Clinical and Histopathologic Study of Apocrine-Type Mixed Tumor of the Skin.

ABSTRACT: Mixed tumor of the skin (MTS) is a tumor characterized by folliculosebaceous-apocrine differentiation. Because of the wide range of histological variations, understanding the unique features of MTS can help improve diagnosis. This study describes the histopathological characteristics of MTS, mainly apocrine-type MTS (AMT), using 166 cases of AMT. We found that nodular aggregates of myoepithelial cells, mucinous changes in the stroma, and follicular differentiation were standard characteristic features of MTS. Among the cases studied, 67% showed prominent follicular germinative cells and 40% showed prominent lipomatous metaplasia in the stroma. These cases often pose difficulties for the diagnosis of AMT because of insufficient evidence of sweat glands or myoepithelial cell differentiation. This is the first study to examine how the histological features of AMT change as the tumor extends deeper into the dermis. We found that the proportion of AMT with folliculosebaceous differentiation and large lumina increased as it got deeper into the dermis. Histopathological diagnosis of MTS is vital because the clinical symptoms lack specificity. This study enhances our understanding of the histopathological characteristics of MTS.

A case of cutaneous syncytial myoepithelioma with extensive adipocytic metaplasia: Usefulness of EWSR1-PBX3 gene fusion analysis.

Cutaneous syncytial myoepithelioma (CSM) is a recently recognized variant of myoepithelioma characterized by an intradermal syncytial proliferation of spindled, ovoid, and histiocytoid cells. Immunohistochemically, tumor cells usually show strong expression of S-100 protein and epithelial membrane antigen (EMA). Here we report a case of CSM in the thigh of a 51-year-old Japanese woman. Histopathological findings showed a sheet-like growth of ovoid cells and histiocytoid cells with an eosinophilic syncytial cytoplasm, and adipocytic metaplasia was widely observed in the tumor. Immunohistochemical staining revealed a diffuse, strong pattern for EMA, smooth muscle actin (SMA), and HHF35, and variable expression of S-100 protein and p63 in ovoid and histiocytoid cells without significant mitotic figures or pleomorphism. In addition, EWSR1-PBX3 gene fusion, which is characteristic of CSM, was observed in the tumor. Based on these findings, we diagnosed the patient as having CSM. Our case shows that CSM can exhibit extensive adipocytic metaplasia, which could make its histopathological diagnosis challenging.

Folliculosebaceous Cystic Hamartoma Arising in Miescher-Type Melanocytic Nevi.

ABSTRACT: Folliculosebaceous cystic hamartoma (FSCH) is a rare cutaneous hamartoma consisting of dilated folliculosebaceous units associated with mesenchymal elements. Ansai et al reported that distinctive features of Miescher-type melanocytic nevi (MMCNs) accompanied 4.6% of FSCH; however, there have been no data about how often FSCH features accompany MMCNs. In this study, we used 7829 cases that had been histopathologically diagnosed as MMCNs of the face, neck, and scalp at the Department of Dermatopathology, Nippon Medical School Musashi Kosugi Hospital and observed whether features of FSCH accompanied them. Of the resected MMCNs, 274 of 7829 (3%) were accompanied by features of FSCH. The nose was the most common resection site, followed by the eyebrow area, ear, and cheek. The coexistence rate for the nevi on the nose and features of FSCH was as high as 10%-20%, and its rate increased with age. We found that FSCH appears mostly in seborrheic areas, such as the nose and cheek, which are rich in normal sebaceous glands. This suggests that nevi, especially on and around the nose, may induce FSCH or similar lesions.

Multicentric endocrine mucin-producing sweat gland carcinoma and mucinous carcinoma of the skin: A case report.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare low-grade sweat gland carcinoma. EMPSGC is thought to be a precursor to mucinous carcinoma of the skin (MCS). Since the first description of EMPSGC in 1997, only a few cases have been reported, and its etiology and mechanisms remain unknown. In this report, we describe a 71-year-old Japanese woman with two isolated EMPSGC and one MCS lesion on her face. She was simultaneously diagnosed with invasive ductal carcinoma of the breast. She had a history of uterine cancer of unknown histopathological diagnosis 24 years previously. The presence of in situ lesions confirmed by myoepithelial cells suggested that the cutaneous lesions were primary tumors. To the best of our knowledge, this is the first case of multiple primary EMPSGC/MCS tumors. Additionally, this might be the first case with multiple primary carcinomas including adnexal cutaneous tumors, breast cancer, and uterine cancer, which may share the common feature of expressing female hormonal receptors. This case indicates that EMPSGC/MCS may be triggered by a hormonal receptor abnormality, perhaps because of genetic defects. A larger number of reports examining this issue may be necessary to further assess our initial observations.

Trichoblastic infundibular cyst should be renamed infundibular cyst with unique papillary projections.

Trichoblastic infundibular cyst (TBIC) was previously reported as a unique keratinous cystic lesion, which was characterized by the papillary projections of follicular germinative-like cells emanating from the cyst wall. Here, we report three additional cases of this cyst and discuss the pathogenesis of this unique entity. In all cases, a unilocular cyst contained keratin, and the cyst wall was composed of squamous epithelium. A number of cords and papillary projections emanated from the basal layer of the cyst wall. They were composed of cells with large nuclei and scant cytoplasm arranged in a peripheral palisade. Immunohistochemically, anti-cytokeratin 15, anti-cytokeratin 20, and anti-epithelial cell adhesion molecule antibodies were negative. Thus, these cells resembled follicular germinative cells or sebaceous mantle morphologically, but we failed to prove the differentiation immunohistochemically. The cyst was surrounded by fibrotic stroma and inflammatory cells, suggesting previous rupture of the cyst. We speculate that the cells of the projections possibly differentiate into the mantle rather than follicular germinative cells, even though we could not provide sufficient immunohistochemical evidence. We also suggest that they may be induced by special reaction to fibrohistiocytic stroma surrounding the infundibular cyst. Therefore, TBIC should be renamed infundibular cyst with unique papillary projections.

Poromas with large lumens histopathologically mimicking syringocystadenoma papilliferum: Report of three cases.

We report on three patients exhibiting tumours with exophytic pedunculated structures with eroded surfaces. All cases showed the basic histopathological features of poroma accompanied by large, invaginated ductal structures lined by multiple layers of columnar or cuboidal cells. The columnar cells of invaginated ductal/cystic structures focally exhibited subtle features reminiscent of decapitation secretion along with dense infiltration of plasma cells in the surrounding stroma, mimicking syringocystadenoma papilliferum.

Bowen Disease With Sebaceous Differentiation: A Case Report and Immunohistochemical Analysis of Adipophilin and Cytokeratin 1.

Bowen disease with sebaceous differentiation has been rarely documented to date. Here, we present a case of Bowen disease with sebaceous differentiation. A 67-year-old man presented with a 6.0 × 3.5 cm erythematous plaque adjacent to a 7.0 × 3.0 cm erythematous plaque on his left abdomen. Dermoscopy revealed yellow structureless areas and dotted vessels on a pink homogenous background in addition to surface scales. Histopathological examination of the upper erythematous plaque showed parakeratosis and acanthosis with proliferation of atypical keratinocytes in the epidermis. Some of the atypical cells had large and hyperchromatic nuclei. Histopathological examination of the lower erythematous plaque showed tumor nests extending from the epidermis. Tumor nests with hyperchromatic and atypical cells had vacuolated cells. The diagnosis of Bowen disease with sebaceous differentiation was made. Immunohistochemistry revealed a positive reaction for cytokeratin 1 (CK1) in tumor cells of Bowen disease and a negative reaction for CK1 in tumor cells with the sebaceous differentiation, whereas immunohistochemistry revealed no apparent adipophilin-positive granules in tumor nests of Bowen disease compared with the prominent staining of adipophilin in tumor nests with sebaceous differentiation. We show Bowen disease with sebaceous differentiation taking advantage of immunohistochemistry of adipophilin and CK1. Those findings of Bowen disease with sebaceous differentiation may deepen our understandings and insights into the pathogenesis of sebaceous carcinoma and Bowen disease.

Tubulopapillary Cystic Adenoma With Apocrine Differentiation: A Unifying Concept for Syringocystadenoma Papilliferum, Apocrine Gland Cyst, and Tubular Papillary Adenoma.

Syringocystadenoma papilliferum (SCAP), apocrine gland cyst (AGC, also called apocrine hidrocystoma or apocrine cystadenoma), and tubular papillary adenoma (TPA) with apocrine differentiation are defined as proliferations of apocrine epithelium with myoepithelial cells. At Sapporo Dermatopathology Institute, we retrieved 308 benign neoplastic lesions diagnosed as SCAP, AGC, or TPA and combinations of these entities. Among the 308 lesions, 202 (66%) exhibited features of only one type, of which 144 (47%) were AGC, 39 (13%) were TPA, and 19 (6%) were SCAP. The other 106 lesions (34%) had features of 2 or more types, including 56 lesions that were AGC + TPA (18%), 2 that were AGC + SCAP (1%), 34 that were TPA + SCAP (11%), and 14 that were AGC + TPA + SCAP (5%). The most frequent site of these lesions was the face (56%), followed by the scalp (13%). Lesions with the features of AGC were more frequently found on the face, especially the periocular region, than at other sites. TPA lesions were more frequent on the face and scalp than at other sites, whereas SCAP lesions were preferentially found on the face, scalp, and trunk. We also retrieved clinicopathological data and other information. We propose a unifying concept for AGC, TPA, and SCAP. Approximately one-third of these lesions are composite entities with the features of 2 or 3 different tumors, and we propose calling such tumors tubulopapillary cystic adenoma with apocrine differentiation.

CD117 (KIT) is a useful immunohistochemical marker for differentiating porocarcinoma from squamous cell carcinoma.

BACKGROUND: Distinguishing porocarcinoma from squamous cell carcinoma (SCC) is clinically significant but can pose a diagnostic dilemma. The present study sought to confirm the diagnostic utility of CD117 immunohistochemistry in distinguishing porocarcinoma from SCC and to examine histologic, carcinoembryonic antigen (CEA) immunohistochemical and CA19-9 immunohistochemical differences between these tumors. METHODS: Immunostaining with anti-CD117, anti-CEA and anti-CA19-9 antibodies was performed for 22 porocarcinomas and 31 SCCs. The extent of CD117, CEA and CA19-9 staining was classified as negative (<1%), rarely positive (1-4%), focally positive (5-29%) or diffusely positive (30-100%). CD117 staining intensity was semi-quantitatively graded as weak, moderate or strong. RESULTS: All (100%) porocarcinomas were positive for CD117, with mainly focal (8/22) or diffuse (11/22) and moderate (9/22) to strong (8/22) staining. In contrast, only 6 of 31 SCCs (19.4%) expressed CD117 focally, and this expression was limited to the basal layer of the tumor in four cases. CEA immunostaining highlighted the lumina of all 22 porocarcinomas; however, CEA expression was not significantly different between porocarcinomas and SCCs (100 vs. 71.0%, respectively). CA19-9 was not expressed in the lumina of 5 of 22 porocarcinomas. CONCLUSIONS: Along with CEA, CD117 immunohistochemistry could be helpful in distinguishing porocarcinomas from SCCs.

Expression of lumican in hidroacanthoma simplex and clonal-type seborrheic keratosis as a potent differential diagnostic marker.

Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. The lumican expression correlates with pathological conditions and the growth and metastasis of various malignancies. In cutaneous neoplasms, the lumican expression is lower in advanced-stage malignant melanomas that invade the dermis than in early-stage melanomas. Furthermore, we have recently reported that the expression pattern of lumican is different from that of actinic keratosis and the Bowen disease. Lumican is positive in the poroid cells of intraepidermal sweat ducts; therefore, we examined the expression patterns of lumican in acanthotic-type seborrheic keratosis and Pinkus-type poroma followed by clonal-type seborrheic keratosis and hidroacanthoma simplex. The neoplastic cells of acanthotic-type seborrheic keratosis exhibited positive immunostaining in only 1 of 31 cases (3.23%), whereas the poroid cells of Pinkus-type poroma exhibited positive immunoreactivity in 26 of 28 patients (92.8%). In the hidroacanthoma simplex cases, lumican was expressed in poroid cells forming intraepidermal nests in 22 of 28 patients (78.6%), whereas the neoplastic cells in most cases of clonal-type seborrheic keratosis were negative for lumican. In some seborrheic keratosis cases that were positive for lumican in neoplastic cells, lumican was observed in squamoid cells but not in basaloid cells. Therefore, it is necessary to evaluate the immunoreactivity of lumican in seborrheic keratosis and in basaloid cells. These findings suggest that lumican is a potent differential diagnostic marker that distinguishes hidroacanthoma simplex from clonal-type seborrheic keratosis.

168 Cases of aneurysmal dermatofibroma and 29 cases of hemosiderotic dermatofibroma: A clinicopathologic study.

OBJECTIVES: Aneurysmal dermatofibroma (ADF) and hemosiderotic dermatofibroma (HDF) are rare variants of dermatofibroma (DF) characterized by distinct histologic features. While HDF is traditionally considered a precursor to ADF, supporting evidence is limited, and the etiology remains unclear. A retrospective analysis of 2128 DF cases (2016-2019) was conducted to investigate the clinicopathologic characteristics of ADF, HDF, and other DFs. METHODS: Histopathologically diagnosed DF cases were examined for ADF and HDF. Univariate analyses were performed to compare clinicopathologic features. RESULTS: Among the cases, 168 (7.9%) were ADF and 29 (1.4%) were HDF. Aneurysmal dermatofibroma and HDF shared several common characteristics, including lower occurrence in females, larger size, and increased cellularity (all P < .0001). Notably, 29% of ADFs lacked hemosiderin deposition. Aneurysmal dermatofibroma primarily manifested on exposed areas (face and forearm, both P < .001). In contrast, 41% of HDFs occurred on the lower leg (P = .018), and all lower leg HDFs exhibited signs of venous stasis, distinguishing them from other HDFs (P < .0001). CONCLUSIONS: Our findings indicate a potential close relationship between ADF and HDF. Contrary to conventional beliefs, we also presented the possibility of ADF progressing into HDFs. Physical trauma may induce ADF, and HDFs may emerge from ADFs in conjunction with venous stasis in the lower extremities.

Lumican as a novel marker for differential diagnosis of Bowen disease and actinic keratosis.

Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. Lumican expression correlates with pathological conditions, including skin fragility, corneal opacification, and corneal and cardiac wound healing. Lumican is overexpressed in tumor cells, including in the breast, colorectal, neuroendocrine cell, uterine cervical, and pancreatic cancers. Lumican expression also correlates with the growth and metastasis of various malignancies. For example, lumican expression is lower in the dermis of malignant melanoma cases than in early-stage melanomas. However, the expression patterns and roles of lumican in nonmelanoma skin cancer have not been elucidated. In this study, we used immunohistochemistry and in situ hybridization to examine the expression patterns of lumican in normal skin, Bowen disease, and actinic keratosis. In normal skin, lumican was expressed in the collagen fibers in the dermis, acrosyringium, follicular epithelium, and sebocytes but not in epidermal keratinocytes. In Bowen disease, lumican was expressed in 34 (91.8%) of 37 patients. Notably, all cases of actinic keratosis were negative for lumican. These findings suggest that lumican plays an important role in the pathogenesis of Bowen disease and actinic keratosis and might be useful as an adjunct to the diagnosis for subtypes of 2 diseases: bowenoid actinic keratosis and Bowen disease in sun-exposed areas.

Keloidal dermatofibroma: Clinicopathological comparison of 52 cases with a series of 2077 other dermatofibromas.

Dermatofibroma is a common benign skin lesion with a contested etiology: some believe it is a neoplasm while others propose minor injuries initiate it. Many dermatofibroma variants have been described, including keloidal dermatofibroma, which is unusual by bearing keloidal collagen. Keloidal dermatofibroma was first described in 1998 and only 15 cases have been reported. Since keloids are driven by skin injuries, the existence of keloidal dermatofibroma has been suggested to support the injury hypothesis of dermatofibroma etiology. To better understand keloidal dermatofibroma characteristics and gain clues regarding dermatofibroma etiology, consecutive keloidal dermatofibroma cases (n = 52) and dermatofibroma without keloidal collagen (n = 2077) that were histopathologically diagnosed in 2016-2019 were identified from the records of a Japanese dermatopathology laboratory and compared in terms of demographic, clinical, and histopathological characteristics by univariate analyses. Compared to other dermatofibromas, keloidal dermatofibromas occurred more frequently on the forearm and hand (P < 0.0001 and 0.0019), especially the wrist dorsum, and in the superficial skin layer (P < 0.0001). Keloidal dermatofibromas also demonstrated more cellularity and hemorrhage (both P < 0.0001). Correlation analyses between keloidal collagen amount and keloidal dermatofibroma size (a proxy of time-since-onset) did not support the notion that keloidal collagen deposition and keloidal dermatofibroma formation are triggered simultaneously. Recent injury, as indicated by fresh hemorrhage, was equally common in putatively older and younger keloidal dermatofibromas. Thus, keloidal collagen in keloidal dermatofibromas could be due to injury to preexisting dermatofibromas, which suggests that the keloidal dermatofibroma entity does not prove the injury hypothesis. Commonalities between keloids and keloidal dermatofibromas suggest a link between genetics, provocative events that induce myofibroblast differentiation, and keloidal collagen production.

Secondary Cutaneous Ossification in Keloids of the Lower Abdomen: A Report of Two Cases.

Cutaneous ossification is a rare benign dermatological condition in which bone forms in the dermis or subcutaneous tissue. It is classified as primary when it emerges without a pre-existing condition and secondary when it is associated with an underlying condition such as trauma, scars, inflammation, or neoplastic disease. The secondary form accounts for most cases of cutaneous ossification. The pathogenesis of cutaneous ossification is not clear. Keloids are benign fibroproliferative skin disorders characterized by chronic inflammation. Their pathogenesis is also not fully understood. We report two cases of postoperative secondary ossification in lower abdominal keloids and review the literature on secondary ossification of the skin. We speculate that severe chronic inflammation in keloids drives osteoblastic transformation of mesenchymal stem cells, endothelial cells, or fibroblasts in the keloids.

Serum Interleukin-18 Provides a Clue to the Diagnosis of Adult-Onset Still's Disease: Findings from 6 Japanese Patients with Adult-Onset Still's Disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder accompanied by skin eruption. However, typical skin eruptions, such as evanescent, salmon-pink erythema, are not specific to AOSD and dermatologists often face difficulty in diagnosing AOSD. In this study, we examined serum IL-18 levels as well as IL-6, ferritin and C-reactive protein in 6 Japanese patients with AOSD. METHODS: Serum levels of IL-6 and IL-18 were evaluated in the acute phase and at the time of remission. Serum levels of IL-6 were analyzed using a commercial chemiluminescent enzyme immunoassay (CLEIA; SRL, Tokyo, Japan). Serum IL-18 levels were measured using a commercial ELISA kit (Medical & Biological Laboratories Co., LTD. Nagoya, Japan). RESULT: In active AOSD, serum ferritin levels and CRP levels were above normal range in 6 patients. In remission, serum ferritin levels of 3 patients were slightly above the normal range, while CRP serum levels of 6 patients were all normalized. Serum IL-18 levels were markedly elevated in 5 cases during the acute phase. In remission, serum IL-18 levels remained at higher values than the normal range in 5 cases. Serum IL-6 levels were also highly elevated in 5 patients in active AOSD and became normalized in remission except in case 2. CONCLUSION: High levels of serum IL-18 will be a clue to the diagnosis of AOSD. CRP is also useful biomarker for monitoring disease activity compared with IL-6 and IL-18.

Sebaceous carcinoma: an immunohistochemical reappraisal.

The rates of distant metastases and tumor death in sebaceous carcinoma (SC) have been reported to be higher than those of other cutaneous carcinomas, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), regardless of whether they occur in ocular or extraocular regions. Therefore, strict differentiation of SC from SCC and BCC is required. In this article, we report immunohistochemical findings of SC and compare these data to those of SCC, BCC, and sebaceoma. An immunohistochemical study was performed using 7 antibodies [anti-carcinoembryonic antigen (CEA), anti-epithelial membrane antigen (EMA), anti-CA15-3, anti-CA19-9, anti-androgen receptor (AR), anti-epithelial antigen (Ber-EP4), and anti-adipophilin (ADP)] on 35 cases of SC (16 cases in ocular and 19 cases in extraocular regions) and 10 cases of each SCC (5 cases in ocular and 5 cases in extraocular regions), BCC (5 cases in ocular and 5 cases in extraocular regions), and sebaceoma (no cases arose on the eyelids). In summary, the typical immunophenotypes of SC were EMA+, CA15-3+, AR+, Ber-EP4-, and ADP+; those of sebaceoma were CEA-, EMA+, Ber-EP4-, and ADP+; those of SCC were CEA-, EMA+, CA19-9-, AR-, Ber-EP4-, and ADP-; and those of BCC were CEA-, EMA-, CA15-3-, Ber-EP4+, and ADP-. Other antibody tests for each neoplasm were positive in about half of the cases. The detection of AR and ADP was useful for differentiating SC from SCC, whereas the determination of EMA, CA15-3, Ber-EP4, and ADP was valuable in differentiating SC from BCC.

A child with giant cell tumor of tendon sheath.

A giant cell tumor of tendon sheath (GCTTS) is a soft tissue tumor consisting principally of a proliferation of synovial cells arising from a tendon sheath. GCTTS is the second most common tumor of the hand in general and a majority of GCTTS cases are in patients between 20 and 50 years of age, whereas pediatric cases of GCTTS are uncommon. This report presents the case of a nine-year-old girl with GCTTS arising on her right index finger.

What Is a Solitary Keratoacanthoma? A Benign Follicular Neoplasm, Frequently Associated with Squamous Cell Carcinoma.

We present histopathological criteria for diagnosing keratoacanthoma (KA). In KA, four histological stages are recognized, which are the early/proliferative stage, well-developed stage, regressing stage and regressed stage. In diagnosing KA, we emphasize that KA consists of the proliferation of enlarged pale pink cells with ground glass-like cytoplasm without nuclear atypia, other than crateriform architecture. KA sometimes exhibits malignant transformation within the lesions. We describe the characteristics of benign and malignant epithelial crateriform tumors that should be differentiated from KA. We also present the data of histopathological diagnosis of lesions clinically diagnosed as KA, its natural course and related lesions after partial biopsy, and incidence of crateriform epithelial neoplasms. Based on these data, we recommend complete excision of the lesion when KA is clinically suspected, especially when the lesion is located on a sun-exposed area of an elderly patient. If complete excision is impossible, partial excision of a sufficient specimen with intact architecture is required. In such a case, however, careful investigation after biopsy will be needed, even if the histopathological diagnosis is KA, because there is some possibility that a conventional SCC lesion remains in the residual tissue.

Infantile Myofibroma: Case Report and Review of the Literature.

We report a case of solitary infantile myofibroma (IM) with partially CD34-positive neoplastic cells on the back of a newborn boy. Ultrasonography showed a multilocular mass with a hypoechoic center surrounded by an isoechoic rim. Histopathological analysis revealed that the lesion was composed of small, round cells that were tightly packed and uniform. The cells had oval nuclei and were pale, CD34-positive, and richly cellular. They had interlacing fascicles of spindle cells with features of myofibroblasts with α-smooth muscle actin positivity. We speculate that neoplastic cells in most IMs differentiate towards myofibroblasts. However, in rare cases, their differentiation is more primitive and they express CD34, with or without α-smooth muscle actin expression.