Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation.

Epithelioid fibrous histiocytoma (EFH) is a rare cutaneous neoplasm, which is characterized by the presence of rearrangements involving the ALK gene. Although EFH was long considered a variant of fibrous histiocytoma, the identification of its unique genetic signature confirmed that it represents a distinct entity. The aim of the present study was to examine a cohort of ALK-immunoreactive EFH cases to further characterize gene fusion partners. Next generation sequencing detected ALK fusions in 11 EFH cases identified in the pathology archives of two different institutions. The most common fusion partner was DCTN1 (N = 4) followed by CLTC (N = 2) and VCL (N = 2), while the remaining cases harbored fusions involving SPECC1L, PPFIBP1, and PRKAR1A. In one case no fusion was detected by NGS and FISH despite suitable sample quality. Notably, IHC demonstrated positive ALK expression and the level of aligned ALK reads was comparable to the fusion-positive cases. To the best of our knowledge, this is the first report of CLTC as a fusion partner in EFH. The two CLTC rearranged cases in our cohort also represent the first two EFH cases in the literature that involve exon 19 of ALK, instead of exon 20. These findings underscore the remarkable plasticity of ALK as an oncogenic driver and further expand the list of its potential fusion partners in EFH. Lastly this is also the first report of ALK-immunoreactive EFH with no underlying fusion suggesting a fusion independent transcription mechanism as seen in other tumors.

Role of Wnt signaling in dermatofibroma induction phenomenon.

BACKGROUND: Dermatofibroma (DF) is a common benign skin neoplasm. Induction above DF lesions, including follicular unit induction, is a frequently observed phenomenon. Wnt signaling is known to be critical in hair follicle morphogenesis. Our study assesses the role of Wnt signaling in DF induction by evaluating intracellular localization of ß-catenin in various types of DF induction. METHODS: Archived tissue collected between 1 October 1980 and 1 October 2013 was stained per protocol using hematoxylin and eosin and anti-ß-catenin monoclonal antibody. Specimens were grouped into categories based on the presence or absence and type of induction. All specimens were scored for nuclear ß-catenin localization. RESULTS: Of 62 specimens, 42 (68%) showed induction while 20 (32%) showed none. Nuclear ß-catenin staining was detected in 23 (55%) of the induction and in none of the no-induction specimens (P-value < 0.001). Types of induction included: 15 (24%) follicular induction, 31 (50%) acanthosis, and 4 (6%) sebaceous induction. For follicular induction, 13 (87%) showed positive nuclear ß-catenin staining compared to 11 (35%) for acanthosis and 1 (25%) for sebaceous induction (P-value = 0.002). CONCLUSION: Our findings support the hypothesis that DFs promote an ectopic activation of Wnt pathway signaling in follicular induction phenomenon.

Cholesterotic fibrous histiocytoma: Case report and literature review.

Cholesterotic fibrous histiocytoma is a particularly rare variant of dermatofibroma that is distinguished histopathologically by the presence of prominent cholesterol deposits within the lesion. We report the case of a 54-year-old male with poorly controlled hyperlipidemia who presented with a firm violaceous papule on the right shin, diagnosed as a cholesterotic fibrous histiocytoma. We also review and summarize the existing literature on this uncommon entity.

Clear Cell Proliferations of the Skin: A Histopathologic Review.

ABSTRACT: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them.

Metastatic aneurysmal fibrous histiocytoma in a 20-year-old woman: A rare case report with review of the literature and discussion of its genomic features.

Aneurysmal fibrous histiocytoma is an uncommon variant of cutaneous fibrous histiocytomas with a local recurrence rate of 19%. We present a case of aneurysmal fibrous histiocytoma in a 20-year-old female with a regional lymph node metastasis and subsequent satellite nodule. The patient initially presented with a 1-month history of two palpable nodules in left lower anterior shoulder and left axilla. Needle core biopsies from both lesions revealed an atypical spindle cell neoplasm with a differential diagnosis of aneurysmal fibrous histiocytoma and angiomatoid fibrous histiocytoma. The axillary dissection confirmed a metastatic deposit in 1 out of 22 lymph nodes. At 6 months a satellite nodule arose between the resection scar and the axilla histopathologically demonstrating a cellular spindle cell nodule at the dermis subcutaneous junction with large, blood-filled pseudovascular spaces lined by histiocytes. The periphery of the lesion showed collagen trapping without a lymphoplasmacytic infiltrate. The lesional cells were diffusely positive for CD10 and focally for CD68 and Illumina RNA fusion panel sequencing was negative. Herein we present this case of metastatic aneurysmal fibrous histiocytoma with review of the literature and discussion of biology, cytogenetic alterations, and differential diagnosis.

Fat necrosis with an associated lymphocytic infiltrate represents a histopathologic clue that distinguishes cellular dermatofibroma from dermatofibrosarcoma protuberans.

BACKGROUND: Cellular dermatofibromas (CDFs) and dermatofibrosarcoma protuberans (DFSP) can be challenging to differentiate from one another. Morphologically, both entities commonly extend into the subcutis, exhibit high cellularity with limited cytologic atypia and have a mixed fascicular-to-storiform growth pattern. We sought to evaluate the significance of fat necrosis with an associated lymphocytic infiltrate as a histopathologic clue for distinguishing CDFs from DFSP. METHODS: We identified cases in our pathology database with a primary diagnosis of CDF or DFSP. Punch or excisional biopsy specimens with extension into the subcutis were selected. Previously biopsied lesions and specimens that did not interact with the subcutis were excluded. Histopathologic features were evaluated in hematoxylin and eosin stained sections. RESULTS: Fat necrosis with lymphocytic infiltrate was present in 20/20 cases of CDF. None of the 20 DFSP cases had fat necrosis with lymphocytic infiltrate although 4/20 had fat necrosis alone. CONCLUSIONS: Fat necrosis with associated lymphocytic response can aid in the distinction between CDF and DFSP.

Multinucleate cell angiohistiocytoma: A clinicopathologic study of 62 cases and proposed diagnostic criteria.

BACKGROUND: Multinucleate cell angiohistiocytoma (MCAH) is an uncommon and likely underdiagnosed entity that is thought to be of vascular and fibrohistiocytic origin. METHODS: We retrospectively reviewed all cases diagnosed as MCAH at the Yale Medicine Dermatopathology laboratory between 1 January 1990 and 1 September 2018. Sixty-two cases were retained. We performed immunohistochemistry on the ten most inflamed lesions found and assessed for a possible alteration within the Wnt/ß-catenin signaling pathway, involved in follicular induction in dermatofibroma. We subsequently established histologic diagnostic criteria to differentiate MCAH from its mimickers. RESULTS: MCAH affected both genders equally. The hands or fingers were affected in 51.6% of cases. We found the most specific histologic criteria to be: (a) presence of odd multinucleated fibroblasts, (b) presence of superficial parallel fibrosis, (c) presence and thickening of superficial papillary dermal vessels, and (d) absence of perifollicular fibrosis. As for immunoreactivity, we found positivity to CD138, CD163, and CD117 in the mononuclear inflammatory infiltrate. There was no histopathologic evidence of follicular induction, as can be seen in dermatofibromas, and no expression of nuclear beta-catenin as seen in dermatofibromas with follicular induction. CONCLUSION: This large case series establishes MCAH as a distinct clinical and histopathologic entity.

Unique histopathologic features of the eyelid dermatofibroma.

Purpose: Dermatofibromas are common cutaneous lesions, but rarely occur in the eyelid skin. The reason for the low incidence in the palpebral skin has not been elucidated. In this study, we analyze the histopathologic features of an illustrative case of dermatofibroma and review previously published cases to determine whether eyelid dermatofibroma develops differently from the prototypical dermatofibroma. Methods: Histopathologic analysis of a new illustrative case of eyelid dermatofibroma and retrospective review of published cases. Results: The distinguishing features of the illustrative lesion included a rounder gross appearance, nonacanthotic epithelium, basophilic staining, cellular character, and a paucity of "collagen trapping." These features deviated from the typical features associated with classic dermatofibroma. Review of the 11 previously published cases of eyelid dermatofibroma revealed that they were more similar in appearance to the illustrative lesion than to classic dermatofibroma. Discussion: The rarity and histological deviations of the eyelid dermatofibroma suggest that the dermal substrate from which the lesion develops differs from that of the classic dermatofibroma. This difference may be explained microanatomically based on the fact that the dermis of the eyelid is predominantly papillary, whereas the dermis of extrapalpebral skin where dermatofibromas are more common is predominantly reticular. Conclusions: Although related, eyelid dermatofibromas appear to be histologically distinct from classic dermatofibromas, owing to the unique dermal composition of the site of origin.

Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases.

Epithelioid fibrous histiocytoma is a rare and distinctive cutaneous neoplasm. Most cases harbor ALK rearrangement and show ALK overexpression, which distinguish this neoplasm from conventional cutaneous fibrous histiocytoma and variants. SQSTM1 and VCL have previously been shown to partner with ALK in one case each of epithelioid fibrous histiocytoma. The purpose of this study was to examine a large cohort of epithelioid fibrous histiocytomas by next-generation sequencing to characterize the nature and prevalence of ALK fusion partners. A retrospective archival review was performed to identify cases of epithelioid fibrous histiocytoma (2012-2016). Immunohistochemistry was performed to confirm ALK expression. Targeted next-generation sequencing was applied on RNA extracted from formalin-fixed paraffin-embedded tissue to identify the fusion partners. Twenty-three cases fulfilled inclusion criteria. The mean patient age was 39 years (range, 8-74), there was no sex predilection, and >75% of cases involved the lower extremities. The most common gene fusions were SQSTM1-ALK (N=12; 52%) and VCL-ALK (N=7; 30%); the other four cases harbored novel fusion partners (DCTN1, ETV6, PPFIBP1, and SPECC1L). The pattern of ALK immunoreactivity was usually granular cytoplasmic (N=12; 52%) or granular cytoplasmic and nuclear (N=10; 43%); the case containing an ETV6 fusion partner showed nuclear staining alone. There was no apparent relationship between tumor morphology and the ALK fusion partner. In summary, SQSTM1 and VCL are the most common ALK fusion partners in epithelioid fibrous histiocytoma; DCTN1, ETV6, PPFIBP1, and SPECC1L represent rare fusion partners. The proteins encoded by these genes play diverse roles in scaffolding, cell adhesion, signaling, and transcription (among others) without clear commonalities. These findings expand the oncogenic promiscuity of many of these ALK fusion genes, which drive neoplasia in tumors of diverse lineages with widely varied clinical behavior. This is the first documented account of ETV6-ALK and SPECC1L-ALK translocations in neoplasms.

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma.

Epithelioid benign fibrous histiocytoma, also known as 'epithelioid cell histiocytoma,' has traditionally been considered a morphologic variant of cutaneous fibrous histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous histiocytoma and separately in two cases reported as 'atypical' fibrous histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous histiocytoma, to determine its value for the diagnosis of epithelioid fibrous histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous histiocytomas, 41 other cases of fibrous histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated (n=13), and not in one ALK expression-negative epithelioid fibrous histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous histiocytoma and histologic variants.

Atypical fibrous histiocytoma of the skin with CD30 and p80/ALK1 positivity and ALK gene rearrangement.

We report the case of a two patients who presented with a solitary, asymptomatic, angiomatoid nodule on the right thigh. Histopathological finding showed a poorly circumscribed lesion, located in the dermis. The morphological aspect strongly suggested the diagnosis of atypical fibrous histiocytoma (AFH), but surprisingly, the neoplastic cells were diffusely CD30+, with a membrane staining devoid of paranuclear dot. The lesions were tested for p80/ALK1 expression. Surprisingly, we found a diffuse cytoplasmic positivity. Interestingly, using break-apart fluorescent in situ hybridization (FISH), we evidenced an ALK rearrangement in nearly 50% of the neoplastic cells. The expression of CD30 and ALK1 with ALK gene rearrangement raised the possibility of three diagnoses: a primary cutaneous anaplastic large cell lymphoma (ALCL), a cutaneous inflammatory myofibroblastic tumor (IMT), an AFH of the skin associated with ALK gene rearrangement and CD30 positivity. The three hypotheses were discussed and finally, although p80/ALK1 expression and cytogenetic abnormalities in fibrous histiocytoma (FH) are not yet reported to the best of our knowledge, we favored the diagnosis of AFH.

Atypical fibrous histiocytoma arising in the perianal area: a case report and review of the literature.

Atypical fibrous histiocytoma (AFH) is an uncommon variant of cutaneous fibrous histiocytoma that can display histologic features associated with malignancy. Fewer than 150 cases have been reported in the literature. The majority of these lesions present on the trunk and extremities of middle-aged women. Genital lesions are rare, with one documented case of vulvar AFH and another case of scrotal AFH in the literature. We report an additional case of a 68-year-old woman who was diagnosed with an AFH in an unusual location, the perianal area. Histologically, the lesion was characterized by a nodular fairly well-circumscribed proliferation of large epithelioid macrophages with scattered lymphocytes and mast cells in the background. The atypical macrophages contained enlarged markedly pleomorphic nuclei with prominent nucleoli. Scattered multinucleated "monster cells" and atypical mitoses were observed throughout the lesion. Immunologically, the lesional cells were focally positive when stained with antibodies against CD163 and Factor XIIIa. They were negative for CD34, CD31, desmin, smooth muscle actin, CAM 5.2, keratin 5/6, S100, CD3, CD20, and CD30. The constellation of histologic and immunologic features was most consistent with an AFH. To our knowledge, this case is the first perianal presentation of AFH to date.

[Endocrine mucin-producing sweat gland carcinoma. three case reports with a brief review of the literature]. / Endokrines muzinproduzierendes Schweißdrüsenkarzinom. Drei Fallberichte mit kurzer Literaturübersicht.

Endocrine mucin-producing sweat gland carcinoma (EMPS) is a rare low-grade sweat gland carcinoma with an infiltrating growth pattern. It occurs mostly in women and shows a predilection for the periorbital region. Histopathologically, the tumor shows analogous features to endocrine ductal carcinoma/solid papillary carcinoma of the breast and shares some clinical and morphological similarities with primary mucinous carcinoma of the skin. The tumor is characterized by large monomorphous epithelial cells with little nuclear pleomorphism and only a few mitotic figures. The solid cystic tumor shows mucin-filled small cystic spaces, cribriform areas and expresses the neuroendocrine markers synaptophysin, chromogranin and neuron-specific enolase with varying staining intensities. The tumor cells are also positive for estrogen and progesterone receptors. We present three cases of this rare tumor with typical clinical, histopathological and immunohistochemical findings, give a short summary of the literature and discuss the most relevant differential diagnoses.

[Atypical fibrous histiocytoma: a clinicopathologic analysis of 24 cases].

OBJECTIVE: To study the clinicopathologic characteristics of atypical fibrous histiocytoma (AFH), with emphasis on differential diagnosis. METHODS: The clinical and pathologic features were reviewed in 24 cases of AFH (from 2007 to 2012). The follow-up data were analyzed. Immunohistochemical study using EnVision method was carried out. RESULTS: There were 10 males and 14 females with age at presentation ranging from 8 to 67 years (mean = 41 years and median = 39 years). The tumor occurred in the extremities (number = 14), trunk (number = 8) or head and neck region (number = 2). Apart from one case, all were located in the dermis. The clinical appearance was similar to those of classic fibrous histiocytoma. Histologically, the tumor was characterized by various number of hyperchromatic bizarre cells scattered in the background. Mitotic figures including atypical ones were noted, especially in the more cellular areas. Immunohistochemical study showed that the tumor cells expressed vimentin. Focal positivity for alpha-smooth muscle actin was demonstrated in some cases. Follow-up information was available in 14 cases. Three of them suffered local recurrence. None of these cases had distant metastasis. CONCLUSIONS: Atypical fibrous histiocytoma represents a pleomorphic variant of fibrous histiocytoma. Although the tumor exhibits worrisome features, it usually pursuits a relatively benign course. Nevertheless, rare cases may recur, especially after incomplete excision. AFH is sometimes mistaken as atypical fibroxanthoma. A distinction between the two entities is warranted as they represent two different entities.

[Cellular fibrous histiocytoma: a clinicopathologic analysis of 27 cases].

OBJECTIVE: To study the clinicopathologic characteristics of cellular fibrous histiocytoma (CFH) with emphasis on diagnosis and differential diagnosis. METHODS: Clinical and pathologic features were reviewed in 27 cases of CFH (encountered during the period from 2008 to 2012) along with outcome analysis. Immunophenotyping was performed with EnVision method. RESULTS: The patients included 13 males and 14 females. The age at presentation ranged from 15 to 61 years (mean, 34 years; median, 32 years). The tumor occurred in the extremities (n = 14), head and neck (n = 7), and trunk (n = 6). Histologically, the tumors were located in the dermis. Some cases showed wedge like extension into the subcutaneous adipose tissue. On high power, they consisted of dense fibroblasts and myofibroblasts. Other cell components such as psammoma-like histiocytes, hemosiderin-containing macrophages or touton-type giant cells were rare. The spindled tumor cells were arranged mostly in intersecting fascicles. Focal storiform architecture was not uncommon. In addition, a few cases showed prominent hemangiopericytoma-like pattern. There was no prominent cellular atypia but increased mitotic figures were not difficult to find. Two cases exhibited necrosis. By immunohistochemistry, the tumor cells showed variable expression of alpha smooth muscle actin. CD34 positive cells were present in some cases, but were distributed mostly in the periphery or bottom of the lesions. They were all negative for desmin, h-caldesmon, S-100 protein and cytokeratin. Follow-up in 19 cases revealed local recurrences in 5 cases and bilateral pulmonary metastases in 1 case after repeated recurrences. CONCLUSIONS: CFH is a cellular form of benign fibrous histiocytoma which has a risk for local recurrence after incomplete excision. Distant metastasis can occur in rare examples. However, there were no morphological parameters predicting the risk of recurrence or metastasis. Increased awareness of the clinocopathological features and immunophenotypes of CFH is helpful in avoiding misdiagnosing the disease as malignant tumors, especially dermatofibrosarcoma protuberans.