Fusion-driven cutaneous and superficial mesenchymal and adnexal tumors-A clinicopathologic and molecular study of 15 cases, including a novel case of ACTB::ZMIZ2-rearranged adnexal carcinoma.

BACKGROUND: While the list of fusion-driven soft tissue neoplasms is expanding rapidly, their importance among cutaneous and superficial mesenchymal and adnexal neoplasms remains poorly understood. This challenge is especially evident in cases with ambiguous histopathology that are difficult to classify based on morphology. AIMS: Our goal was to investigate the benefits of next-generation sequencing in diagnosing complex cutaneous neoplasms. MATERIALS & METHODS: Departmental archives were searched for fusion-driven cutaneous neoplasms. Slides were retrieved and clinical information including follow-up was obtained. RESULTS: Fifteen cases occurred in eight female and seven male patients, with a median age of 26 years (range: 1-83) at diagnosis. Tumors involved the extremities (9), scalp (5), and head and neck (1). Predominant features included myoepithelial (5), nested spindled with clear cytoplasm (2), atypical adnexal/squamoid (2), small round blue cell (2), cellular spindled (3), and fibrohistiocytic morphology (1). Most frequently encountered fusions involved EWSR1 (6) fused to ERG (1), FLI1 (1), CREB1 (2), CREM (1), PBX3 (1), followed by PLAG1 (4) with LIFR (2), TRPS1 (1) and CHCHD7. Additional fusions encountered were YAP1::NUTM1, EML4::ALK, SS18::SSX1 (2), and a novel fusion: ACTB::ZMIZ2. Integration of histologic features and molecular findings led to final diagnoses of primary cutaneous Ewing sarcoma (2), soft tissue myoepithelioma (4), cutaneous syncytial myoepithelioma (1), cutaneous adnexal carcinoma (1), porocarcinoma (1), inflammatory myofibroblastic tumor (1), synovial sarcoma (2), clear cell sarcoma (2), and angiomatoid fibrous histiocytoma (1). DISCUSSION AND CONCLUSION: Our results show that fusion testing can be a helpful diagnostic tool, especially in cases with unusual or uncommon morphology in superficial sites. Furthermore, it can allow for the identification of potential therapeutic targets in some instances.

Proliferating Pilar Tumors in the Scalp Over a Period of 23 Years in a General Hospital in Mexico City.

BACKGROUND: Proliferating pilar tumors are an unusual skin tumor, and they have a cystic component with trichilemmal keratinization and epithelial proliferation. These arise from the outer root sheath of hair follicles. It mainly affects women. The scalp is the most affected area. Diagnosis can be made by biopsy. Surgical excision is the best treatment option. OBJECTIVE: Report the frequency of proliferating pilar tumors in the scalp in general hospital in Mexico over a period of 23 years. METHODS: The authors reviewed the database of the dermatopathology service of the General Hospital "Dr Manuel Gea González" from 1999 to August 2022, selecting diagnosticated cases of proliferating pilar tumor, pilar cyst, trichilemmal cyst, or proliferating trichilemmal cyst in the scalp. RESULTS: The authors discovered 17 cases, 13 were women, the average age was 54.9 years, all the tumors affecting the scalp, and just 3 cases were reported as malignant. CONCLUSION: In comparison with the existing data, the authors can observe that most of their patients were women and the scalp is the most affected area. Most did not present associated symptoms. As the authors can see, most are benign and long-lasting: however, the authors cannot ignore that a small percentage can be malignant.

Atypical Melanocytic Matricoma: A Case Report with Molecular Studies.

ABSTRACT: Melanocytic matricoma is a rare benign pilar tumor characterized by matrical differentiation and interspersed dendritic melanocytes. It may show cellular atypia and brisk mitotic activity. Histological characterization of some lesions may be difficult. In addition, because the reported cases are few and have limited follow-up, there is insufficient experience to define outcome-based criteria for malignancy. Some cases of melanocytic matricoma with more prominent atypia have been reported as malignant, but their clinical behavior is uncertain. We present a melanocytic matricoma with interspersed benign dendritic melanocytes, but moderate basaloid atypia, focally brisk mitotic activity, and atypical mitoses. Despite the apparently good delimitation of this tumor, higher magnification revealed a slightly irregular border. However, overt malignant features such as necrosis, frank asymmetry, deep infiltration, and ulceration were not present. This tumor showed a complex aberrant genomic profile with multiple whole chromosomes or chromosomal arms, losses, and duplications. The tumor mutational burden was high. A loss-of-function alteration in CDKN2A and a loss-of-function mutation in TP53 were also present. This unexpected molecular profile contrasts with the relatively bland histology of the tumor and is in line with the difficulties in microscopic differential diagnosis between melanocytic matricoma and an indolent malignant pilomatrical tumor. We suggest that molecular studies and longer follow-up periods may help to further understand and more precisely categorize borderline pilomatrical tumors with melanocytic hyperplasia.

The complex and often confusing history, histology and histogenesis of mesonephric, STK11 adnexal tumour and mesonephric-like neoplasms of the upper female genital tract (including broad ligament).

Mesonephric lesions in the female genital tract are uncommon, with those arising from the upper tract being much less frequent than those developing in the lower tract (mesonephric hyperplasia and carcinoma). The most common upper tract lesions include rete cyst/cystadenoma and female adnexal tumour of Wolffian origin (FATWO). The integration of morphological, immunohistochemical and molecular studies on FATWOs has enabled recognition of a novel entity, the STK11 adnexal tumour, which is often associated with Peutz-Jeghers syndrome (~50%) and frequently has a salivary gland morphology but an unknown origin. Similarly, 'mesonephric-like' adenocarcinoma, an entity with striking similarities to mesonephric carcinoma but currently favoured to be of Müllerian derivation based on its association with other Müllerian tumours and molecular findings, has also been recently described, and may histologically mimic both FATWOs and STK11 adnexal tumours. In this review, we provide a historical overview of upper female genital tract mesonephric proliferations and discuss mesonephric lesions, STK11 adnexal tumour, mesonephric-like adenocarcinoma, and mimickers, the most common being endometrioid carcinoma.

Melanocytic matricoma: A report of three cases, review of the literature, and suggestion of a new terminology.

Melanocytic matricoma is a rare, biphasic adnexal tumor. It typically presents as a pigmented papule on the sun-damaged skin of elderly patients. Histopathology shows a dermal nodule composed of basaloid cells, ghost cells, and deeply pigmented dendritic melanocytes. The basaloid cells are usually positive for ß-catenin and these tumors show overlapping histopathological and molecular features with pilomatricoma. Here, we review the literature on melanocytic matricoma and present three new cases. We suggest different terminology to reflect the overlapping features with pilomatricoma that recognizes that melanocytic matricoma is likely to be a variant of pilomatricoma associated with melanocytic hyperplasia. Although melanocytic matricoma is usually considered benign, malignant transformation has been reported. This highlights the need for increased awareness of this entity.

The Utility of Myoepithelial Cell Layer Identification in Adnexal Carcinomas.

ABSTRACT: The distinction of metastatic carcinomas to the skin (MCS) from cutaneous adnexal carcinomas can pose a significant diagnostic challenge. The differentiation between (MCS) from a primary cutaneous adnexal tumor is one of the most difficult tasks in the field of dermatopathology, and immunohistochemistry has only been partially helpful in solving this problem. In routine diagnostic surgical pathology, it is essential to identify the myoepithelial cell layer by immunohistochemistry to distinguish between an in situ and invasive breast carcinomas and when establishing the presence of microinvasion. The purpose of this study was to evaluate the role of myoepithelial cell layer expression in difficult cases of cutaneous adnexal carcinomas in which histologically it was challenging to separate them from MCS. We studied 38 adnexal carcinomas and evaluated them for myoepithelial markers to confirm the primary nature of the neoplasm. The used markers to search for myoepithelial cell layer retention included calponin, p63, and smooth muscle actin. Of the 38 cases, we found that 13 cases showed myoepithelial layer retention, confirming the primary cutaneous origin of the neoplastic process. The results of our study suggest that the presence of an identifiable retention of the myoepithelial cell layer in adnexal carcinomas could be a useful adjunct observation in the diagnosis of primary adnexal carcinomas, especially in the clinical setting of a questionable primary adnexal versus metastatic neoplasm.

In Vivo Reflectance Confocal Microscopy of Adnexal Tumors: Evaluation of Trichoepithelioma, Sebaceoma, and Fibrofolliculoma.

ABSTRACT: Cutaneous adnexal tumors are benign and malignant neoplasms that undergo morphological differentiation into cutaneous adnexa, comprising pilosebaceous, eccrine, or apocrine units. Reflectance confocal microscopy is a noninvasive diagnostic method that enables in vivo visualization of tissues at a similar resolution as conventional histopathology. The use of this method in skin imaging over the past several years has improved dermatological diagnoses, potentiating its wide application, especially for benign and malignant skin tumors. We describe the use of reflectance confocal microscopy in cases of trichoepithelioma, sebaceoma, and fibrofolliculoma and correlate the resulting clinical, histopathological, and confocal microscopy images.

Microcystic adnexal carcinoma with germinative follicular differentiation.

Microcystic adnexal carcinoma (MAC) is a low-grade adnexal carcinoma with controversial lines of differentiation. We present here an example of MAC showing histopathologic findings of germinative follicular differentiation in the form of solid aggregates of trichoblastoma intermingled with neoplastic aggregates of MAC. Immunohistochemical findings, showing positivity for PHLDA1 and negativity for BerEp4 in neoplastic aggregates of trichoblastoma, also supported a germinative follicular differentiation. Follicular differentiation in MAC supports an apocrine line of differentiation for this neoplasm.

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

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

Skin tumors in xeroderma pigmentosum: Evaluation of a large series and a literature review.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare genodermatosis with a lifelong propensity to develop malignant skin tumors. METHODS: In this retrospective study, 24 XP patients were evaluated with regard to frequency and clinicopathological features of benign and malignant skin tumors. RESULTS: Seventeen patients had at least one malignant skin tumor diagnosed: basal cell carcinoma (BCC) in 13 patients (n = 72), basosquamous carcinoma in three patients (n = 4), squamous cell carcinoma in six patients (n = 13), keratoacanthoma in three patients (n = 15), and melanoma in six patients (n = 18). Most melanomas (n = 15) were in situ lesions. Several benign skin tumors were noted such as tricholemmoma (n = 1), trichoepithelioma (n = 1), trichoblastoma (n = 1), follicular infundibulum tumor (n = 1), keratoacanthoma-like follicular lesion (n = 1), adnexal tumors with folliculosebaceous (n = 1) and tricholemmal differentiation (n = 1), and neurofibroma (n = 1). Benign vascular proliferations including pyogenic granulomas (n = 8), widespread telangiectasias, and senile angioma-like lesions were also observed in 3, 5, and 5 patients, respectively. CONCLUSIONS: Similar to many reports, BCC was found to be the most common malignant skin tumor. The high prevalence of benign adnexal tumors of follicular differentiation, some of them showing mixed histopathological features and various vascular proliferations in our series raises the question of whether they indicate a formerly undescribed association with XP.

Expression of Hedgehog signalling molecules in microcystic adnexal carcinoma.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. AIM: To assess expression profiles of Hedgehog (HH) signalling molecules in MAC and control tumours. METHODS: Immunohistochemistry was performed for Sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched 1 (PTCH1) and Smoothened (SMO) on patient MAC tissue (n = 26) and control tumour tissue, including syringoma (SyG; n = 11), trichoepithelioma (TE; n = 11) and basal cell carcinoma (BCC; n = 12) tissues. RESULTS: Patched 1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE or MAC (P < 0.001 and P < 0.03, respectively). The highest IHH expression was observed in BCC and TE compared with SyG and MAC (P < 0.04). Notably, the highest SHH protein expression was observed in SyG compared with MAC, TE and even BCC (P < 0.001). In patients with MAC, SMO immunoreactivity significantly (r = 0.51; P < 0.01) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). CONCLUSION: Our results indicate that alterations of the HH signalling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Malignant Proliferating Trichilemmal Tumor of the Scalp: A Systematic Review.

OBJECTIVES: Malignant proliferating trichilemmal tumors of the scalp can exhibit aggressive presentation and recurrences. Our objective was to perform an evidence-based systematic review evaluating clinical presentation, tumor characteristics, and treatment modalities used to determine which treatment strategies had the best outcomes. METHODS: The databases PubMed, Embase, and Cochrane Library were searched for relevant literature by the authors. Patient demographics, imaging, treatments, and other clinical characteristics were obtained. The results were reported using the Preferred Reporting Systems for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Thirty-nine studies with a total of 65 patients were identified. The most common presentation was a history of slow-growing, painless swollen mass on the scalp. In total, 10 patients (15.4%) presented with spread to the regional lymph nodes and 6 (9.2%) additional patients presented with metastasis to distant locations. In total, 61 patients (93.8%) underwent surgery. Various chemotherapy and radiation therapy regimens were used. Of the 45 cases with documented follow-up, 11 (24.4%) patients had one or multiple instances of local, lymph node or metastatic tumor recurrence. CONCLUSIONS: Surgery is favored, and the exact approach should be based on clinical judgment. However, Mohs micrographic surgery should strongly be considered because of its superior margin control against such an invasive tumor. Radiotherapy and chemotherapy have been used as adjuvant therapy in aggressive cases or recurrence. Patients should be followed closely and examined often to frequently assess recurrence or metastasis. Randomized controlled trials are needed to further clarify these findings.

Trichoblastoma: A Consecutive Series of 349 Sporadic Cases Analyzed by Ackerman Subtypes.

ABSTRACT: Trichoblastoma (TB) is a benign biphasic follicular neoplasm with differentiation toward the germinative cells and a specific follicular mesenchyme. We subtyped 349 sporadic TB according to a classification proposed by Ackerman. Two hundred forty-six (246/349, 70.5%) neoplasms were comprised of mixed subtypes. TB composed exclusively of a single pattern was less common (103/349, 29.5%). The most common pure subtype was cribriform TB followed by small nodular TB. Twelve cases (12/349, 3.4%) had unique features and are reported herein as novel histopathologic subtypes of the neoplasm.

Microcystic Adnexal Adenoma: The Benign Counterpart of Microcystic Adnexal Carcinoma.

ABSTRACT: Microcystic adnexal carcinoma (MAC) is a low-grade malignant neoplasm of slow growth and low metastatic potential, but locally aggressive. Architecturally, MAC is usually a poorly circumscribed neoplasm that tends to extend deeply into the dermis and subcutaneous tissue. We present here a lesion in which the histopathologic study showed a well-demarcated nodular lesion involving the mid dermis and composed of small cystic keratinous structures, solid aggregates of pale squamous cells without cytologic atypia and ductal structures. Although these neoplastic components resembled those of MAC, the sharp delimitation of the lesion as well as the absence of deep extension and perineural involvement supported the benign nature of this lesion. We have named this neoplasm microcystic adnexal adenoma, as the benign counterpart of MAC.

Management of multiple trichoepithelioma: A review of pharmacological therapies.

Trichoepithelioma is a rare benign adnexal neoplasm that can occur in various forms including solitary, multiple, familial or nonfamilial. Multiple facial trichoepithelioma can be associated with significant psychosocial burden. Conventional treatment modalities such as surgical excision and ablative laser have variable results and can be associated with unacceptable complications and tumour regrowth. Pharmacological interventions such as topical and systemic agents are potentially effective but clinical data are limited and treatments are poorly standardised. We review the available evidence to determine the role of pharmacological therapies in the management of multiple trichoepithelioma. Demographic and clinical data were retrospectively collected from the available English literature. Majority of cases treated with pharmacological therapies (93.75%) had a positive treatment outcome, achieving partial lesion response. Adverse effects associated with pharmacological therapies were generally well tolerated and did not interrupt treatment. There are limitations as to how our results can be interpreted owing to the paucity of good quality evidence, spectrum of disease severity, and diversity of study designs utilised in the included articles. Nonetheless, the results of our study indicate that while most pharmacological interventions for multiple trichoepithelioma produce a partial response, they can be employed as effective suppressive therapies, either alone or in conjunction with conventional treatments. The current evidence for pharmacological therapies remains largely anecdotal justifying the need for further clinical studies in this area.

Morphologically high-grade microcystic adnexal carcinoma: a report of two cases.

AIMS: Microcystic adnexal carcinoma is a distinctive sweat duct carcinoma of low-grade malignant potential with a risk for locally destructive growth and local recurrence. Distant metastases and disease-related mortality are exceptional. The histological hallmarks of these tumours are the diffusely infiltrative growth within the dermis, the frequent invasion of subcutaneous structures, the presence of perineurial invasion, and the bland cytological features. The tumours are organised in cords and strands, and show keratocyst formation and duct differentiation in varying proportions. Marked cytological atypia, nuclear pleomorphism, brisk and atypical mitotic activity and necrosis are not typically seen in these tumours. METHODS AND RESULTS: We report two patients presenting with large, slowly growing tumours on the face showing areas of morphologically high-grade carcinoma arising on a background of unequivocal microcystic adnexal carcinoma. Both patients are alive with follow-up of up to 6 years, with no evidence of disease. CONCLUSIONS: Morphologically high-grade transformation in microcytic adnexal carcinoma is a rare phenomenon that does not appear to confer a risk for aggressive behaviour. Recognition depends on sampling of the areas of conventional microcystic adnexal carcinoma.

Ln-γ 2 chain of laminin-332 is a useful marker in differentiating between benign and malignant sclerosing adnexal neoplasms.

AIMS: Laminin (Ln)-γ 2, one of the chains of Ln-332, is a marker of invasive tumours and is frequently expressed as a monomer in malignant tumours. Desmoplastic trichoepithelioma (DTE), some types of basal cell carcinoma (BCC) (infiltrating and morphoeic BCC) and microcystic adnexal carcinoma (MAC) belong to a group of tumours known as sclerosing adnexal neoplasms (SAN) that are frequently difficult to differentiate and often require immunohistochemistry for diagnosis. The aim of this study was to assess the usefulness of Ln-γ 2 expression in the differential diagnosis of DTE, infiltrating/morphoeic BCC, MAC and syringoma. METHODS AND RESULTS: In this study, we compared the expression of Ln-γ 2 in infiltrating/morphoeic BCC (n = 28), DTE (n = 26), MAC (n = 10) and syringoma (n = 20). Immunohistochemically, Ln-γ 2 positivity was noted in 96% (27 cases) of infiltrating/morphoeic BCC and 90% (nine cases) of MAC, while all DTE and syringoma cases were negative. Furthermore, Ln-γ 2 expression pattern in infiltrating/morphoeic BCC was different from that in MAC. Ln-γ 2 expression was found in the cytoplasm of tumour cells in infiltrating/morphoeic BCC tumour cells, while in MAC linear expression was noted both along tumour nests and in the cytoplasm. CONCLUSION: Ln-γ 2 is a helpful adjunct in the differential diagnosis of SAN.

Aplasia cutis congenita of the scalp: Histopathologic features and clinicopathologic correlation in a case series.

BACKGROUND: Aplasia cutis congenita (ACC) is a rare and heterogeneous disorder characterized by congenital absence of skin. The scalp is the most commonly affected site and lesions may overlie deeper ectodermal abnormalities. The exact etiology is still unknown, and histopathologic features are poorly defined. METHODS: A series of 10 cases from nine patients was analyzed to characterize the clinicopathologic spectrum and age-related changes of ACC of the scalp. Hematoxylin and eosin, S100, Elastica van Gieson, and Weigert elastic stains were performed, and clinical information was retrieved from archived medical files. RESULTS: Patient ages ranged from 1 day to 39 years (median 57 months). All cases resembled deep-reaching scars with almost complete loss of all adnexal structures. Isolated residual hair follicles were present in 8/10 and sweat glands and ducts in 2/10 cases. The subcutis was thinned or absent. Elastic fibers were always more fragmented than in normal tissue, and the thickness and density increased over time. There was no gain of adnexal structures with increasing age. CONCLUSIONS: ACC represents a congenital scarring alopecia with permanent loss of skin appendages. Histopathologic changes resemble a deep-reaching scar with fragmented elastic fibers and differentiate ACC from all other forms of non-traumatic congenital alopecias.

Rare Case of Lipomatous Mixed Tumor With Follicular Differentiation.

Cutaneous mixed tumors are adnexal neoplasms characterized by a mixture of epithelial, myoepithelial, and stromal components of varying proportions. The diagnosis may be of little challenge when chondroid or myxoid components are dominant. However, there are variants of the cutaneous mixed tumor where more uncommon features predominate, making the diagnosis more challenging. Here, we present a case of a rare variant of the cutaneous mixed tumor with extensive adipocytic and follicular differentiation. This is the second case of such a tumor reported to literature to our knowledge.

Solid Microcystic Adnexal Carcinoma on the Thigh: An Unusual Location.

Solid carcinoma, probably the solid variant of microcystic adnexal carcinoma, is an apocrine adnexal tumor first described in 1998. The authors report an additional new case of the tumor at an unusual localization. A 78-year-old man presented with an asymptomatic firm plaque on his right thigh that had been present for 15 years. A biopsy was taken, and then, the lesion was removed. A pathological study showed a huge number of islands made up of aggregations of neoplastic epithelial cells. The epithelial islands showed variable sizes and shapes at scanning magnification, arranged columns, cords, and strands at the basis of the tumor. The neoplastic cells were embedded within a fibrotic stroma. Ductal differentiation, cystic structures, and neurotropism were also observed. Immunohistochemically, the neoplastic cells expressed high-molecular-weight keratin (cytokeratin 5/6), broad-spectrum keratin (AE1/AE3), p40, and p63. No immunoreactivity was found for BerEP4, cytokeratin 7, cytokeratin 19, cytokeratin 20, chromogranin A, carcinoembryonic antigen, and S-100. The lesion was completely removed with slow-Mohs micrographic surgery. Two stages and previous debulking were necessary to obtain free margins. The second stage included the muscular fascia. The patient remains free of tumor after a year of follow-up. Solid microcystic adnexal carcinoma is a rare skin tumor that seems to occur more frequently in the scalp than in the face, but no area of the body can be excluded, as reported in our case. Differential diagnosis should include sclerosing and clear-cell basal cell carcinoma, clear-cell dermal duct tumor, or desmoplastic trichoepithelioma. Mohs micrographic surgery is the treatment of choice.