Dermatopathology

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are highly prevalent and a significant cause of morbidity. Image-guided superficial radiation therapy (IGSRT) uses integrated high-resolution dermal ultrasound to improve lesion visualization, but it is unknown whether efficacy varies by histology. This large retrospective cohort study was conducted to determine the effect of tumor histology on freedom from recurrence in 20,069 biopsy-proven NMSC lesions treated with IGSRT, including 9928 BCCs (49.5%), 5294 SCCs (26.4%), 4648 SCCIS cases (23.2%), and 199 lesions with ≥2 NMSCs (1.0%). Freedom from recurrence at 2, 4, and 6 years was 99.60%, 99.45%, and 99.45% in BCC; 99.58%, 99.49%, and 99.49% in SCC; and 99.96%, 99.80%, and 99.80% in SCCIS. Freedom from recurrence at 2, 4, and 6 years following IGSRT did not differ significantly comparing BCC vs. non-BCC or SCC vs. non-SCC but were slightly lower among SCCIS vs. non-SCCIS (p = 0.002). There were no significant differences in freedom from recurrence when stratifying lesions by histologic subtype. This study demonstrates that there is no significant effect of histology on freedom from recurrence in IGSRT-treated NMSC except in SCCIS. These findings support IGSRT as a first-line therapeutic option for NMSC regardless of histology. Full article

Background: Tumor collision is a rare event, with an estimated incidence of 0.0017%. Seborrheic keratosis, melanocytic nevi, and basal cell carcinoma (BCC) are by far the most common entities involved in collisions. Most authors consider collision to be an incidental event. I planned a retrospective study comparing BCC/apocrine–sebaceous–follicular unit (ASFu) neoplasm collisions with squamous cell carcinoma (SCC)/ASFu neoplasm collisions. Materials and methods: Files from 2005 to 2017 from Dr. José Molina Orosa Hospital were assessed; in the review, cases of collisions between BCCs or SSCs and ASFu tumors, including cysts, were identified. Results: Out of 3247 BCC cases, 12 biopsies were retrieved. Of 825 biopsies, none belonged to the SCC group. The ASFu tumors that collided with a BCC were as follows: four hidrocystomas, three infundibular cysts, two steatocystomas, two trichilemmomas, one spiradenoma, and one clear-cell hidradenoma (one patient had two cysts associated with a BCC). These cases correspond to seven female patients and five male patients aged between 26 and 91 years old. A quarter of these patients were immunosuppressed. Most ASFu neoplasms were found to be located beneath the BCC (8/12). Discussion: To the best of my knowledge, this report describes three new collisions of BCCs with ASFu neoplasms (infundibular cysts, steatocystomas, and a spiradenoma). My results also suggest that immunosuppression could be a factor that predisposes a patient to these collisions. I review current hypotheses in an effort to explain these collisions and contribute some new theories. Full article

TRPS1 (Tricho-rhino-phalangeal syndrome 1) is a GATA transcriptional activator gene encoding for a protein used as a sensitive immunohistochemical marker of breast carcinomas. In dermatopathology, TRPS1 is used as a marker of mammary and extramammary Paget’s disease and is also expressed by a variety of primary cutaneous tumors, mostly of adnexal origin. So far, very limited data exist on the expression of TRPS1 in metastatic skin tumors. We studied the immunohistochemical expression of TRPS1 in 72 cutaneous metastatic tumors from the breast (n: 19) and other origins (n: 53) in order to assess its diagnostic usefulness. The intensity of TRPS1 immunostaining was expressed as a histoscore: the product of the percentage of positive cells (scored semi-quantitatively 0–4) and the staining intensity (scored 0–3). In normal skin, nuclear TRPS1 expression was predominantly observed in cells of adnexal structures (pilosebaceous follicles and sweat glands). Eighteen (18/19, 94.7%) metastatic breast carcinomas showed diffuse and strong TRPS1 positivity (histoscore 12). Lower reactivity was found in some other metastases, including from the lung (11/22), the female genital tract (3/4), and the kidney (2/4), whereas most (20/22) metastases from the digestive system and peritoneum, along with a case of metastatic prostate carcinoma, were negative. These results suggest that a high histoscore for TRPS1 is in favor of the mammary origin of metastatic cutaneous carcinoma. Although TRPS1 is not absolutely specific or sensitive to a particular primary, we consider that it can be added to a panel of other markers when investigating the origin of a cutaneous metastasis, namely when this is the first manifestation of the neoplastic disease. Full article

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive soft tissue sarcoma with a poor prognosis. The patients are usually found to have metastasis when the primary tumor is diagnosed. Eccrine syringofibroadenoma (ESFA) is a rare cutaneous adnexal lesion of eccrine duct origin. There are five subtypes, one of which is reactive ESFA, known to occur in reaction to an inflammatory or neoplastic process. In this article, we report a case of the co-existence of both UPS and ESFA in a 70-year-old male patient, presenting with a painless, erythematous, irregular surface nodule with a peripherally extended brownish hyperkeratotic plaque on the right palm. The histologic findings revealed an ill-defined dermal tumor of atypical epithelioid and spindle-shaped cells with large pleomorphic hyperchromatic nuclei and abundant eosinophilic cytoplasm. Some of those cells were multinucleated giant cells in the stroma with vascular proliferation and mixed inflammatory cell infiltrate. The tumor cells, which were only positive for vimentin, supported the diagnosis of undifferentiated pleomorphic sarcoma (UPS). Meanwhile, the overlying epidermis demonstrated hyperkeratosis, papillated epidermal hyperplasia, and proliferation of anastomosing slender cords and strands of cuboid cells within loose fibrovascular stroma. These findings are the characteristics of eccrine syringofibroadenoma (ESFA). We describe here a patient in whom reactive ESFA occurred on and surrounded the UPS tumor. Full article

Considerable controversy exists within the field of dermatopathology in differentiating keratoacanthoma (KA) from squamous-cell carcinoma (SCC). KAs are rapidly growing, benign squamous tumors that are typically well differentiated. This controversy stems from the diverging perspectives on the management, classification, and diagnosis of each entity. Many believe that KAs are benign neoplasms in which intervention may be unnecessary since they are self-limiting and resolve on their own. On the other hand, SCC needs to be treated, as it carries significant morbidity and mortality risks. Early diagnosis and treatment are vital to prevent serious consequences of SCC. Nevertheless, KAs may resemble SCC grossly and microscopically. Various ancillary tests, including immunohistochemical (IHC) staining, have been proposed to differentiate between these entities, though mixed patterns of expression can limit the diagnostic utility of these techniques. Research into this topic is ongoing, with newer genetic and molecular findings illuminating the previously difficult-to-understand aspects of KA and increasing our understanding of this entity. In this review, KA and SCC will be compared along the lines of histological features, genetic, immune, and molecular markers, differential diagnosis, and management to clarify the similarities, differences, and misconceptions about both entities. Full article

A 11-year-old Caucasian girl presented to our Dermatology Unit with a 2-month history of an erythematous nodule, localized to the medial portion of her left eyebrow, rapidly growing in the two weeks before presentation. The histopathological examination revealed a dermal multi-nodular epithelial neoplasm composed of clear cells, squamous cells, and glandular cells, characterized by cytologic atypia, high mitotic activity, and an infiltrative deep growth pattern. The immunohistochemical profile of the lesion was as follows: CKAE1/AE3+, EMA+, CK8/18+, CK7+, CK19+, AR negative, p63 focally +, Ki67 25%, rare cells GCDFP15+, p53+. Full article

Dermatologic care within the military faces unique ethical challenges. Service members are stationed across nationally and globally diverse settings, and therefore, dermatologic care rendered ranges from within resource-rich, advanced military medical treatment facilities to austere, resource-limited, deployed field environments. Additionally, military service members are often at unique risk for dermatologic disease, given occupational, environmental, and geographic exposures not commonly faced by their civilian counterparts. This review explores topics in dermatoethics via case analyses of ethical considerations within the scope of dermatologic care for military service members. Full article

Skin tumors, especially melanoma, which is highly aggressive and progresses quickly to other sites, are an issue in various parts of the world. Nevertheless, the one and only way to save lives is to detect it at its initial stages. This study explores the application of advanced deep learning models for classifying benign and malignant melanoma using dermoscopic images. The aim of the study is to enhance the accuracy and efficiency of melanoma diagnosis with the ConvNeXt, Vision Transformer (ViT) Base-16, and Swin Transformer V2 Small (Swin V2 S) deep learning models. The ConvNeXt model, which integrates principles of both convolutional neural networks and transformers, demonstrated superior performance, with balanced precision and recall metrics. The dataset, sourced from Kaggle, comprises 13,900 uniformly sized images, preprocessed to standardize the inputs for the models. Experimental results revealed that ConvNeXt achieved the highest diagnostic accuracy among the tested models. Experimental results revealed that ConvNeXt achieved an accuracy of 91.5%, with balanced precision and recall rates of 90.45% and 92.8% for benign cases, and 92.61% and 90.2% for malignant cases, respectively. The F1-scores for ConvNeXt were 91.61% for benign cases and 91.39% for malignant cases. This research points out the potential of hybrid deep learning architectures in medical image analysis, particularly for early melanoma detection. Full article

Netherton syndrome (NS) is a rare autosomal recessive disorder that occurs due to a loss-of-function mutation in SPINK5; this loss results in significant inflammation, as well as perturbations of the skin barrier’s integrity and functionality. While it is unclear which inflammatory pathways contribute to the development of NS, recent studies have demonstrated the expression of interleukin (IL)-17/IL-36, as well as several Th2 cytokines. Consequently, immunohistochemistry (IHC) with IL-36 may serve as a potential tool for aiding the histopathological diagnosis of this condition. In this case series, we present two cases of NS and capture their immunostaining pattern with IL-36. Both cases demonstrated robust expression of IL-36. This finding bolsters the hypothesis that NS is partially driven by Th17 activation and suggests the potential utility of IL-36 IHC as part of the workup for this rare and diagnostically elusive entity. LEKTI IHC was negative in one biopsy, revealing a limitation of this stain in diagnosing NS. Full article

IgG4-RD is a multisystem fibroinflammatory disease characterized by the infiltration of tissues by IgG4 plasma cells. Combined skin and biliary tract involvement in IgG4-RD has not been described. We present perhaps the most comprehensive analysis of lymphocyte subsets in the first case of IgG4-related generalized skin rash and first case of combined skin and biliary tract manifestations. A 55-year-old male presented with painful jaundice and generalized macular pigmented pruritic eruptions, and CT abdomen revealed biliary obstruction. Ampulla and skin biopsies were subjected to histology and immunostaining. Naïve, central memory (T_CM), effector memory (T_EM), terminally differentiated effector memory (T_EMRA) subsets of CD4+ and CD8+ T cells, T follicular helper subsets, naïve, transitional, marginal zone (MZ), germinal center (GC), IgM memory, and class-switched memory (CSM) B cells, and T follicular regulatory, regulatory B cells, CD4 Treg, and CD8 Treg were analyzed. Serum IgG4 was elevated at 448 mg/dL. Ampula biopsy showed lamina propria fibrosis and increased IgG4-positive plasma cells. Skin punch biopsy showed lymphoplasmacytic infiltrates with a 67% ratio of IgG4+:IgG+ plasma cells. CD4+T_N and CD4+T_CM decreased, whereas CD4+T_EM increased. Naïve B cells increased; transitional, MZ, CSM, GC B cells, and plasmablasts decreased compared to control. CD4 Treg increased, whereas CD8 Treg and Breg decreased. In conclusion, IgG-RD may present with combined biliary tract and generalized dermatological manifestations. Changes in regulatory lymphocytes suggest their role in the pathogenesis of IgG4-RD. Full article

A cutaneous carcinosarcoma (cCS) is a rare and aggressive skin cancer characterized by both carcinomatous (epithelial) and sarcomatous (mesenchymal) components, making it a biphasic tumor. Despite its occurrence in various organs, a cCS is exceptionally rare in the skin, predominantly affecting older males. The etiology of a cCS is unclear, but it may originate from a single progenitor cell capable of dual differentiation or from a collision of carcinoma and sarcoma cells. Clinically, a cCS presents as a rapidly growing, painful, ulcerated nodule or plaque on sun-exposed skin, with a high risk of local invasion and metastasis. Histopathologically, a cCS includes various epithelial components, such as squamous cell carcinoma and basal cell carcinoma, along with undifferentiated sarcomatous components resembling atypical fibroxanthoma. The tumor may also exhibit heterologous differentiation like angiosarcomatous or rhabdomyosarcomatous features. We present three cases of a cCS, highlighting their clinical and histological characteristics and comparing them with previously reported cases. Understanding a cCS is complicated by its rarity and diverse presentation, emphasizing the need for further research to elucidate its pathogenesis and optimal management. Full article

Although extensively studied in cutaneous epithelial neoplasms, the TRPS1 immunoreactivity in cutaneous mesenchymal neoplasms and tumors of uncertain differentiation (CMNTUDs), such as atypical fibroxanthoma (AFX), remains largely unexplored. We assessed TRPS1 immunoreactivity in 135 CMNTUDs, comprising 46 fibrohistiocytic/fibroblastic tumors, 28 vascular tumors, 24 peripheral nerve sheath tumors (PNSTs), 21 tumors of uncertain differentiation, and 16 smooth muscle tumors. Additionally, we included selected cases of melanoma with spindled cell morphology or desmoplastic features (n = 9) and sarcomatoid squamous cell carcinoma (SSCC) (n = 5) to compare TRPS1 expression patterns with those of AFX. TRPS1 expression was prevalent in dermatofibromas (24/24), leiomyomas (8/8), AFXs/pleomorphic dermal sarcoma (PDS) (20/21), dermatofibrosarcomas protuberans (14/22), and leiomyosarcomas (6/8). It was uncommon in angiosarcomas (3/20), Kaposi sarcomas (2/8), and neurofibromas (5/17) and absent in perineuriomas (0/2). AFXs/PDS exhibited the highest median H-score of 240, contrasting with minimal TRPS1 immunoreactivity in vascular neoplasms and PNSTs, with median H-scores consistently below 10. Significant differences in H-score were observed between AFXs/PDS and angiosarcomas (p < 0.001), melanomas (p < 0.001), and leiomyosarcomas (p = 0.029). However, no significant difference was found compared to SSCCs, suggesting limited discriminatory power of TRPS1 in this context. This study sheds light on TRPS1 expression patterns in a subset of CMNTUDs, extending beyond prior studies primarily focused on epithelial tumors, while underscoring potential pitfalls associated with TRPS1 immunohistochemistry. Full article

ACE2 is a mono-carboxypeptidase with remarkable vasculo-protective properties, and its expression in the human placenta plays a central role in blood pressure homeostasis and fetal perfusion. Therefore, an alteration in the placental expression of ACE2 could be responsible for reduced placental perfusion and infantile hemangioma (IH) development. Study placentae were collected from patients affected by IHs who were referred to our Dermatology Clinic from 2016 to 2022, while control placentae were randomly collected while matching cases for gestational age. Immunohistochemical investigations were performed with a recombinant anti-ACE2 rabbit monoclonal antibody. A total of 47 placentae were examined, including 20 study placentae and 27 control ones. The mean placental weight was significantly lower in the study group (380.6 g vs. 502.3 g; p = 0.005), while subclinical chorioamnionitis occurred more frequently in the study group (20% vs. 0%, p = 0.03). The mean ACE2 expression was dramatically lower in the study group (χ2 = 42.1 p < 0.001), and the mean placental weight was significantly lower when ACE2 was not expressed compared to the 25–75% and >75% classes of expression (p < 0.05). This study demonstrated that ACE2, as a marker for tissue hypoxia, is dramatically hypo-expressed in placentae belonging to mothers who delivered one or more babies with IH compared to the controls. Full article

Pleomorphic dermal sarcomas can be clinically aggressive, with a higher tendency to cause local recurrence, metastasis, and death. Atypical fibroxanthoma and pleomorphic dermal sarcoma are histopathologically similar, and their distinction requires a systematic examination of the entire excised tumor. Since Mohs micrographic surgery is commonly utilized to treat atypical fibroxanthoma, a histopathologic evaluation of debulk specimens by permanent pathology is prudent to avoid underdiagnosing pleomorphic dermal sarcoma. This approach can improve risk assessment and treatment decisions, ultimately enhancing patient outcomes. Also, the proper distinction will facilitate the future development of accurate staging criteria and additional treatment modalities. Full article

Digital papillary adenocarcinoma (DPA) is a rare malignant neoplasm which arises from the sweat glands and has metastatic potential. DPA exhibits a wide range of architectural features and exhibits low-grade to high-grade features, so distinguishing DPA from benign skin neoplasms, including acral hidradenoma, poses significant diagnostic challenges. The recent literature suggests a strong association between DPA and human papillomavirus (HPV) 42, a low-risk HPV (LR-HPV) subtype, and a possible association between DPA and BRAF p.V600E. To explore these associations, we assessed the utility of in situ hybridization (ISH) for LR-HPV (types 6, 11, 40, 42, 43, 44) and immunohistochemistry (IHC) for BRAF p.V600E in diagnosing DPA and distinguishing DPA from acral hidradenoma. With institutional review board approval, we retrospectively identified 15 specimens of DPA (from 13 patients) and 3 cases of acral hidradenoma. Of the 13 DPA cases, 6 were negative for LR-HPV and BRAF p.V600E; 6 were positive for only LR-HPV; and 1 was positive for only BRAF p.V600E but negative for LR-HPV. All three cases of acral hidradenoma were negative for LR-HPV and BRAF p.V600E. As our sample size is limited, larger studies are needed to assess the value of detecting LR-HPV and BRAF p.V600E in the distinction of DPA and acral hidradenoma. However, our findings indicate a stronger association of DPA with LR-HPV than with BRAF p.V600E. Full article

Primary cutaneous lymphomas (PCLs), especially mycosis fungoides (MF), pose significant diagnostic and therapeutic challenges. This study aims to correlate initial histological features with the disease course and survival in MF patients. A retrospective–prospective cohort study was conducted on 83 patients diagnosed with early-stage MF at the Departments of Dermatovenerology and Pathology, UHC Zagreb, from January 2003 to December 2012. The analyzed histopathological parameters included lichenoid dermal lymphocyte infiltrate, Pautrier microabscesses, and lymphocyte atypia. Patients with more than 30 guardian lymphocytes per 100 keratinocytes exhibited worse overall and progression-free survival. Furthermore, those with over 50% atypical lymphocytes demonstrated a faster progression rate. A dense lichenoid dermal infiltrate and a high count of lymphocyte “keepers” significantly increased the mortality risk within five years of diagnosis. This study did not fully confirm the hypothesis regarding the prognostic value of large Pautrier microabscesses but highlighted the importance of dense lichenoid infiltrates. The study identified new potential histopathological prognostic factors in early-stage MF, suggesting the need for larger studies to confirm these findings. The identification of such predictors could enhance the prognostic stratification and guide more tailored therapeutic approaches for MF patients. Full article

A 74-year-old woman in good general health presented with a 5-year history of progressive hair loss over several years, interpreted as female androgenetic alopecia (AGA), and was treated with topical 5% Minoxidil without improvement. The patient’s relevant medical history revealed infiltrating, triple-negative apocrine carcinoma of the right breast four years before, treated by quadrantectomy, radiation, lymphadenectomy and chemotherapy, with no recurrence at the last follow-up. On examination, there was an asymptomatic 15 × 15 cm firm and whitish area of scarring alopecia on the central scalp. Dermoscopy revealed multiple arborizing vessels and many telangiectasia. The clinical considerations included mainly cutaneous metastasis of breast carcinoma (alopecia neoplastica), pseudopelade of Broque and morpheaform basal cell carcinoma (BCC). A histopathologic examination revealed characteristic changes of morpheaform BCC with basaloid islands and cords of atypical basaloid cells diffusely infiltrating the dermis, embedded in a sclerotic and hypervascularized stroma. Secondary alopecia neoplastica due to morpheaform BCC on the scalp is an exceedingly rare entity, possessing subtle clinical features that may mimic both scarring and non-scarring alopecia. Delayed recognition may contribute to aggressive behavior and extensive local destruction. Treatment with hedgehog inhibitors in locally advanced BCC of the scalp, both in adjuvant and neoadjuvant modalities, is promising. Full article

Poikilodermatous plaque-like hemangioma (PPH) is a recently described clinical and pathological entity, with only 18 cases reported in the literature. Although uncommon, this benign condition presents consistent clinical and histological findings. We present a new case of PPH in an 81-year-old male and review the existing literature. The persistence over time and the need to distinguish PPH from more significant lesions underscore the importance of its clinical and pathological recognition. Full article