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Part 2 of this series on granulomatous diseases focuses on skin biopsy findings. Whereas the first part treated noninfectious conditions (metabolic disorders and tumors, among other conditions), this part mainly deals with various types of infectious disease along with other conditions seen fairly often by clinical dermatologists.

This series of 2 articles on dermatopathologic diagnoses reviews conditions in which granulomas form. Part 1 clarifies concepts, discusses the presentation of different types of granulomas and giant cells, and considers a large variety of noninfectious diseases. Some granulomatous diseases have a metabolic origin, as in necrobiosis lipoidica. Others, such as granulomatous mycosis fungoides, are related to lymphomas. Still others, such as rosacea, are so common that dermatologists see them nearly daily in clinical practice.

We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis.

Deep penetrating nevus (DPN) is an intradermal, sometimes compound benign melanocytic lesion, which involves the reticular dermis, occasionally reaching the subcutis, which can raise concern for melanoma both clinically and histologically. Recently, it has been genetically defined by the combination of MAPK activating and β-catenin activating mutations. We sought to investigate genetic alterations in 2 cases of combined nevi of congenital melanocytic and DPN. Case 1 was a 16-year-old woman with a pigmented lesion on the trunk since birth, which was completely excised. Histopathological examination revealed a combined congenital nevus with a DPN. Comparative genomic hybridization showed no major genetic alterations, except for gain of 6q11.1 and point mutation of B-RAF V600E. Case 2 was a 62-year-old woman with a congenital pigmented lesion on the back. The lesion was diagnosed as a combined nevus of congenital and DPN. Comparative genomic hybridization showed no genetic alterations, and the NRAS Q61K was detected in both components. DPN is in most cases part of a combined nevus. Our cases showed strong and uniform nuclear expression of β-catenin and cyclin D1 in the DPN component suggesting the evolution of the congenital nevus to the DPN clone by acquiring β-catenin activating mutation.

Giant cell tumor of soft tissue (GCTST) is a rare neoplasm genetically unrelated but histopathologically indistinguishable to its osseous counterpart. Histologically, GCTST is characterized as a multinodular proliferation of bland histiocytoid mononuclear cells intermixed with osteoclast-like giant cells. GCTST most commonly presents as a soft-tissue mass located in the extremities of middle-aged adults. In this report, we describe a case of a dermal GCTST arising in the periocular region of a 3-year-old girl. This is the youngest patient diagnosed with GCTST reported in the literature and is also singular because of its anatomic location: Only a handful of head and neck GCTSTs have been reported to date. Furthermore, GCTST most often presents as a superficial or deep soft-tissue mass and much less commonly as a dermal-based skin tumor, as was our case. On microscopic examination, the resected lesion demonstrated classical features including numerous osteoclast-like giant cells embedded in a background of mononuclear ovoid cells which displayed brisk mitotic activity and were surrounded by variable stromal hemorrhage. Tumor cells presented a vaguely fascicular arrangement. Immunohistochemical profile demonstrated positivity for smooth muscle actin and CD68 and negativity for desmin, myo-D1, S100, HMB-45, Melan-A, p16, and NKIC3. The unusual characteristics of this case emphasize the clinicopathologic heterogeneity of GCTST.

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder, more frequent in children, characterized by an abnormal accumulation of Langerhans cells admixed with eosinophils, lymphocytes, neutrophils, and macrophages. The clinical presentation is variable and depends on whether a single or multiple organs are affected. Skin lesions are common in LCH (40% of cases) and represent a frequent form of presentation (in up to 80% of cases). Cutaneous manifestations of LCH are highly variable, frequently presenting as crusted papules or scaly seborrheic-like lesions localized in the scalp. We report the first case of a localized acral sclerosing LCH, a new form of LCH. This case highlights the broad and surprising form of presentation of LCH which may be overlooked and can significantly delay its diagnosis. The development of systemic disease may occur months to years after the initial skin presentation. Prompt diagnosis and treatment may prevent progression to systemic disease, as documented in some cases.

Neurocristic cutaneous hamartomas (NCHs) are rarely reported tumors with divergent differentiation derived from persistently active pluripotent cells from the neural crest. They result from aberrant development of the neuromesenchyme, and they can express fibrogenic, melanocytic, and/or neurosustentacular differentiation. Thus, congenital melanocytic nevus also represents a neurocristic dysplasia of the skin in which cells are melanogenic cells arrested in development located in the reticular dermis, and nodular proliferative neurocristic hamartoma may arise within a congenital melanocytic nevus. The real importance of NCHs is that, although few cases have been reported in the literature, some cases have shown development of melanoma. Moreover, the only previously reported case of a similar "proliferative neurocristic nodule" analyzed with comparative genomic hybridization showed an aberration pattern similar to melanoma. We present a rare case of NCH associated with a congenital nevus in a 7-year-old boy, with classical histological and immunohistochemical features suggesting a "proliferative neurocristic hamartoma". Comparative genomic hybridization assay showed that chromosomal aberrations were absent in the congenital nevus, whereas, interestingly, the proliferative neurocristic proliferation had an aberration pattern similar to proliferative nodules with gains or losses of entire chromosomes only, similar to typical proliferative nodules and supporting the benign behavior of this lesion.

Background Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer. Objectives To investigate the role of the mitochondrial proteins, β-subunit of the H+ -ATP synthase (β-F1-ATPase), and heat-shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression. Materials and methods The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81-61-PA) and highly (C8161-HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation. Results The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease-free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4-1·2) is an independent predictor for overall survival. Conclusions A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation.

The malignant counterpart of cutaneous clear cell hidradenoma (CCH), hidradenocarcinoma, is an aggressive neoplasm that may have a fatal outcome. However, some cases of benign looking CCH with isolated lymph node involvement and excellent prognosis have been described. "CCH-like neoplasm of uncertain malignant potential" or "atypical hidradenoma" have been proposed as designations for these lesions. We report 3 cases of CCH with lymph node involvement. Ages ranged from 29 to 51 years old. All cases involved the inguinal lymph nodes: 2 of them presented with an isolated lymph node lesion, and the third case had lymph node and cutaneous involvement following the resection of a previous cutaneous lesion. Imaging studies showed no systemic involvement. None of the lesions exhibited histopathologic features of malignancy. All neoplasms were well circumscribed, had cystic spaces, did not display atypia or necrosis, and had less than 4 mitoses per high power field. No recurrence has been observed at follow-up after resection in all cases. All published cases of CCH with lymph node involvement so far affected a single lymph node in the axillary or inguinal regions, lacked features of malignancy, and had excellent long-term prognosis. Some cases previously reported as hidradenocarcinoma probably fit into this category. Our series adds more evidence to this rare phenomenon of "benign metastasis." Aggressive treatment should be avoided in these cases, and a long-term follow-up is warranted.

The novel coronavirus disease (COVID-19) is a rapidly spreading pandemic, secondary to severe acute respiratory syndrome coronavirus 2. The severity and the little knowledge that we have of the disease have made us focus mostly on the respiratory symptoms. As we bend the curve, other findings reported in association with COVID-19 become of importance for specialists to recognize. We describe the spectrum of clinicopathologic lesions in the skin that can be the only symptom or the first manifestation of COVID-19 and demonstrate the origin of the virus. We collected 25 patients with skin lesions in this context. We recognized 5 types of cutaneous manifestations including acute acroischemic or chilblain-like lesions (11), purpura palpable (2), exanthemas (9), urticarial eruptions (1), and other lesions (2) that might appear with more unspecific pictures. Chilblain-like lesions were the most common form of presentation, which tend to appear as self-healing, erythematous-necrotic plaques mostly on the feet, in young patients with no systemic symptoms associated. Importantly, we visualized viral particles with electron microscopy in 5 of 13 cases analyzed. In this study, we seek to draw a picture of the spectrum of clinicopathologic lesions that may appear in the skin in the context of COVID-19. Although apparently skin lesions are not correlated with disease severity, it may help in some cases to recognize and control the spread of the infection sooner.

The presence of a granulomatous reaction in cutaneous lymphomas has been described in the past, especially in mycosis fungoides (MF), where a "granulomatous" variant of the disease is well known. We describe a patient with granulomatous MF (GMF) who has been followed for 13 years presenting with erythematosquamous plaques on his fingers and toes, ankles, heels, and abdomen, which on microscopic examination showed a lichenoid granulomatous reaction admixed with a neoplastic proliferation of small-sized, atypical CD4 lymphocytes. GMF is characterized by a granulomatous reaction intermingled with the dermal infiltrate of MF which may even reach the subcutaneous tissue. Only 7 cases of GMF in which the granulomas were located within the papillary or superficial dermis have been described to date. We report for the first time a unique case of lichenoid GMF where the granulomatous reaction obscures the interface between the epidermis and dermis. Sequential biopsies and complete phenotypic studies were necessary to get an accurate diagnosis.

Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The era of targeted therapy has introduced a new therapeutic perspective for melanoma patients. Treatment with BRAFV600 inhibitors has improved overall and disease-free survival in metastatic melanoma patients whose tumors harbor BRAFV600 mutations. Although the BRAFV600E mutation appears to have a critical role in tumor initiation, its expression during tumor progression remains controversial. In fact, various authors claim that BRAFV600E heterogeneity is evident in melanoma tumors. Herein, we investigated the pattern of BRAFV600E expression in matched primary and metastatic samples from 140 patients. Using a combination of real-time PCR and immunohistochemical analyses, we demonstrated that BRAFV600E expression is homogeneous in melanoma tumors and hypothesized that the heterogeneity described by others might be attributable to technical issues when molecular methods are used. We also demonstrated the high efficiency of the anti-BRAFV600E VE1 antibody for the detection of BRAFV600E mutations in melanoma tumors.

Desmoplastic melanoma is an uncommon variant of melanoma with sarcomatous histology, distinct clinical behavior and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes in a validation cohort of 42 cases. A high mutation burden (median of 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen, indicating a superficially located cell of origin. Newly identified alterations included recurrent promoter mutations of NFKBIE, encoding NF-κB inhibitor ɛ (IκBɛ), in 14.5% of samples. Common oncogenic mutations in melanomas, in particular in BRAF (encoding p.Val600Glu) and NRAS (encoding p.Gln61Lys or p.Gln61Arg), were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS and PIK3CA, some of which are candidates for targeted therapies.

The discovery of BRAF mutations in 40%-60% of melanomas led to the development of BRAF inhibitors, which exhibit objective response in over 50% of patients. However, up to 98% of the patients develop at least 1 side effect. We report for the first time a patient with metastatic melanoma harboring BRAF V600E mutation that develops a primary, cutaneous small/medium CD4 T-cell lymphoma secondarily to the treatment with vemurafenib. A 54-year-old man with a history of metastatic melanoma treated with the oral BRAF inhibitor vemurafenib presents, 4 months after the initiation of the treatment, with multiple, nodular firm nonulcerated lesions on his back. Two skin biopsies from the lesions revealed a primary, cutaneous small/medium CD4 T-cell lymphoma.The extensive use of recently approved mutation-specific RAF inhibitors seems to be speeding up the emergence of unknown nonpreventable toxicities of these agents. Our patient developed a primary, cutaneous small/medium CD4 T-cell lymphoma, which presented 4 months after the commencement of vemurafenib. Although no treatment interruption is normally required, a close monitoring of the patients with advanced melanomas treated with vemurafenib seems imperative to optimize the management strategies.

Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.

Congenital melanocytic nevi (CMN) are benign melanocytic proliferations that are usually present at birth. A somatic mosaicism for an NRAS point mutation is responsible for the several phenotypic abnormalities that may be associated with congenital nevi. We report the case of a 7-year-old boy with a proliferative nodule (PN) arising in a Giant CMN completely excised and with several visceral and intraspinal melanoma metastases with no evidence of primary cutaneous melanoma. The careful analysis of the clinical, morphologic, and molecular features allowed the distinction of between the benign PN (BPN) and the melanoma. The BPN showed a characteristic comparative genomic hybridization pattern with gains or losses of whole chromosomes, whereas the melanoma displayed gains or losses involving complex partial chromosomal copy number gains or losses. Leptomeningeal melanocytes are more susceptible to transformation by oncogenic NRAS than cutaneous melanocytes, and central nervous system melanomas are more common than cutaneous melanomas in the setting of CMN. Thus, it has been recommended to characterize the congenital disease in patients with 2 CMN at birth, independently of size and site, with a single magnetic resonance imaging screening younger than the age of 1 year.

Previous studies have demonstrated the utility of fluorescence in situ hybridization (FISH) as an ancillary method in the diagnostic workup of histopathologically ambiguous melanocytic neoplasms. A combination of probes targeting 3 loci on chromosome 6 and 1 on 11q has been reported to distinguish unequivocal melanomas and nevi with a sensitivity and specificity of 87% and 96%, respectively. However, information on how FISH should be integrated into routine clinical testing is limited. We report our experience of FISH testing of 804 ambiguous melanocytic lesions performed as part of routine workup at University of California, San Francisco. The main category (47% of all cases) for which FISH testing was requested was Spitz tumors. Other categories included the distinction of possible melanoma from combined nevi (9%), acral or mucosal nevi (9%), Clark/dysplastic nevi (7%), and blue or deep penetrating nevi (6%) and to assess the possibility of nevoid melanoma (4%). Of the ambiguous tumors successfully tested, 88% received a more definitive benign or malignant final diagnosis. Of the 630 cases that tested negative by FISH, the final diagnosis was benign in 489 (78%) cases, ambiguous in 91 cases (14%), and malignant in 50 cases (8%). A positive FISH result was observed in 124 cases, with a final diagnosis of melanoma in 117 (94%). One (1%) FISH-positive case had an equivocal final diagnosis, and 6 (5%) were interpreted, despite the positive FISH result, as melanocytic nevi. We conclude that FISH testing can help reduce the number of equivocal diagnoses in ambiguous melanocytic neoplasms, in particular if FISH testing is positive, and discuss the challenges and limitations of FISH in clinical practice.

Purpose: Recent studies have shown activating KIT mutations in melanoma originating from mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive role of KIT mutation, amplification, or overexpression for response to treatment with the kinase inhibitor sunitinib. Experimental Design: Tumor tissues from 90 patients with stage III or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and immunohistochemistry of KIT protein (CD117). Patients with mutations, amplifications, or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Eleven percent of the melanomas tested had mutations in KIT, 23% in BRAF, 14% in NRAS, and none in GNAQ. Of 12 patients treated with sunitinib, 10 were evaluable. Of the 4 evaluable patients with KIT mutations, 1 had a complete remission for 15 months and 2 had partial responses (1- and 7-month duration). In contrast, only 1 of the 6 patients with only KIT amplification or overexpression alone had a partial response. In 1 responder with rectal melanoma who later progressed, the recurring tumor had a previously undetected mutation in NRAS, which was found in addition to the persisting mutation in KIT. Interestingly, among patients with manifest stage IV disease, KIT mutations were associated with a significantly shortened survival time (P < 0.0001). Conclusions: Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma. Clin Cancer Res; 18(5); 1457–63. ©2012 AACR.

Background: WT1, first recognized as a tumor suppressor gene involved in the development of Wilms' tumor, may have apparently contradictory findings and functions. As WT1 has been identified as a molecular target for cancer immunotherapy, immunodetection of WT1 in tumor cells has become an essential step in cancer studies. Methods: We compare the expression of this protein among different types of melanocytic nevi and among stages in primary melanoma progression. Tissue microarrays containing normal tissues and 271 primary melanocytic lesion samples (163 primary melanomas and 108 nevi) were studied by immunohistochemistry using monoclonal antibody against WT1. Results and Discussion: The present study shows these: 1. WT1 protein is predominantly expressed in the cytoplasm of the neoplastic cells. 2. A higher rate of WT1 staining in melanocytic nevi against melanomas has been observed. 3. WT1 expression is increased in advanced stages of melanoma progression: a significant (p < 0.05) increase of expression of WT1 was detected in vertical cases 46.5% vs. radial cases 16.0%, in high levels of Clark (IV, V) 57.4% vs. low levels (I, II, III) 33.0% and when comparing depth of invasion within thickness subgroups. 4. Finally, this study establishes an association of WT1 protein expression with shorter overall survival in melanoma. Garrido-Ruiz MC, Rodriguez-Pinilla SM, Perez-Gomez B, Rodriguez-Peralto JL. WT 1 expression in nevi and melanomas: a marker of melanocytic invasion into the dermis.

BACKGROUND Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. METHODS We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. RESULTS We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. CONCLUSIONS Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).

Syringomas are benign, eccrine, sweat gland tumors that clinically appear as small skin-colored or yellow papules. Eruptive syringomas are rare variants that typically develop on the body's cutaneous anterior surface. Syringomas on the genital area have rarely been reported, although several authors maintain that syringoma should be considered in the differential diagnosis of pubic pruritic papular dermatitis. We present a case of a 31-year-old man with multiple, eruptive, asymptomatic papules involving the pubic area developed after waxing of the zone. Histological examination revealed disseminated syringomata. We postulate that the lesions were induced by depilation with a subsequently reactive inflammatory process resulting in a hyperplastic reaction of the eccrine ducts. This case supports the previous hypothesis suggesting that some of the so-called "eruptive syringomas" may start as a primary inflammatory eccrine reaction.

Background Actinic keratosis (AK) is an intraepidermal malignancy precursor form of cutaneous squamous cell carcinoma (SCC), which generally occurs in fair-skinned individuals with long-term sun exposure. We present a case series of AKs on the eyelid. Methods This was a retrospective study. Data of patients seen from 1994 to 2005 were used in the analyses. Results There were 21 cases of eyelid AKs in 18 patients, 11 men, and seven women, with a mean age of 70 (range 43–80) years. Most tumors were located on the upper eyelid. The mean size was 0.8 ± 0.4 cm. The most frequent AK type was type I (76.2%). Men had bigger lesions and more frequent free-margin eyelid involvement. Conclusions In our series, tumors were more frequent and had worse clinical and histopathological features in men. AKs are closely related to SCC and need to be removed before they turn into SCC. They can be safely and effectively removed, and therapy is therefore warranted.

Resumen Introduccion El sarcoma sinovial es un tumor de partes blandas poco frecuente en cabeza y cuello y excepcional en la mandibula. Presentacion del caso Presentamos un caso de un paciente de 74 anos previamente diagnosticado y tratado de osteosarcoma mandibular, que muestra una tumoracion en el remanente mandibular con extension infratemporal. El diagnostico con microscopia optica, tecnicas inmunohistoquimicas y ultraestructura fue de sarcoma sinovial monofasico. Se realizo estudio genetico para la traslocacion t (x;18) que resulto positiva, confirmandose el diagnostico de recidiva local por sarcoma sinovial. La biopsia previa estaba erroneamente diagnosticada. Conclusiones El sarcoma sinovial monofasico requiere diagnostico diferencial con otras entidades. Es una tumoracion que recidiva en mas de la mitad de los casos y presenta un riesgo elevado de metastasis. Su diagnostico exacto necesita un buen procesamiento tisular, tecnicas inmunohistoquimicas, ultraestructurales y estudio genetico.

Recent advances in targeting BRAF mutations, which occur in roughly 50% of the melanomas, have improved response rates and overall survival in patients with advanced disease. With the increasingly extensive use of the drug, new, nonpreventable, cutaneous and noncutaneous toxicities keep arising as infrequent adverse effects. We report a 55-year-old man with a history of metastatic melanoma treated with the dabrafenib who presented, 10 months after the initiation of the treatment, with erythematous, slightly squamous, round plaques on his upper trunk and on his left upper arm. Two skin biopsies from the lesions revealed a granulomatous dermatitis in the superficial reticular dermis. One of them showed admixed abundant melanophages from tumoral melanosis. No melanoma cells were seen in any of the specimens. No interruption of the treatment was necessary. Our observation indicates that such a response may represent a positive immune activation triggered by BRAF inhibitors. The erythematous rash was initially concerning for progression of metastatic disease, which suggests that a close monitoring of the patients with advanced melanomas treated with vemurafenib is advisable to prevent unnecessary discontinuation of the therapy.

We report the case of a 77-year-old diabetic patient with asymptomatic papular eruption developed over a cutaneous scar after the resection of a squamous cell carcinoma. Histological examination revealed a clear cell proliferation involving the secretory portion of the eccrine glands. This entity has been previously named as papular clear cell hyperplasia of the eccrine duct. This clear cell change might be caused by glycogen deposition because of diabetes. We postulate that papular clear cell hyperplasia could be a precursor lesion of clear cell syringoma.

Primary cutaneous spindle cell lymphoma is a unique morphologic variant of cutaneous B-cell follicle center lymphoma characterized by a prominent population of spindle-shaped, medium, and large B lymphocytes with a poorly formed storiform pattern.We report a case of a 35-year-old woman who presented with a well-defined erythematous plaque with 2 nodular, nontender nonscaling nonulcerated lesions on her right cheek mimicking acne rosacea. Microscopic examination revealed a tumor mainly centered in the reticular dermis and mostly composed of spindle-shaped large B lymphocytes exhibiting bizarre shapes with "boomerang-like" or "spermatozoa-like" appearance. The immunohistochemical staining demonstrated neoplastic lymphocytes positive for CD20, CD79α, and BCL-6, and negative for CD3, CD43, CD10, BCL-2, and MUM-1. These results supported the diagnosis of a follicle center B-cell lymphoma with spindle cells.Although this rare variant of primary cutaneous B-cell lymphoma is not included in the recent WHO-EORTC classification, the rarity of this tumor and its unique morphologic appearance frequently leads to misdiagnosis and delays its treatment.

Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma. This entity may present with a wide spectrum of clinicopathological manifestations and mimic different dermatoses. Among its histopathological variants, spongiosis is an infrequent finding, and spongiotic microvesiculation is particularly rare. Mucinous deposition is a common event in folliculosebaceous units of folliculotropic MF but rarely described within the epidermis. Herein, we report a patient with eczematous palmoplantar lesions whereby the histological, immunohistochemical, and molecular studies confirmed to be a unique case of MF showing epidermal microvesiculation mucinosis.

Benign fibrous histiocytoma is one of the most frequent benign neoplasms mainly composed of a mixture of fibroblastic and histiocytic cells, especially found in the skin (dermatofibroma), particularly in the limbs. The diagnosis of cutaneous benign fibrous histiocytoma is generally easy; however, rare variants may be difficult to identify, and the diagnosis only confirmed after exhaustive histopathological examination. Thus, deep subcutaneous dermatofibroma may be difficult to distinguish from dermatofibrosarcoma protuberans and dermatofibroma with monster giant cells from malignant fibrous histiocytoma and atypical fibroxanthoma. We report a case of a 38-year-old woman with a painless swelling on the abdominal wall, which was totally excised and histopathologically diagnosed as subcutaneous atypical fibrous histiocytoma. The lesion was deeply located within the subcutaneous tissue and consisted of interlacing fascicles of predominant histiocyte-like spindle cells intermingled with pleomorphic giant cells with bizarre large nuclei (bilobed and multilobed) and prominent eosinophilic nucleoli. Only 1 mitotic figure was found in the whole lesion. Prominent hyaline collagen bundles surrounded by tumor cells were observed, predominantly at the periphery of the lesion. Immunohistochemical study showed positivity only for vimentin and factor XIIIa, whereas pan-keratins, actin, desmin, CD34, CD10, and S-100 protein were negative. Recognition of dermatofibroma is important, allowing sequential excision and optimal results. Definitive diagnosis, although especially difficult in our case, is established by characteristic histological and immunohistochemical criteria. To the best of our knowledge, we report the first case of subcutaneous fibrous histiocytoma with monster cells.

Sarcoidosis is a chronic multisystemic granulomatous disease of unknown etiology, characterized by the formation of noncaseating granulomas in the involved organs. Cutaneous involvement is about 25% with different clinical expressions, the lichenoid pattern being one of the rarest types of cutaneous sarcoidosis. Lichenoid sarcoidosis clinically manifests with multiple scale papules involving extensive skin areas, especially the trunk, limbs, and face mimicking a lichen planus. Although diverse histologic patterns have been previously related, a lichenoid granulomatous infiltrate involving the dermo-epidermal junction has never been reported in lichenoid sarcoidosis. We report a case of a 43-year-old woman presenting with skin-colored pruritic papules, slightly scaling in trunk, extremities, and ears. These symptoms condition continued to expand and worsen for several years. The patient was otherwise in good health with no lymphadenopathies. Histopathologic examination of a skin biopsy showed an upper dermal granulomatous infiltrate of epithelioid cells, without necrosis, distributed in a lichenoid pattern with many cytoid bodies. We consider this may be the first case presenting a characteristic microscopic granulomatous lichen-like pattern in the setting of a clinically lichenoid type of sarcoidosis.

Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas. Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.

BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.

Recently, genetic alterations activating the receptor tyrosine kinase KIT have been demonstrated in some types of melanoma. KIT mutations can be successfully targeted by approved drugs in other cancers. Emerging evidence suggests that melanomas with KIT activation may also respond to KIT inhibitors that are already in clinical use. If confirmed in ongoing clinical trials, this experience would underscore the importance to recognize the biological diversity among melanomas, representing a first decisive step towards individualized and mechanism-based treatment of melanoma.

Dermatofibroma or cutaneous fibrous histiocytoma is a common benign skin lesion with multiple, distinct histologic variants, including cellular, aneurismal, epithelioid, atypical, lipidized "ankle-type," palisading, and cholesterotic. Although dermatofibromas are considered benign neoplasms, certain variants including cellular and aneurismal ones have shown to have a notable tendency to locally recur after excision. Indeed, although extremely rarely, metastases have been associated with the cellular and aneurysmal/atypical variants. Signet-ring cells are formed by cytoplasmic accumulations of various substances that push the nucleus toward the cellular border. The finding of signet-ring cells in a skin neoplasm always raises the suspicion of metastatic adenocarcinoma, although a number of reports have shown their occurrence in primitive cutaneous neoplasms as well. Signet-ring cell formation, however, has never been described in dermatofibroma. We present, for the first time, a new, distinctive variant of dermatofibroma, so-called signet-ring cell dermatofibroma, in a 16-year-old man with a slowly growing skin tumor on the lateral side of his right leg. Histologic examination demonstrated a striking signet-ring cell appearance of most of the cells in an otherwise fibrohistiocytic looking proliferation. Histochemical and immunohistochemical stainings confirmed the diagnosis of dermatofibroma. The phenomenon described in this case enlarges the histologic spectrum of cutaneous fibrous histiocytoma and may cause substantial differential diagnostic problems.

Desmoplastic melanomas (DMs) comprise 4% of the overall melanoma burden and have a 5-year survival rate of 85%. DMs are dermal tumors characterized by spindled melanocytes situated within abundant desomplastic stroma. These unusual histological features commonly lead to misdiagnosis. Currently, there are no known genetic drivers. A better understanding of the underlying biology of desmoplastic melanoma would provide biomarkers and therapeutic opportunities. Towards this goal, we performed low-coverage genome and high-coverage exome sequencing of 20 DMs in a discovery cohort, followed by targeted sequencing of 293 candidate genes on a validation cohort of 42 cases. Additionally, high-resolution aCGH was performed on samples from both cohorts. A high mutation burden (median 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers sequenced to date. Mutation patterns strongly indicate that UV-radiation is the dominant mutagen and implicate a superficially located cell of origin despite their predominantly intradermal presentation. Novel alterations included recurrent promoter mutations and amplification of NF-kappa B inhibitor epsilon, NFKBIE (IkBϵ) in 14.5% of samples. The promoter mutations typically affect both alleles and occur over a highly conserved DNA region. The mutations are predicted to disrupt a canonical Ets Like Factor 1 (ELF1) binding site. In total, these data imply aberrant NF-kappa B signaling as a pathogenic feature of desmoplastic melanoma. Commonly mutated oncogenes in melanomas, in particular BRAF V600E and NRAS Q61K/R, were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS, and PIK3CA. Rb and p53 pathway alterations occurred respectively in 71% and 66% of tumors, affecting RB1, FBXW7, CDK4, PPP6C, CCND1, CDKN2A, TP53, and MDM2. Finally, TERT promoter mutations or amplifications occurred in 90% of tumors. The consequences of the mutations on protein expression levels was confirmed by immunostaining for NF1, EGFR, Rb, CDK4, CCND1, p16, p53, and Mdm2. Collectively, many of these oncogenic mutations are potentially druggable. In conclusion, desmoplastic melanomas harbor distinct genetic alterations that explain their unique biology, and this study illuminates genetic biomarkers and nominates targets for therapeutic intervention. Citation Format: Alan H. Shain, Maria Garrido, Thomas Botton, Eric Talevich, Iweh Yeh, Zack Sanborn, Jongsuk Chung, Nicholas Wang, Hojabr Kakavand, Graham Mann, John Thompson, Thomas Wiesner, Ritu Roy, Adam Olshen, Alexander Gagnon, Joe Gray, Nam Huh, Joe Hur, Klaus Busam, Richard Scolyer, Raymond Cho, Rajmohan Murali, Boris Bastian. Exome sequencing of desmoplastic melanoma reveals recurrent NFKBIE promoter mutations and diverse MAPK/PI3K pathway activating mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2968. doi:10.1158/1538-7445.AM2015-2968

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis. Usually, liver failure, rapidly progressing jaundice, and an increase in alkaline phosphatase levels are suggestive diagnostic features. We report two cases of patients with primary sclerosing cholangitis who developed cholangiocarcinoma without jaundice and with no changes in their serum biochemistry. Both patients were taking ursodeoxycholic acid at the time of tumor diagnosis. Initial suspicion of malignancy was based on the development of superficial thrombophlebitis. Liver histology showed evidence of bile duct epithelial dysplasia in areas free from tumor in one patient, and in the other, bile duct epithelial dysplasia preceded the appearance of cholangiocarcinoma by at least 18 months. In one of the cases, the dysplastic epithelium stained positively for carcinoembryonic antigen. The histological finding of bile duct epithelial dysplasia in patients with primary sclerosing cholangitis may suggest either imminent or actual development of cholangiocarcinoma and may thus affect consideration of orthotopic liver transplantation. In addition, the development of superficial thrombophlebitis in patients with primary sclerosing cholangitis should arouse suspicion of the presence of cholangiocarcinoma even if there is no evidence of deterioration of the liver function or a dominant stricture on endoscopic retrograde cholangiography.