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Cutaneous angiosarcomas (AS) are uncommon and morphologically heterogeneous. Recently, a distinctive lymphatic-type AS with prominent lymphocytic infiltrate has been observed. Although conventional AS typically bear poor prognosis, lymphatic-type AS with prominent lymphocytic infiltrate and pseudolymphomatous AS show prolonged survival with rare extracutaneous spread. We describe a unique case of AS in a 55-year-old woman who received surgical resection and radiation therapy for her prior myxoid liposarcoma. She developed a suspected recurrence 15 years later. Microscopically, the lesion showed an infiltration of the reticular dermis by irregular interanastamosing vascular spaces lined by atypical endothelial cells with nuclear "hobnailing" and hyperchromasia. A prominent intratumoral and peritumoral lymphocytic infiltrate obscuring the tumor cells was also present. The tumor cells were diffusely positive for endothelial cell markers, including D2-40. Notably, there was no evidence of MYC gene amplification by FISH. Additional NGS-based molecular analysis demonstrated no significant genetic mutations. The patient is alive with a history of two local recurrences, but no evidence of metastasis. We present this case to raise awareness of MYC-nonamplified secondary lymphatic-type AS with prominent lymphocytic infiltrate (pseudolymphomatous AS) and to discuss its differential diagnosis.

Our understanding of adipocytic tumors classification and diagnosis continues to evolve. We present a brief review and updated summary of selected adipocytic tumors involving the head and neck region. For the practicing pathologist, knowledge of these established and emerging entities is critical for the correct pathologic diagnosis and treatment of the patient.

Deintensification therapy for human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV(+) OPSCC) is under active investigation. An adaptive treatment approach based on molecular stratification could identify high-risk patients predisposed to recurrence and better select for appropriate treatment regimens. Collectively, 40 HPV(+) OPSCC FFPE samples (20 disease-free, 20 recurrent) were surveyed using mass spectrometry-based proteomic analysis via data-independent acquisition to obtain fold change and false discovery differences. Ten-year overall survival was 100.0 and 27.7% for HPV(+) disease-free and recurrent cohorts, respectively. Of 1414 quantified proteins, 77 demonstrated significant differential expression. Top enriched functional pathways included those involved in programmed cell death (73 proteins, p = 7.43 × 10-30), apoptosis (73 proteins, p = 5.56 × 10-9), β-catenin independent WNT signaling (47 proteins, p = 1.45 × 10-15), and Rho GTPase signaling (69 proteins, p = 1.09 × 10-5). PFN1 (p = 1.0 × 10-3), RAD23B (p = 2.9 × 10-4), LDHB (p = 1.0 × 10-3), and HINT1 (p = 3.8 × 10-3) pathways were significantly downregulated in the recurrent cohort. On functional validation via immunohistochemistry (IHC) staining, 46.9% (PFN1), 71.9% (RAD23B), 59.4% (LDHB), and 84.4% (HINT1) of cases were corroborated with mass spectrometry findings. Development of a multilateral molecular signature incorporating these targets may characterize high-risk disease, predict treatment response, and augment current management paradigms in head and neck cancer.

Histologic characteristics cannot adequately predict which patients are at risk of developing metastatic disease after excision of primary cutaneous melanoma. The aim of this study was to identify immunomodulatory genes in primary tumors associated with development of distant metastases.Thirty-seven patients with primary melanoma underwent surgical excision. RNA was extracted from the primary tumor specimens. cDNA was synthesized and used with Human Gene Expression microarray. Differential expression of 74 immunomodulatory genes was compared between patients who developed distant metastases and those who did not.Six of 37 patients developed distant metastases during the time of the study. Differential expression of microarray data showed upregulation of four immunomodulatory genes in this group. These four genes-c-CBL, CD276, CXCL1, and CXCL2-were all significantly overexpressed in the metastatic group with differential expression fold change of 1.15 (P = 0.01), 1.16 (P = 0.04), 2.51 (P 0.001), and 1.68 (P 0.02), respectively. CXCL1 had particularly high predictive value with an area under the curve of 0.80. Multivariate analysis showed only expression of CXCL1 (P = 0.01) remains predictive of distant metastases in melanoma patients. This result was confirmed using quantitative real-time polymerase chain reaction.CXCL1, CXCL2, c-CBL, and CD276 are immunomodulatory genes present in primary melanoma that are strongly associated with development of metastatic disease. Identification of their presence, particularly CXCL1, in the primary tumor could be used as a predictor of future risk of metastatic disease and thereby to identify patients who might benefit early from immunotherapy.

Periungual pyogenic granulomas are benign vascular tumors that present as painful, round, spontaneously bleeding lesions composed of rapidly proliferating capillaries and excess tissue. The vast majority of pyogenic granulomas are caused by physical trauma or infectious agents and they may resolve spontaneously. Herein, we highlight a very rare case of periungual pyogenic granulomas induced by the regularly prescribed oral retinoid acitretin during treatment for congenital palmoplantar keratoderma. This unique case showed that it is feasible to continue acitretin therapy in the presence of pyogenic granuloma development if proper dose reduction and topical therapies are utilized. The patient's lesions resolved within two weeks of this protocol's initiation and the pyogenic granulomas did not recur over the course of a six-month follow-up observation period. In addition, we performed a systematic review of the literature using PubMed databases for the clinical features and treatments in other reported acitretin-induced pyogenic granuloma cases; we compiled a comprehensive list of other prescription drugs known to cause pyogenic granulomas up-to-date.

Vascular tumors are a diagnostically challenging area. This is particularly true in the case of epithelioid vascular tumors. Not only is the distinction between different epithelioid vascular tumors challenging, but also the differential diagnosis may be substantially expanded by the inclusion of melanoma, carcinomas, and other epithelioid soft tissue tumors. Recently developed immunohistochemical markers and more comprehensive genetic characterizations continue to advance our understanding of epithelioid vascular tumors. The present paper briefly reviews and updates basic concepts with regard to the following epithelioid vascular tumors: epithelioid hemangioma, epithelioid angiomatous nodule, pseudomyogenic hemangioendothelioma, composite hemangioendothelioma, epithelioid hemangioendothelioma, and epithelioid angiosarcoma.

Introduction Large high-grade sarcomas are commonly managed with five weeks of pre-operative radiation with chemotherapy followed by surgical resection. Wound complications occur in about one out of three patients with this regimen. Hypofractionated radiation therapy (HFRT) is a developing pre-operative approach that delivers radiation over a shorter duration of 5–10 treatments. Presentation of case Two patients underwent HFRT with neoadjuvant chemotherapy followed by tumor resection. The first patient had high-grade de-differentiated liposarcoma, and the second patient a high-grade myxofibrosarcoma. Neither patient developed post-operative wound complications despite the massive tumor size. Discussion Less is understood regarding rates and risk factors associated with wound complications using this shortened radiation approach. With attention to surgical detail, and advancing radiation delivery technologies, rates of complications can be minimized. Conclusion We discuss our experience with a neoadjuvant hypofractionated chemoradiation protocol in two patients with large volume sarcomas resected from the chest wall and the thigh who did not develop acute wound complications. Further evaluation of this shortened regimen is warranted., Highlights • Wound complications are common after sarcoma resection with preoperative radiation. • Hypofractionated Radiation Therapy (HFRT) may be a safe alternative to conventional dose radiation. • HFRT can be utilized with massive volume sarcomas safely.

Although melanoma occurs more rarely than several other skin cancers, patients' long term survival rate is extremely low if the diagnosis is missed. Diagnosis is complicated by a high discordance rate among pathologists when distinguishing between melanoma and benign melanocytic lesions. A tool that allows pathology labs to sort and prioritize melanoma cases in their workflow could improve turnaround time by prioritizing challenging cases and routing them directly to the appropriate subspecialist. We present a pathology deep learning system (PDLS) that performs hierarchical classification of digitized whole slide image (WSI) specimens into six classes defined by their morphological characteristics, including classification of "Melanocytic Suspect" specimens likely representing melanoma or severe dysplastic nevi. We trained the system on 7,685 images from a single lab (the reference lab), including the the largest set of triple-concordant melanocytic specimens compiled to date, and tested the system on 5,099 images from two distinct validation labs. We achieved Area Underneath the ROC Curve (AUC) values of 0.93 classifying Melanocytic Suspect specimens on the reference lab, 0.95 on the first validation lab, and 0.82 on the second validation lab. We demonstrate that the PDLS is capable of automatically sorting and triaging skin specimens with high sensitivity to Melanocytic Suspect cases and that a pathologist would only need between 30% and 60% of the caseload to address all melanoma specimens., Comment: Accepted at ICCV 2021 CDpath workshop

Noonan syndrome is a common autosomal dominant disorder associated with an increased risk of malignancy. We report a 16-year-old female with Noonan syndrome (KRAS gene variant, Q22R) and diffuse-type tenosynovial giant cell tumor, a proliferative disorder that has been rarely reported in this population. These tumors may represent a complication of the dysregulated RAS/MAPK signaling pathway that underlies Noonan syndrome. They lack typical clinical features, causing misdiagnosis and delays in management, which could lead to osseous invasion requiring more complicated surgical procedures. Increased awareness of this association will improve the clinical outcomes of patients with Noonan syndrome who develop diffuse-type tenosynovial giant cell tumors.

We introduce a new needleless microjet injector that uses laser pulse energy to inject tattoo pigments for scalp micropigmentation (SMP) directly through the skin without a needle. It has the advantage of an almost painless experience, eliminating the need for anesthesia. ### How a Traditional

Mammary analog secretory carcinoma of salivary glands is a relatively recently recognized entity that harbors the ETV6-NTRK3 fusion transcript. To date, only rare cases of mammary analog secretory carcinoma of the skin have been reported. A 57-year-old man presented with a 6.0 cm cystic mass in the axilla, involving the dermis and superficial subcutis. Microscopically, the tumor exhibited nodular aggregation of tubular and microcystic structures embedded in the dense fibrotic and hyalinized stroma. Characteristic 'colloid-like' eosinophilic secretory material was present within intraluminal spaces. Tumor cells were largely characterized by vesicular nuclei with inconspicuous nucleoli and pink vacuolated cytoplasm. With respect to immunohistochemistry, tumor cells were intensely positive for AE1/AE3, Cam 5.2, and CK7, whereas Ber-EP4 and CEA were completely negative. A dual color break-apart fluorescence in situ hybridization probe identified rearrangement of the ETV6 gene locus on chromosome 12. The patient is alive with no evidence of recurrent disease or metastasis 3 years after the initial surgery. In conclusion, we report a rare example of mammary analog secretory carcinoma of the skin with ETV6 rearrangement. Awareness of this unique cutaneous tumor and subsequent reporting of additional cases is necessary for better characterization of its completely clinicopathologic spectrum.

Summary Perivascular epithelioid cell neoplasms (PEComas) are a group of mesenchymal tumours with concurrent melanocytic and myogenic differentiation. Although many cases are sporadic, PEComas can be associated with tuberous sclerosis. A distinct subset of deep-seated PEComas has been shown to carry TFE3 fusions. To our knowledge, this is the first reported case of primary subcutaneous malignant PEComa with molecular confirmation of TFE3 gene rearrangement.

Aim We studied ERG expression in a large series of chondrogenic bone and soft tissue tumours to assess the value of ERG as a possible marker of chondroid/cartilaginous differentiation. Methods Formalin-fixed, paraffin-embedded whole sections from 111 bone and soft tissue tumours with chondroid differentiation or a morphology that may mimic cartilaginous differentiation were retrieved. Immunohistochemistry was performed using anti-ERG monoclonal antibody directed against the N terminus. Nuclear staining was scored as negative ( 51%). Results Nuclear ERG expression was seen in all cases of soft tissue chondroma (8), chondromyxoid fibroma (7), chondroblastic osteosarcoma (6) and clear cell chondrosarcoma (1). 10/12 conventional chondrosarcomas were also positive for ERG. In cases of dedifferentiated chondrosarcoma, the well-differentiated component was positive in 7/9 cases, while all dedifferentiated foci were negative. In cases of mesenchymal chondrosarcoma, the hyaline cartilage component was positive in 2/4 cases, whereas the primitive component in all cases was negative. Variable positivity was identified in extraskeletal myxoid chondrosarcomas (4/9), chondroblastomas (3/8) and mixed tumours/myoepitheliomas (2/11). Only 1/12 chordoma was positive for ERG (1+). Interestingly, 15/17 enchondromas were negative for ERG. Conclusions In this study, we further characterise the expression of ERG in mesenchymal tumours and found relatively constant nuclear ERG expression in selected chondrogenic tumours including conventional chondrosarcoma, chondromyxoid fibroma, chondroblastic osteosarcoma and clear cell chondrosarcoma. We also show that ERG may be a helpful ancillary tool in certain select diagnostic scenarios and that awareness of ERG expression in tumours with cartilaginous differentiation is important.

Generalized eruptive histiocytosis, described in 1963 by Winklemann and Muller, is a reactive, self-healing form of non-Langerhans histiocytosis. Rare cases of atypical generalized eruptive histiocytosis have been reported in patients with hematopoietic malignancy, but the biological relationship between the two disorders is not known. We report an 84-year-old man with chronic myelomonocytic leukemia who presented with coalescing erythematous papules and plaques on the posterior neck, ear and lower lip, followed by development of blast crisis. Skin biopsy revealed a thick band-like dermal infiltrate of cells that exhibited morphologic features of macrophages or histiocytes and prominent elastolytic phagocytosis. These cells demonstrated a mature immunophenotype, expressing CD14 and CD68, with partial expression of CD13 but not CD1a, CD43, CD56, CD123, Langerin, or S-100 protein. Karyotype and fluorescence in situ hybridization analyses showed loss of the Y chromosome in bone marrow and skin specimens, providing evidence of a clonal relationship between the cutaneous eruption and the underlying chronic myelomonocytic leukemia. The presence of the same clone in skin and bone marrow specimens from our patient supports the possibility that atypical generalized eruptive histiocytosis is a marker for underlying hematopoietic malignancy. Discovery of additional cases may shed further light on the pathogenesis of this rare entity.

Background. Malignant melanoma of the nail apparatus is exceedingly rare. Increasingly, genetic studies have been employed to aid in distinguishing between malignant melanoma and benign melanocytic nevi. Methods. Archived nail apparatus melanomas were analyzed by fluorescence in situ hybridization (FISH) using probes targeting the genes at 6p25 (RREB1), 11q13 (CCND1), 8q24.1 (MYC), 6q23 (MYB), 9p21 (CDKN2A) and the centromeres of chromosomes 8 (D8Z2) and 6 (D6Z1). The results were correlated with clinical and demographic information. Results. Mean patient age was 57.8 years (range 23-92 years). In all, 5 of 7 (71%) cases involved the upper extremity digits. RREB1 gain was seen in all cases. CCND1 gain was seen in 6 of 7 (86%) cases, 3 of which were amplified. MYB loss and MYC gain were both seen in 5 of 7 (71%) cases. Homozygous loss of CDKN2A was not observed in any case. Two of 7 (28.6%) patients had lymph node metastasis and died of widely metastatic disease. These 2 patients harbored the most genetic aberrations: gains of RREB1, CCND1, and MYC, and MYB loss. Both benign melanocytic nevi controls showed normal FISH results. Conclusions. RREB1 and CCND1 gains are common in nail apparatus melanoma as in most melanomas, and an increased number of genetic aberrations may be associated with a poorer prognosis, though the limited number of cases precludes definitive correlation. FISH appears to be a useful adjunct in the diagnosis of nail apparatus melanomas and improves diagnostic confidence even in the setting of unambiguous histomorphology.

The cutaneous lesions of radiation-induced pemphigus or pemphigoid disease may resemble other skin diseases, including recurrent underlying cancer. We performed a computerized search of Mayo Clinic (Rochester, Minnesota) archives and identified 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for breast, cervical, and metastatic malignancies, respectively. In 2 of these patients, the disease was initially confined to the irradiated field but subsequently disseminated to other parts of the patients' bodies, including mucosal surfaces. In all 3 patients, the blistering disease occurred 5 to 14 months after the onset of radiation therapy. All 3 were treated with corticosteroids and demonstrated complete recovery of the skin eruption after radiotherapy was discontinued. Although the precise mechanism of this cutaneous eruption is unknown, clinicians should be alert for this potentially serious complication and evaluate all cutaneous eruptions developing during and after radiotherapy.

Angiosarcomas may be primary in the skin, primary in soft tissue or viscera, or secondary to irradiation. All angiosarcomas have a poor prognosis. Taxanes may have efficacy in the treatment of angiosarcoma. Expression of TLE3 has been associated with improved outcome in taxane-treated breast cancers. We studied a series of angiosarcoma with TLE3 immunohistochemistry. Cases of angiosarcoma (98 total cases; 37 cutaneous, 48 soft tissue/visceral and 13 post-irradiation) were retrieved and follow up was obtained. Tumors were classified as 'vasoformative', 'spindled', 'epithelioid' and 'mixed'. TLE3 immunohistochemistry was performed. Statistical analyses were performed. Patients (50 males and 48 females) had a median age of 60.2 years. Tumors had a median size 7.5 cm and were vasoformative (N = 43, 44%), spindled (N = 21, 21%), epithelioid (N = 16, 16%) and mixed (N = 18, 18%). Follow up was available for 89/98 patients (91%): 32 (36%) were dead due to disease, 36 (41%) were dead due to other causes and 21 (24%) remained alive. The median time to death was 2.1 years. TLE3 reactivity was observed in 0/37 (0%) cutaneous angiosarcomas, in 28/48 (58%) cases from soft tissue/viscera and in 4/13 (31%) post-irradiation angiosarcomas. (p =

Background: We sought to further determine the histochemical, immunohistochemical and ultrastructural properties of eosinophilic cytoplasmic inclusion bodies in melanocytic nevi. Methods: Skin specimens from four patients with a known diagnosis of conventional melanocytic nevus (3) or Spitz nevus (1) and containing intracytoplasmic eosinophilic inclusion bodies were selected. In addition, melanomas (25), Spitz nevi (10) and blue nevi (4) were examined to determine the frequency of the inclusions. Results: Inclusions tended to be located in multinucleated melanocytes with abundant vacuolated cytoplasm. In conventional (hematoxylin and eosin-stained) sections, the degree of density and eosinophilia of intracytoplasmic inclusions varied with size. Periodic acid-Schiff, Fontana and Congo red stains showed no reactivity. All bodies were immunoreactive for ubiquitin but negative for tyrosinase, keratin and vimentin. Ultrastructurally, inclusion bodies were non-membrane bound, ranged from 4 to 7 µm, and were comprised of radiating filamentous structures with or without an electron-dense core. Electron probe x-ray microanalysis revealed no significant peaks. None of additional melanomas, Spitz nevi and blue nevi that were evaluated showed similar inclusions. Conclusions: The inclusion bodies described herein bear no resemblance to other cytoplasmic inclusion bodies previously described in melanocytic lesions. There is no discernible relationship to melanosomes by ultrastructural analysis. We postulate a relationship with dysfunction of ubiquitin-mediated protein degradation occurring in melanocytes. Shon W, Wada DA, Gibson LE, Flotte TJ, Scheithauer BW. Distinctive eosinophilic cytoplasmic inclusion bodies in melanocytic nevi: an immunohistochemical and ultrastructural study.

A significant proportion of angiosarcoma arises in the setting of chronic lymphedema, often following surgery for breast carcinoma (Stewart-Treves syndrome). Massive localized lymphedema (MLL), a relatively recently described and rare pseudotumor most often occurring in morbidly obese patients, is thought to be the result of derangements in lymphatic drainage secondary to excessive adipose tissue. Only a very small number of cases of angiosarcoma have been reported in patients with MLL. We reviewed the clinical and pathological features of five patients with angiosarcoma arising in this unusual clinical setting. The tumors arose in three women and two men, who were in the age range from 36 to 81 years (median: 52 years). All patients were or had recently been morbidly obese (mean body mass index = 47.2 kg/cm(2) ; range:37.6-68.5 kg/cm(2) ) and had long-standing soft tissue changes of MLL. The tumors arose in the thigh (two cases), lower leg (two cases) and abdomen/proximal thigh (one case) and ranged from 6 to 28.5 cm in size (mean: 15.9 cm). All tumors were conventional high-grade angiosarcomas and microscopically exhibited an admixture of vasoformative, spindled and epithelioid features. Microscopic changes of MLL, including dermal fibrosis, expansion of interlobular fibrous septa and lymphangiectasia, were identified in all cases. Clinical follow-up (four cases; mean: 13.8 months; range: 2-32 months) showed one patient to be dead of disease, one patient to be dead from therapy-related complications and two patients to be alive without disease. One case was too recent for meaningful clinical follow-up. We conclude that lymphedema secondary to obesity should be recognized as a significant risk factor for the development of angiosarcoma. The clinical and pathological features of angiosarcoma arising in this distinctive clinical setting appear to be identical to those of other lymphedema-associated angiosarcomas. With the continuing epidemic of obesity in Western societies, the incidence of obesity-related angiosarcoma is probably to increase. Consequently, it is critical that lymphedematous areas in obese patients be carefully examined for clinical evidence of early angiosarcoma, with the hope that timely diagnosis may lead to improved patient outcome.

Basaloid cancers of the lower gastrointestinal tract are rare. The lack of mucosal involvement of this type of tumor is uncharacteristic and, to our knowledge, has not been described. In addition, the cylindroma-like appearance of this cancer has only a few examples in the literature. A 51-year-old male presented to us with a history of ulcerative colitis (UC) and obstruction of the anal canal. Imaging and colonoscopy revealed an entirely extraluminal tumor. Percutaneous biopsy yielded a diagnosis of cylindroma-like basaloid carcinoma of the anal region. Neoadjuvant chemotherapy and radiation resulted in stable disease by RECIST criteria. Surgical planning ensued, which led to R0 resection of the tumor, total colectomy and end ileostomy for his UC, and reconstruction of the perineal defect with a rectus myocutaneous flap. Surveillance at 6 months demonstrated no evidence of disease.

Reticulated acanthoma with sebaceous differentiation (RASD) represents a rare benign cutaneous epithelial neoplasm with sebaceous differentiation. There has been much speculation about the relationship between RASD and Muir-Torre syndrome (MTS). We report a 53 year-old man who presented with RASD in addition to a prior history of sebaceous adenomas. Immunohistochemically, the tumour cells in the RASD and sebaceous adenomas showed a significantly reduced MSH6 protein expression, whereas there was no loss of MLH1, MSH2 and PMS2. This benign neoplasm, which can be mistaken for various other cutaneous lesions with sebaceous differentiation, deserves wider recognition for its possible association with MTS.

Background Endocrine mucin-producing sweat gland carcinoma (EMPSGC), a low-grade sweat gland carcinoma with a predilection for the eyelids, often shows areas of benign eccrine cysts, atypical intracystic proliferation and associated mucinous carcinoma, suggesting tumor progression. Wilms tumor 1 (WT1) protein, a transcription factor, is overexpressed in many tumors and plays a role in oncogenesis. Methods A computer-based search for tumors diagnosed between 1989 and 2009 was conducted. Clinical data were obtained from pathology reports and patient records. Biopsies were reviewed for histologic features. Immunostaining was performed for WT1, chromogranin, synaptophysin, estrogen receptor (ER), epithelial membrane antigen (EMA), polyclonal carcinoembryonic antigen (P-CEA), cytokeratin 7 (CK7), cytokeratin 20 (CK20) and MIB-1. Results Eight women and five men (mean age: 61.2 years; range: 40–77 years) presented with slow-growing eyelid nodules. Cases of EMPSGC were characterized by the presence of dermal nodules with various growth patterns. Adjacent eccrine cysts were present in five patients, atypical epithelial proliferation within the cyst wall in four patients, and an associated mucinous carcinoma in one patient. All tumors were positive for WT1, CK7, ER, P-CEA and EMA and negative for CK20. Tumors were positive for synaptophysin in 12 cases and chromogranin in nine cases. The MIB-1 proliferation index was low in most cases. No WT1 staining was observed in the overlying epidermis, adnexal structures or areas of benign eccrine cyst. WT1 expression was observed in areas of atypical epithelial proliferation, and the neoplastic cells. Conclusions The present study shows WT1 expression in the neoplastic epithelial cells of EMPSGC, areas of atypical intraductal proliferations, and mucinous carcinoma. The absence of WT1 expression in areas of benign eccrine cyst and cutaneous sweat glands suggests WT1 upregulation plays a role in tumor cell proliferation and progression of EMPSGC.

Cutaneous metastasis from Hürthle cell carcinoma of the thyroid is an extremely rare phenomenon. As far as we can determine, there has been only a single case documented. Our patient, a 68-year old man with a history of Hürthle cell carcinoma of the thyroid, had cutaneous nodules in the scrotum and right chin. Histologic and immunohistochemical examinations confirmed the diagnosis of metastatic Hürthle cell carcinoma of the thyroid. To the best of our knowledge, this is the first reported case of scrotal skin metastasis. This case emphasizes the importance of thorough clinicopathologic correlation for any patient with a malignant scrotal cutaneous neoplasm with Hürthle cell or oncocytic differentiation.

MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of well-characterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sun-exposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2-3+: 6 cases, 16%; 1+: 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2-3+ immunostaining showed high-level gene amplification. One additional case with 3+ immunostaining showed higher level aneusomy of chromosome 8 (5-8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3-5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.

Osseous sarcoidosis of the axial skeleton is typically asymptomatic and not routinely imaged with MRI. The natural history of sarcoidosis is generally felt to be resolution spontaneously or with treatment, or unremitting progression. We report a case of recurrent active symptomatic disease after an initial response to immunomodulator treatment with an unusual halo of T2-hyperintensity surrounding treated fibrofatty vestigial lesions.

Cartilaginous tumors of soft tissue are uncommon, with benign chondromas of soft parts greatly outnumbering rare soft-tissue chondrosarcomas. Over the past several years, we have seen in consultation a distinctive, benign-appearing chondroid soft-tissue lesion of the plantar foot that differs in a number of respects from chondroma of soft parts. Herein we report our experience with this distinctive lesion. A retrospective review of all cases from the foot in our soft-tissue consultation and institutional surgical pathology archives identified 9 similar cases, most often previously coded as 'fibroconnective tissue with chondroid metaplasia'. Six cases were submitted in consultation due to concern for a neoplastic process, in particular chondroma of soft parts or fibro-osseous pseudotumor of the digits. The patients were 4 young males (age range 8-16 years, mean 11.5 years) and 5 older patients, including 4 women and 1 man (age range 34-78 years, mean 56.4 years). All cases occurred in the subcutaneous plantar soft tissues of the feet, including four cases confined to the toes, and presented as non-specific, variably painful masses. Radiographic studies, available in six cases, did not show any evidence of bone involvement. Histologically, the lesions were characterized by a partially circumscribed, variably cellular proliferation of bland fibroblastic cells in a fibromyxoid background in areas showing distinct stromal basophilia and a chondroid appearance. Small foci of true cartilaginous metaplasia with lacuna formation were occasionally seen. Cartilaginous differentiation was confirmed in three cases with immunohistochemistry for S100 and ERG proteins. Intralesional cystic change was common, as were a variety of other reactive-appearing changes in the surrounding connective tissue. Characteristic morphological features of chondroma of soft parts and/or fibro-osseous pseudotumor of the digits were absent. Clinical follow-up (7 patients, 2-115 months, median 38 months) showed all patients to be without recurrent disease. We have identified a morphologically distinctive lesion of the foot that appears to represent a reactive, metaplastic process, presumably secondary to chronic mechanical stress. The morphological features of myxochondroid metaplasia of the plantar foot are reminiscent of those of nuchal fibrocartilaginous pseudotumor and the equine digital cushion, further suggesting a reactive/reparative etiology. Awareness of the unique features of this lesion should allow its ready distinction from other neoplastic and pseudoneoplastic (osteo) cartilaginous lesions of the feet.

Angiosarcoma is an uncommon but aggressive tumor of endothelial origin that may occur in the upper extremities of patients with postmastectomy lymphedema (Stewart-Treves syndrome) as well as in other regions. We present an unusual case of angiosarcoma associated with congenital nonhereditary lymphedema in an 18-year-old man. Our case underscores the need for a careful clinical examination and shows the importance of appropriate sampling and thorough pathologic examination of suspicious areas to exclude the presence of a malignant process.

Reticulated acanthoma with sebaceous differentiation (RASD) represents a rare benign cutaneous epithelial neoplasm with sebaceous differentiation. There has been much speculation about the relationship between RASD and Muir-Torre syndrome (MTS). We report a 53 year-old man who presented with RASD in addition to a prior history of sebaceous adenomas. Immunohistochemically, the tumour cells in the RASD and sebaceous adenomas showed a significantly reduced MSH6 protein expression, whereas there was no loss of MLH1, MSH2 and PMS2. This benign neoplasm, which can be mistaken for various other cutaneous lesions with sebaceous differentiation, deserves wider recognition for its possible association with MTS.

Purpose To determine the outcomes of surgical excision in the management of angioleiomyomas of the upper extremity. Methods We retrospectively reviewed the medical records of 26 patients undergoing a surgical excision of an angioleiomyoma in the upper extremity between 1975 and 2012, who had at least 1 year of follow-up. There were 12 men and 14 women, with an average age of 55 ± 20 years. The most common location was the hand (n = 14). The onset of symptoms was on average 6 ± 5 years before presentation. The most common problem was a painful mass (19 of 26 patients). Average tumor size was 10 ± 7 mm. Results Patients over the age of 60 years tended to have smaller tumors. There was no significant difference between average preoperative and postoperative grip strength in the affected and unaffected extremities. None of the lesions was diagnosed based on radiographic imaging. There was 1 postoperative complication. No recurrence was noted at an average 8.6-year follow-up (range, 1.0–21.0 y). Conclusions Angioleiomyomas present as a small, painful masses that can be reliably treated with marginal surgical excision. Type of study/level of evidence Therapeutic IV.

Acinic cell carcinoma (AcCC) is an uncommon salivary gland malignancy. We aim to characterize the clinical and pathologic characteristics of AcCC with and without high-grade transformation (HGT). Importantly, cases of mammary analogue secretory carcinoma, a recently described histologic mimic of AcCC, have been excluded by using cytogenetics and molecular studies.Archival surgical pathology material was obtained for patients diagnosed with AcCC at Mayo Clinic Rochester between 1990 and 2010. Tumors harboring the ETV6-NTRK3 fusion transcript were excluded from analysis by using cytogenetics and molecular studies. Tumors with HGT were characterized by areas with an infiltrative growth pattern, nuclear anaplasia, prominent nucleoli, brisk mitotic activity, geographic necrosis, and stromal desmoplasia. Demographic and clinical data were extracted from the medical records.AcCC with HGT was seen in 8 of 48 cases (17%). Patients with AcCC with HGT were significantly older than patients without HGT (median 69 vs 54 years; P = .04). Angiolymphatic invasion was more common in AcCC with HGT (P = .02). Relapse-free survival and overall survival were significantly worse for cases of AcCC with HGT (hazard ratio 10.4 and 9.3, respectively; P.0001 for both comparisons). Locoregional recurrence-free survival was not significantly different (P = .12), but distant metastases-free survival was significantly worse in patients with HGT compared with non-HGT patients (P.0001).Prognosis for overall survival and distant relapse for AcCC patients with HGT is significantly worse than that for patients without HGT.

Purpose To evaluate outcomes in patients with malignant melanoma of the head and neck with resected regional lymph node (LN) metastases treated with adjuvant hypofractionated intensity modulated radiation therapy (IMRT). Methods and Materials A retrospective review was performed of 46 patients with malignant melanoma of the head and neck with regional LN metastases treated with lymphadenectomy and adjuvant IMRT. Patients underwent neck dissection (n = 42) or local excision (n = 4) for regional metastases at initial diagnosis (n = 19) or recurrence (n = 27). Adjuvant IMRT was delivered twice per week over 2.5 weeks for a total dose of 30 Gray (Gy) in 5 fractions. Acute and late adverse events were recorded using the Common Toxicity Criteria for Adverse Events version 4. Site of first recurrence was defined as local-regional (LR, above the clavicles) or distant. Overall survival, disease-free survival, and disease recurrence risks were determined using Kaplan-Meier estimates. Results The median follow-up in living patients was 2.8 years (range, 0.2-6.9). Most patients experienced acute grade 1-2 dermatitis (80%) and mucositis (85%). One patient (2%) experienced an acute grade 3 adverse event. Seven patients (16%) experienced late grade 2 adverse events. No patient experienced grade 3 or higher late adverse events. Site of first recurrence was LR alone (n = 5), both LR and distant (n = 1), and distant alone (n = 25). Five of the 6 LR recurrences were inside the IMRT planning target volume (PTV). In-PTV and total LR control at 3 years were 85% and 76%, respectively. Overall survival and disease-free survival at 3 years were 63% and 25%, respectively. Conclusions Adjuvant hypofractionated IMRT (30 Gy in 5 fractions) was associated with a high rate of in-PTV control and a low risk of serious adverse events.

Generalized eruptive histiocytosis, described in 1963 by Winklemann and Muller, is a reactive, self-healing form of non-Langerhans histiocytosis. Rare cases of atypical generalized eruptive histiocytosis have been reported in patients with hematopoietic malignancy, but the biological relationship between the two disorders is not known. We report an 84-year-old man with chronic myelomonocytic leukemia who presented with coalescing erythematous papules and plaques on the posterior neck, ear and lower lip, followed by development of blast crisis. Skin biopsy revealed a thick band-like dermal infiltrate of cells that exhibited morphologic features of macrophages or histiocytes and prominent elastolytic phagocytosis. These cells demonstrated a mature immunophenotype, expressing CD14 and CD68, with partial expression of CD13 but not CD1a, CD43, CD56, CD123, Langerin, or S-100 protein. Karyotype and fluorescence in situ hybridization analyses showed loss of the Y chromosome in bone marrow and skin specimens, providing evidence of a clonal relationship between the cutaneous eruption and the underlying chronic myelomonocytic leukemia. The presence of the same clone in skin and bone marrow specimens from our patient supports the possibility that atypical generalized eruptive histiocytosis is a marker for underlying hematopoietic malignancy. Discovery of additional cases may shed further light on the pathogenesis of this rare entity.

Tenosynovitis with psammomatous calcification, described in 1983 by Gravanis and Gaffney, is a distinctive clinicopathologic variant of "idiopathic calcifying tenosynovitis" or "calcific tendonitis." However, tenosynovitis with psammomatous calcification is poorly recognized by pathologists and for this reason has not been adopted widely as a distinct entity. We present the clinicopathologic features of 6 cases of tenosynovitis with psammomatous calcification. Cases involved the tendons, peritendinous soft tissues, and adjacent synovium of the distal extremities (3 fingers, 2 feet, and 1 carpal tendon) of women who ranged in age from 16 to 83 years (mean 48 y). The lesions presented a painful mass. A history of occupational or sports-related repetitive motion and/or persistent mild trauma was noted in all patients. No patient had a history of hyperphosphatemia. All lesions were treated by surgical excision and described clinically as variably cystic nodules composed of amorphous "cheese-like" debris. Histologically, the lesions were centered in the tendon or peritendinous soft tissue and composed of a mixed (myo) fibroblastic and histiocytic proliferation in association with a degenerating tendinous tissue, which was undergoing dystrophic calcification, with the formation of distinctive psammoma body-like spheroidal bodies. The clinical and morphologic characteristics of tenosynovitis with psammomatous calcification (distal location, absent hyperphosphatemia, and psammomatous calcifications) differ from those of typical idiopathic calcifying tenosynovitis/calcific tendinitis (proximal location and dystrophic tendinous calcification) and tumoral calcinosis (hyperphosphatemia and amorphous soft tissue calcification), and it should be recognized as a distinct clinicopathologic entity. Improved recognition of these unique features by pathologists should allow ready diagnosis of this unusual pseudotumor in most instances.