROUND: Cysts of the skin are observed frequently and their diagnoses are generally straightforward. However, atypical cystic lesions for which differentiation is indistinct have been noted. METHODS: We examined five cases of trichilemmal cyst with proteinaceous material (TCPM), which required differentiation from sweat duct/gland tumors. We investigated the histopathological findings of TCPMs and evaluated the immunohistochemical expression of cytokeratin (CK) 10, CK13, CK17, CK19, CD8, and CD117. Immunohistochemical analysis was performed on the 5 TCPMs, 10 trichilemmal cysts (TCs), 5 clear-cell hidradenomas, 5 poroid hidradenomas, and cutaneous normal adnexa. RESULTS: Apoptotic cells were present in the cyst wall with a small amount of keratin or calcification in the cavity of TCPMs. The TCPMs and TCs were negative for CK19 and CD117, on the other hand clear-cell hidradenoma and poroid hidradenoma were positive for CK19 and CD117. The restricted positivity for CK10 was detected in the suprabasal layers of the cyst walls of TCPMs and TCs. The immunostaining patterns of TCPMs and TCs were similar to those of normal follicular isthmus. CONCLUSIONS: The histopathological findings with characteristics of TCs and a panel of immunohistochemical antibodies including CD117, CK19, and CK10 contributed to a correct diagnosis of TCPM.

Proximal-type epithelioid sarcoma in pubic region expressing L-type amino acid transporter 1: A case report.

Proximal-type epithelioid sarcoma is an aggressive malignant soft-tissue neoplasm, a "proximal" variant of epithelioid sarcoma, resistant to multimodal therapy and involved in early tumor-related death. Pertinent treatments are, therefore, continually being explored. A 24-year-old woman with nonmetastatic proximal-type epithelioid sarcoma, originating subcutaneously on the right side of the vulva, underwent surgical resection; the lesion recurred, however, leading to death 3 months after the second surgery. Here described is a case of proximal-type epithelioid sarcoma expressing L-type amino acid transporter 1 (LAT1) that transports essential amino acids and p-borono-L-phenylalanine (BPA)-the chemical compound used in boron neutron capture therapy (BNCT)-and is highly expressed in many malignant tumors. Recently, LAT1 has drawn attention, and relevant treatments have been studied-LAT1 inhibitor and BNCT. LAT1 expression in proximal-type epithelioid sarcoma may lead to cogent treatments for the disease.

Signet-ring cell/histiocytoid carcinoma of the axilla: a clinicopathological and genetic analysis of 11 cases, review of the literature, and comparison with potentially related tumours.

AIMS: The aim of this study was to determine the clinicopathological and genetic characteristics of axillary signet-ring cell/histiocytoid carcinoma (SRCHC) and the relationship between axillary SRCHC, eyelid SRCHC, and conventional apocrine carcinoma (AC). METHODS AND RESULTS: Eleven cases of axillary SRCHC, four cases of eyelid SRCHC, eight cases of axillary AC and five cases of invasive lobular carcinoma (ILC) were retrieved. Additionally, 14 axillary and 43 eyelid SRCHC cases from the literature were reviewed. Male predominance was prominent for axillary SRCHC (24:1) and eyelid SRCHC (42:5). Axillary SRCHC formed a circumscribed plaque or nodule, unlike eyelid SRCHC. Lymph node metastasis was predominantly seen in axillary SRCHC cases (72%, 18/25), but not in eyelid SRCHC cases (19%, 9/47). Axillary SRCHC and eyelid SRCHC were histopathologically similar and showed rare tubular formations. Immunoexpression of cytokeratin 7, cytokeratin 19, mucin 1, mucin 5AC, BerEP4 and androgen receptor was seen in all tested cases of the four diseases. Oestrogen and progesterone receptors were negative in both types of SRCHC and AC, but were strongly positive in ILCs. Complete loss of E-cadherin expression was seen in approximately one-quarter of both types of SRCHC and in all ILCs. PIK3CA mutations were detected in all three sequenced cases (two axillary SRCHCs and one eyelid SRCHC). CONCLUSION: The histopathological, immunohistochemical and genetic findings suggest that both types of SRCHC are phenotypic variants of AC, although there are differences in sex, macroscopic findings and the frequency of lymph node metastasis among the three. In contrast, ILC differs from the other three tumour types.

Intradermal Band-like Lipomatous Metaplasia Can Be Associated With the Regression of Overlying Skin Neoplasms: A Clinicopathologic Study of 20 Cases.

ABSTRACT: Lipomatous metaplasia has been rarely reported in both neoplastic and inflammatory dermatological disorders. Most neoplastic cases show the lipomatous change within the tumor silhouette, but band-like lipomatous metaplasia in the dermis under tumors has not been well-described. The aim of this study was to reveal the characteristics and relationship of intradermal band-like lipomatous metaplasia and coexisting skin tumors. A total of 20 cases with intradermal band-like lipomatous metaplasia were retrieved from 10,992 archive cases between April 1997 and March 2020 at Hyogo Cancer Center, and subjected to a detailed clinicopathologic analysis. Nine (45%) patients had superficial variant basal cell carcinoma as a coexisting neoplasm. Eight (40%) patients had squamous cell carcinoma, 5 of which were in situ. The remaining 3 (15%) cases were invasive extramammary Paget disease. All 20 cases showed at least one of 3 signs of tumor regression, namely, partial loss of overlying neoplasia, significant inflammatory infiltrate under the tumor, and fibrosis around the tumor. We concluded that intradermal band-like lipomatous metaplasia could be seen in association with the regressing process of cutaneous superficially-spreading neoplasms.

Japanese Dermatological Association Guidelines: Outlines of Guidelines for Cutaneous Squamous Cell Carcinoma 2020.

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews.

Japanese Dermatological Association Guidelines: outlines of guidelines for cutaneous squamous cell carcinoma 2020

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews.

A case of Muir-Torre syndrome with a keratoacanthoma and sebaceous neoplasms: Clinicopathological features and a speculation on the pathogenesis of cutaneous tumor type.

Muir-Torre syndrome is a hereditary condition characterized by occurrence of sebaceous neoplasms or keratoacanthomas and visceral tumors. The most common mechanism for this syndrome is a constitutional defect in the mismatch repair genes. We report the case of a 67-year-old woman with a mutator L homologue 1 (MLH1) mutation. She had a history of endometrial and colorectal cancers. The patient presented with a typical keratoacanthoma on the right cheek and numerous sebaceous neoplasms on the face and trunk. Seven sebaceous adenomas and a low-grade sebaceous carcinoma were excised. Most sebaceous adenomas showed dermoscopic features such as some yellow comedo-like globules and curved vessels in creamy-white areas. Moreover, they revealed pathological features such as keratoacanthoma-like architecture and peritumoral or intratumoral lymphocytes. One of these sebaceous adenomas indicated histopathologically spontaneous regression and another was continuous with the hair follicle. Immunohistochemical staining for mismatch repair proteins revealed loss of expression for MLH1 and postmeiotic segregation increased 2 (PMS2) proteins in tumor cells nuclei in both keratoacanthoma and sebaceous adenoma. Nuclei in overhanging epithelial lips of the keratoacanthoma were also negative. These findings suggest that the type of Muir-Torre syndrome-related cutaneous tumor may have been affected by mismatch repair protein deficient sites in the pilosebaceous unit.

Malignant melanoma in situ associated with underlying sarcoidal granuloma: A histopathological mimicker of invasive epithelioid melanoma cells.

Malignant melanoma is known to show diverse cellular morphologies, including a histiocyte-like morphology. Therefore, many non-melanocytic proliferations or infiltrates can mimic melanoma, and be confusing especially when they coexist with a true melanoma. Herein, we report an unusual case of a melanoma in situ with an underlying sarcoidal granuloma, which mimicked dermal invasion of melanoma. This case expands insight into non-neoplastic lesions closely mimicking melanoma.

MYB Translocations in Both Myoepithelial and Ductoglandular Epithelial Cells in Adenoid Cystic Carcinoma: A Histopathologic and Genetic Reappraisal in Six Primary Cutaneous Cases.

ABSTRACT: Adenoid cystic carcinoma (ACC) is an infiltrating carcinoma composed of 2 cell types, myoepithelial and ductoglandular epithelial cells. Although approximately 70% of ACC exhibit translocations of the MYB proto-oncogene or MYB proto-oncogene like 1 (MYBL1), expression of MYB is known to be limited in myoepithelial cells. We investigated the histopathologic and genetic characteristics of ACC in 6 primary cutaneous cases. Histopathologically, 3 cases (50%) exhibited well-demarcated nodules composed of large nests, easily misdiagnosed as polymorphous sweat gland carcinoma. Two cases (33%) harbored large cystic structures resembling spiradenoma, hidradenoma, and digital papillary adenocarcinoma. A papillary pattern was focally observed in 2 cases (33%). A melting phenomenon within the myxoid stroma was seen in one case (17%). Fluorescence in situ hybridization (FISH) revealed MYB break-apart in 3 cases (50%). A combined FISH and immunohistochemical method revealed MYB break-apart signals in both p63-positive myoepithelial and p63-negative ductoglandular epithelial cells, suggesting that both cell types constitute elements of the tumor in ACC. Moreover, we established a well-circumscribed variant of ACC and proposed 3 new patterns of cystic, papillary, and melting in addition to the 3 patterns of cribriform, tubular, and solid growth.

Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review.

Agminated nevus refers to a clustered group of melanocytic nevi confined to a localized area of the body. It rarely involves acral skin, but recognition of acquired agminated nevus (AAN) in the acral area is clinically important because it may mimic acral lentiginous melanoma (ALM). However, acral AAN has only been described in a few case reports and its clinical characteristics remain unclear. We report three additional cases of acral AAN to further analyze the differential points between ALM. Clinical images, including those of dermoscopy, of three cases of acral AAN were reviewed. The lesions were located on the sole or lateral border of the foot. All acral AAN were flat and large in size (>20 mm in greatest dimension), and associated with asymmetry and irregular border. However, no parallel ridge pattern suggesting ALM was observed on dermoscopy. In two patients, the lesions on the sole were totally resected; microscopic evaluation of these two lesions confirmed junctional nests of banal melanocytes. AAN lesions on the sole with chronic mechanical pressure are slightly larger and more diffuse; thus, they may be more likely to be overdiagnosed as malignancy upon inspection than those in the non-acral area. Understanding the concept of the disease and careful dermoscopic evaluation leads to an accurate diagnosis.

Systemic treatment of patients with advanced cutaneous squamous cell carcinoma: response rates and outcomes of the regimes used.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Few patients with cSCC experience metastases, but the prognosis of advanced cSCC (acSCC) is dismal. Evidence regarding systemic therapy for acSCC is limited. Therefore, we aimed to determine the most effective systemic treatment for acSCC. PATIENTS AND METHODS: This retrospective study involved 16 Japanese institutions. We documented patient and tumour characteristics and disease course of patients with acSCC who received systemic therapy between 1st January 2006 and 31st December 2015. We compared the overall survival (OS) and progression-free survival (PFS) for (1) platinum versus non-platinum groups, (2) radiation plus chemotherapy first-line therapy (RCT) versus non-RCT groups and (3) platinum-based RCT versus non-platinum-based RCT groups. RESULTS: Although the use of platinum-based systemic therapy was not associated with statistically significant improvements in PFS and OS, there were significant differences between the RCT and non-RCT groups (PFS: p < 0.001, OS: p = 0.003). In the subgroup analysis, RCT significantly prolonged PFS and OS in the nodal SCC (nSCC) group. For the RCT and non-RCT groups, the median OS was 110 and 14 months, respectively, and the 5-year OS rate was 54% and 21%, respectively. CONCLUSION: RCT could improve OS in patients with nSCC. However, further multicenter prospective studies are needed to establish evidence for superiority of RCT.