A homozygous truncating mutation of FGL2 is associated with immune dysregulation.

BACKGROUND: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2-/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. OBJECTIVE: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies. METHODS: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro. RESULTS: The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation. CONCLUSIONS: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.

The degree of sclerosis is associated with prognosis in well-differentiated liposarcoma of the retroperitoneum.

BACKGROUND AND OBJECTIVES: Well-differentiated liposarcomas (WDL) are often partly composed of sclerotic tissue, however, the amount varies widely between tumors, and its prognostic significance is unknown. We hypothesized that tumors with more sclerosis would behave more aggressively. METHODS: Primary retroperitoneal WDL from 29 patients resected at our institution with follow-up were histologically evaluated by soft tissue pathologists blinded to outcome. Tumors with ≥ 10% sclerosis were designated "sclerotic" while tumors with < 10% sclerosis were designated as "minimally sclerotic". Cellular and dedifferentiated tumors were excluded. Clinical parameters and radiologic assessments on computed tomography (CT) were recorded. RESULTS: Histological evaluation identified 13 minimally sclerotic WDL and 16 sclerotic WDL. Median follow-up was 9 years (range, 3-20). Median recurrence-free survival (RFS) and median overall survival (OS) were 6.16 and 13.9 years, respectively. Compared with patients with sclerotic WDL, those with minimally sclerotic WDL had superior RFS (HR = 0.17 [95% CI, 0.06-0.53], P = .002) and OS (log-rank test, P = .002). Sclerotic WDL exhibited higher Houndsfield Units than minimally sclerotic WDL (26 vs 1, P = .040). CONCLUSIONS: Minimally sclerotic WDL were associated with more favorable outcome compared with sclerotic tumors. Assessment of sclerosis in WDL is likely a useful prognostic marker.

Traumatic Neuroma With Melanoma Perineural Invasion.

Traumatic neuroma is a reactive non-neoplastic neural proliferation that results from trauma. Although such type of lesions found surgical scars due to different reasons, its involvement by residual or recurrent malignancies is rarely reported. In this article, we describe an unusual case of traumatic neuroma with perineural invasion by invasive melanoma.

Acral dermatofibrosarcoma protuberans with myoid differentiation: A report of 2 cases.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade mesenchymal neoplasm with a tendency for local recurrence; it is rarely metastatic. Dermatofibrosarcoma protuberans typically arises in the trunk and proximal extremities. However, it can arise in unusual sites such as the hands and feet. Several variants have been described, including DFSP with myoid differentiation, which is very uncommon. This variant tends to be observed more with the fibrosarcomatous variant, and it can be either in the form of myoid bundles and nodules with no vascular relationship or represent hyperplastic blood vessels within the tumor. Here, we report 2 cases of DFSP with myoid differentiation (ordinary and fibrosarcomatous) on the foot. To the best of our knowledge, these cases represent the first 2 cases of acral DFSP with myoid differentiation.

Targeted therapies for sarcomas: new roles for the pathologist.

Sarcomas are a heterogeneous family of mesenchymal malignancies that employ an impressive variety of pathogenetic mechanisms. The traditional role of the pathologist in this field has been to ensure accurate diagnosis and histological grading to direct therapy. More recently, with the advent of targeted therapies directed at particular molecular alterations, the role of the pathologist has expanded and increased awareness of the genetic features of sarcomas is needed to deliver optimal multidisciplinary care. This review discusses these trends and briefly enumerates many of the molecular derangements and targeted agents currently used or under investigation in soft tissue sarcoma. A few sarcomas are highlighted in more detail to illustrate how pathologists can exert positive influence on patient care - not just through diagnosis and grading, but also with molecular characterizations. Featured sarcomas include alveolar soft part sarcoma, dermatofibrosarcoma protuberans, gastrointestinal stromal tumour, inflammatory myofibroblastic tumour and PEComas.

KIAA1549-BRAF Gene Fusion Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Pattern in a Pediatric Patient: A Case Report.

Spindle cell sarcoma with KIAA1549-BRAF fusion is a type of childhood sarcoma that closely resembles infantile fibrosarcoma by morphologic criteria and harbors molecular alteration other than the ETV6-NTRK3 fusion gene. This neoplasm was diagnostically challenging without molecular tests, including next-generation sequencing. The discovery of BRAF translocation in this tumor contributes to the promise of the clinical implication of selecting new therapeutic options for the treatment of progressive diseases that are refractory to conventional chemotherapy. Here we present the case of a three-year-old girl who was diagnosed with spindle cell sarcoma with KIAA1549-BRAF fusion gene and had a favorable outcome three years after surgery.

Dermal pleomorphic liposarcoma resembling pleomorphic fibroma: report of a case and review of the literature.

Pleomorphic liposarcoma (PLPS) is a rare, high-grade sarcoma defined by the presence of pleomorphic lipoblasts. Constituting 5% of all liposarcomas, PLPS usually arises in deep soft tissues of the extremities, with rare occurrences in the dermis and subcutis. We describe a unique case of an 85-year-old Caucasian gentleman with a 1 year history of a pedunculated, pink, non-tender papule on the dorsum of his left arm, measuring 1.0 cm in maximum dimension. Biopsy revealed a dermal collection of atypical epithelioid and spindle cells superimposed on a sclerotic background, resembling a pleomorphic fibroma on low power. On high power, a central focus of discrete adipocytic differentiation with pleomorphic lipoblasts was present. Tumor cells were positive for S-100 and negative for desmin, actin, CD68, keratin, MART-1 and CD34. Clinicopathologic findings were consistent with PLPS and the diagnosis was made. PLPS is rarely localized to the dermis and one with low power features resembling a pleomorphic fibroma has not been previously described in the literature.

Pleomorphic fibroma and dermal atypical lipomatous tumor: are they related?

Pleomorphic fibromas represent dome-shaped or polypoid cutaneous lesions characterized by a paucicellular and densely fibrotic background punctuated by scattered atypical to pleomorphic spindle and multinucleated giant cells. Some of these tumors will have incorporated adipose tissue, although these adipocytic areas lack distinct cytologic atypia and may represent entrapped normal periadnexal or subcutaneous adipose tissue. Nonetheless, owing to the similarity of some of the morphologic features of pleomorphic fibroma with cutaneous atypical lipomatous tumor, diagnostic confusion can ensue. The potential diagnostic challenges are further highlighted by a recent report of a lesion with histopathologic features of both. In response, we studied the presence of 12q15/ MDM2 amplification by fluorescence in situ hybridization and MDM2 expression by immunohistochemistry in a series of 15 pleomorphic fibromas to investigate whether these two entities share a common pathogenic origin. One case of cutaneous atypical lipomatous tumor was used as positive control for 12q15 amplification. All 15 cases were negative for MDM2 by immunohistochemistry with no demonstrable 12q15/MDM2 amplification by fluorescence in situ hybridization. Therefore, these two entities are best regarded as pathogenetically distinct. MDM2 immunohistochemistry or fluorescence in situ hybridization studies can be used to differentiate between the two if needed.

Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors.

BACKGROUND: Trichilemmoma (TL) can occur as a solitary sporadic lesion usually on the face or as multiple facial lesions almost invariably associated with Cowden syndrome (CS). CS is a multisystem disorder caused by a germline inactivating mutation in PTEN (10q23.31), a tumor suppressor gene. We sought to identify PTEN loss by immunohistochemistry (IHC) in sporadic and CS-associated TL to determine whether IHC is a useful tool to assess an individual for CS. METHODS: Six TL biopsies associated with CS and 33 biopsies without CS were retrieved. IHC for PTEN was performed. RESULTS were scored as positive (reactivity in TL cells) or negative (no reactivity in TL cells); normal squamous epithelium and vascular endothelium served as internal positive controls. RESULTS: Complete PTEN loss was noted in 5/6 (83%) CS-associated TL and 1/33 (3%) sporadic (non-CS) TL. CONCLUSION: Demonstration of complete PTEN loss in TL by IHC is strongly suggestive of association with CS, but retention of PTEN staining does not entirely exclude CS. Therefore, PTEN IHC in TLs may be helpful in screening TL for association with CS, but should be used in context with other established clinical criteria, and possibly germline PTEN genotyping to confirm a diagnosis of CS.

Diagnosis, management, and outcome of patients with dedifferentiated liposarcoma systemic metastasis.

BACKGROUND: Dedifferentiated liposarcomas (DDLPSs) result in worse patient outcomes than well-differentiated tumors despite shared molecular derangements. Prevalence and pattern of DDLPS systemic metastases have not been extensively reported; information regarding diagnosis, treatment, and outcomes of metastatic DDLPS patients is limited. Our study seeks to address this knowledge gap. METHODS: Metastatic patients were identified from a clinical database consisting of 277 DDLPS patients treated at the University of Texas M D Anderson Cancer Center (UTMDACC) (1993-2010). Only patients with radiologically demonstrable distant metastases were included. Patient, tumor, treatment, and outcome variables were recorded. Available imaging studies and tumor FFPE blocks were assessed. RESULTS: A total of 40 patients were identified, translating into a DDLPS metastatic rate of 14% (17% for de novo DDLPS and 9% for secondary dedifferentiation). The average patient age was 61 years with a male predilection. The retroperitoneum and lungs were the most common primary and metastatic tumor sites. Any of the 4 described DDLPS morphological subtypes harbored metastatic potential; MFH/UPS-like morphology was the most common. The median time from primary diagnosis to metastasis was 25 months; more than 50% of metastases developed without local failure. The median survival of metastatic patients was 11.5 months; the 5-year DSS was 5.2%. Patients amenable to complete surgical extirpation (n = 14) faired significantly better (P = .001; log rank). CONCLUSIONS: Metastatic spread is an ominous consequence of DDLPS, especially regarding de novo tumors. Occurring relatively early in the course of disease and exhibiting a pulmonary predilection, these lesions are highly aggressive and commonly fatal. Further studies to identify metastatic biomarkers are needed.

Sebaceous gland loss and inflammation in scarring alopecia: a potential role in pathogenesis.

BACKGROUND: Primary scarring alopecia (SA) comprises a group of disorders with poorly defined origins. Improving diagnostic and therapeutic capabilities requires a better understanding of their pathogenesis. OBJECTIVES: We sought to assess the frequency of sebaceous gland loss in SA and to identify the role of sebaceous gland and sebaceous gland duct inflammation in the pathogenesis of SA. METHODS: Ninety specimens submitted with a clinical history of alopecia, both scarring and nonscarring, were reviewed. Samples were scored based on sebaceous gland, sebaceous duct, and follicle inflammation. RESULTS: Sebaceous gland loss was much more common in cases of SA (>53% of follicles on average) than non-SA (<5% of follicles on average). Many cases of SA showed residual affected follicles with an absence of sebaceous glands. Sebaceous gland duct inflammation was often more frequent and severe than gland inflammation in SA. LIMITATIONS: Sample size was limited in some alopecia entities. Inflammation was graded by means of subjective observation. CONCLUSIONS: This study demonstrates that sebaceous gland loss is a common and early finding among SA. In addition, sebaceous gland and/or duct inflammation may play a role in initiating or accelerating follicular damage during the development of SA.

Intra-scrotal extra-testicular schwannoma: A case report and literature review.

Intra-scrotal schwannoma is a rare neoplasm and a few reports were describing this entity in the literature and mostly difficult to be diagnosed pre operatively(1) We recently treated a case of intra-scrotal extra-testicular schwannoma which was discovered in a patient with history of painless scrotal lesion for 5 years. paratesticular lesion excision was done which was result as schwannoma tissue. follow up with US scrotum was unremarkable for the patient. surgical excision will provide diagnostic and therapeutic goals. Even tough recurrence is rare a urologist should take care to ensure complete surgical resection.

Corrigendum to "Case report of intra-articular synovial sarcoma in the hip joint" [Radiology Case Reports 15 (2020) 1256-1260].

[This corrects the article DOI: 10.1016/j.radcr.2020.05.026.].

Oncocytic adrenal cortical tumor with cytoplasmic inclusions and hyaline globules.

Adrenal cortical tumors, particularly oncocytic tumors, have been reported to contain a variety of intracytoplasmic and intramitochondrial inclusions. Oncocytic cortical tumors can also morphologically mimic pheochromocytomas. We report an unusual, partially oncocytic cortical neoplasm with nesting architecture, intranuclear inclusions, and hyaline globules reminiscent of pheochromocytoma, together with numerous, small, brightly eosinophilic, periodic acid-Schiff-positive cytoplasmic inclusions and typical cytoplasmic lipid droplets. Ultrastructural study revealed oncocytes containing numerous mitochondria with intramitochondrial crystals and lipid droplets. Immunohistochemistry and immunoblots were utilized to further characterize the tumor. Immunohistochemistry demonstrated immunoreactivity of both the eosinophilic inclusions and the hyaline globules for adipose differentiation-related protein (ADRP), which is one of a group of proteins associated with storage of neutral lipids in many cell types. Immunoblots confirmed the presence of ADRP and demonstrated an imbalance between ADRP and perilipin, another neutral lipid-associated protein, in tumor tissue compared to normal adrenal cortex. The findings suggest that mitochondrial dysfunction in oncocytic cortical tumors may lead to abnormal processing of proteins related to the lipid-storing functions of the adrenal cortex, resulting in unusual cytoplasmic inclusions and extracellular globules resembling the globules in pheochromocytomas. The finding of ADRP as a constituent of inclusions in adrenal cortical tumors has not been previously reported.

Molecular profiling of sarcomas: new vistas for precision medicine.

Sarcoma is a large and heterogeneous group of malignant mesenchymal neoplasms with significant histological overlap. Accurate diagnosis can be challenging yet important for selecting the appropriate treatment approach and prognosis. The currently torrid pace of new genomic discoveries aids our classification and diagnosis of sarcomas, understanding of pathogenesis, development of new medications, and identification of alterations that predict prognosis and response to therapy. Unfortunately, demonstrating effective targets for precision oncology has been elusive in most sarcoma types. The list of potential targets greatly outnumbers the list of available inhibitors at the present time. This review will discuss the role of molecular profiling in sarcomas in general with emphasis on selected entities with particular clinical relevance.