Palmer Nodular Fasciitis Harboring a Novel SREBF1::USP6 Fusion Gene.

The diagnosis of low-grade fibroblastic/myofibroblastic tumors of acral sites can be challenging. These tumors encompass a diverse group of neoplasms with a spectrum of biologic potential ranges from benign to overtly malignant. They often demonstrate significant clinical, radiologic, and immunophenotypic overlap, in which the molecular phenotype may play an important diagnostic role to arrive at the final diagnosis. Herein, we report a case of soft tissue mass lesion presented on the palm of an adult patient for four months. Histologically, the tumor consisted of primarily low-grade spindle cells expressing smooth muscle actin. Molecular testing revealed a novel SREBF1::USP6 fusion gene, confirming the final diagnosis of nodular fasciitis and ultimately expanding its molecular profile. This case highlights the diagnostic value of single, cost-effective, targeted molecular panel to arrive at an accurate diagnosis and provide helpful therapeutic information.

Non-Small Cell Lung Carcinoma With Clear Cell Features and FGFR3::TACC3 Gene Rearrangement : Clinicopathologic and Next Generation Sequencing Study of 7 Cases.

Seven cases of primary lung tumors characterized histologically by clear cell morphology and a distinctive FGFR3::TACC3 gene rearrangement are described. The tumors arose in 4 women and 3 men, aged 47 to 81 years (mean=68). They occurred in peripheral locations, predominantly subpleural, and ranged in size from 1.4 to 6.5 cm (mean=4.1 cm). All tumors showed a solid growth pattern with abundant central areas of necrosis and marked nuclear pleomorphism. The tumors demonstrated clear cell histology, with large cohesive tumor cells displaying atypical nuclei and abundant clear cytoplasm. Immunohistochemical stains identified a squamous phenotype in 5 cases and an adenocarcinoma phenotype in 2 cases. One case was a squamous cell carcinoma with focal glandular component, and one of the squamous cell carcinomas showed focal sarcomatoid changes. Next generation sequencing identified FGFR3::TACC3 gene rearrangements in all 7 cases. One case demonstrated a concurrent activating FGFR3 mutation and a second case demonstrated concurrent FGFR3 amplification. Two cases harbored a concurrent KRAS G12D mutation. One case harbored both KRAS and EGFR mutations, and 1 case had a concurrent TP53 mutation. Non-small cell lung carcinoma harboring FGFR3::TACC3 gene rearrangements is extremely rare, and this rearrangement may potentially be enriched in tumors that demonstrate clear cell histology. Identification of FGFR3::TACC3 in patients with lung carcinomas with clear cell features may be of importance as they could potentially be candidates for therapy with tyrosine kinase inhibitors.

Comprehensive Clinical-Pathologic Assessment of Malignant Phyllodes Tumors: Proposing Refined Diagnostic Criteria.

The latest World Health Organization classification of breast tumors recommends diagnosing malignant phyllodes tumors (MPTs) when all 5 morphologic features are present: permeative borders, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses per 10 high-power fields (HPF), and stromal overgrowth. We assessed the performance of this recommendation to capture MPTs and features predictive of distant metastasis in a multi-institutional retrospective study. Of 65 MPTs, most cases had at least focally permeative borders (58, 89%), with marked stromal cellularity in 40 (61.5%), marked atypia in 38 (58.5%), ≥10 mitoses per 10 HPF in 50 (77%), and stromal overgrowth in 56 (86%). Distant metastases were observed in 20 (31%) patients (median follow-up 24.5 mo, 1 to 204). Only 13 of 65 (20%) cases had all 5 morphologic features, while only 7 of 20 (35%) cases with distant metastases had all 5 features. In univariate analysis, only marked stromal atypia ( P =0.004) and cellularity ( P =0.017) were associated with decreased distant metastasis-free survival. In multivariate Cox regression, the combination of stromal overgrowth, marked stromal cellularity, and atypia (C-index 0.721, 95% CI: 0.578, 0.863) was associated with decreased distant metastasis-free survival. The current World Health Organization recommendation will miss a significant number of MPTs with distant metastases. We propose refined diagnostic criteria for MPTs: (1) stromal overgrowth combined with ≥1 feature(s) (marked cellularity, marked atypia, or ≥10 mitoses per 10 HPF), or (2) in the absence of stromal overgrowth, marked cellularity combined with ≥1 feature(s) (permeative borders, marked atypia, or ≥10 mitoses per 10 HPF).

Periosteal Fasciitis With Unusual Radiologic Features Harboring a Novel STAG1::USP6 Fusion Gene.

Periosteal fasciitis is a subtype of nodular fasciitis originating from the periosteum. The diagnosis can be challenging and requires radiologic-pathologic correlation. Advances in molecular analysis confirmed that nodular fasciitis and its related lesions harbor a USP6 gene rearrangement with one of the several potential partners. Herein, we report a case of periosteal fasciitis with metaplastic bone formation detected incidentally during a radiologic survey for breast carcinoma. Radiologic examination revealed a 2.4 cm, heterogeneous, avidly enhancing lesion of the right femoral distal metaphysis concerning for low-grade periosteal chondrosarcoma. Histological examination of a core needle biopsy revealed a tumor composed of bland spindle cells with myofibroblastic and osteoblastic phenotypes admixed with immature bone and cartilaginous elements. Molecular analysis revealed a novel STAG1::USP6 fusion that helped arrive at the right diagnosis and further expands the molecular profile of USP6-associated neoplasms.

Spindle Cell Sarcoma of the Uterus Harboring MEIS1::NCOA1 Fusion Gene and Mimicking Endometrial Stromal Sarcoma.

MEIS1::NCOA1/2 sarcomas are a newly recognized group of exceedingly rare low-grade spindle cell sarcomas that often involve the genitourinary and gynecologic tracts. Due to its deceptively low-grade morphology and the non-specific immunoprofile, these neoplasms may pose a diagnostic challenge by histologically mimicking other entities such as endometrial stromal sarcoma, smooth muscle tumor, or uterine perivascular epithelioid cell tumor (PEComa). Histologically, MEIS1::NCOA1/2 sarcomas typically show spindle cell proliferation with hyperchromatic nuclei and a generalized cytologic uniformity, arranged in short fascicles and exhibiting alternating zones of hypo- and hypercellularity. Among the previously reported cases, molecular analysis revealed the MEIS1::NCOA2 fusion as the most commonly detected fusion gene, whereas the MEIS1::NCOA1 fusion gene has been reported in only a single case that involved kidney. Herein we report the first case of uterine sarcoma harboring the MEIS1::NCOA1 fusion gene that was initially misclassified as low-grade endometrial stromal sarcoma, demonstrating its clinicopathologic features, and highlighting the essential role of molecular pathology to arrive at the accurate diagnosis that may alter disease classification and inform therapy.

Epithelioid and Clear Cell Solitary Fibrous Tumors: Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 13 Cases.

Solitary fibrous tumors (SFTs) are ubiquitous soft tissue neoplasms known for their protean histology and potentially aggressive behavior. Although most cases are composed of a monotonous proliferation of spindle cells, some tumors show unusual cytologic features. We have studied 13 SFTs that were characterized by a predominant population of round epithelioid cells with abundant eosinophilic cytoplasm and clear cell changes. The tumors occurred in 8 women and 5 men, aged 36 to 80 years (mean=63 y), and were located within the orbit (3), lower extremity (3), retroperitoneum (2), abdominal cavity (2), and superficial soft tissues of the neck, pelvis, and pubis (1 each). The tumors measured from 3.5 to 24.5 cm. Using a risk assessment system, 6 cases were stratified as low-risk tumors; 3 of these showed no evidence of recurrence or metastases from 6 to 18 years, and 1 tumor in the orbit recurred and led to the patient's demise. Five cases were of intermediate risk; clinical follow-up showed no evidence of recurrence or metastases from 3 to 4 years in 3 patients, and 1 patient suffered a recurrence 4 years after diagnosis. Two cases were high risk; 1 patient died after 1 year and the second patient experienced local recurrence at 4 years. Immunohistochemical studies showed nuclear positivity for STAT6 in 10 cases. CD34 immunohistochemistry was positive in 11 cases. A NAB2::STAT6 rearrangement was present in all cases. Epithelioid and clear cell SFT should be considered in the differential diagnosis of soft tissue neoplasms with epithelioid and clear cell morphology.

Desmoplastic Adamantinoma-like Thymic Carcinoma: Clinicopathologic, Immunohistochemical, and Molecular Study of 5 Cases.

Five cases of a heretofore unreported rare variant of thymic carcinoma characterized by a striking resemblance to adamantinoma of the mandible are described. The tumors occurred in 4 women and 1 man aged 58 to 76 years (mean: 67.8 y); they arose in the anterior mediastinum and measured from 5.3 to 12.0 cm in greatest diameter (mean: 8.9 cm). Presenting symptoms included chest pain, shortness of breath, and in 2 patients, pleural effusion. One tumor was asymptomatic and discovered incidentally. Histologically, the tumors were extensively desmoplastic, and the cellular proliferation was characterized by multiple islands of squamous epithelium with striking peripheral palisading of nuclei and central areas containing clear cells resembling a stellate reticulum. Areas of preexisting spindle cell thymoma were identified in 2 cases; these areas gradually merged with the higher-grade component of the lesion. Cystic changes were noted in 3 cases. Immunohistochemical studies in 3 cases showed the tumor cells were positive for cytokeratins, p40 and p63, and all showed a high proliferation rate (>50% nuclear positivity) with Ki-67. Next-generation sequencing was performed in 2 cases that showed amplification of the AKT1 gene (copy numbers 6 and 13). Clinical follow-up in 3 patients showed recurrence and metastasis after 1 and 2 years; 1 patient passed away 2 years after diagnosis due to the tumor. Desmoplastic adamantinoma-like thymic carcinoma represents an unusual histologic variant of thymic carcinoma that needs to be distinguished from metastases from similar tumors to the mediastinum.

Intramuscular Tenosynovial Giant Cell Tumor Harboring a Novel CSF1-CD96 Fusion Transcript.

Tenosynovial giant cell tumors typically arise in the synovium of joints, bursae, or tendon sheaths. They may occur in an intra- or extra-articular location and can be divided into localized and diffuse types. The neoplastic nature of the lesion has been supported by a recurrent CSF1 gene rearrangement in a small subset of lesional cells, of which the most common fusion partner is COL6A3. Herein, we report a case of intramuscular localized tenosynovial giant cell tumor harboring a novel CSF1-CD96 fusion transcript, thus expanding the molecular profile of this tumor.

Prognostic Significance of Subungual Anatomic Site in Acral Lentiginous Melanoma.

CONTEXT.­: Acral lentiginous melanoma is a rare and aggressive type of cutaneous melanoma that arises on the acral skin and the nail unit. The prognostic significance of subungual anatomic site in acral lentiginous melanoma is not established. OBJECTIVE.­: To assess the impact of subungual anatomic site on overall survival and disease-specific survival in acral lentiginous melanoma. DESIGN.­: Retrospective cohort analysis. Clinicopathologic characteristics of 627 primary acral lentiginous melanomas (45 [7%] subungual and 582 [93%] nonsubungual) were summarized, and the impact of these characteristics on overall survival and disease-specific survival was determined using univariate and multivariable analyses. RESULTS.­: No significant differences in clinicopathologic features were identified between the subungual and nonsubungual acral lentiginous melanomas. The 1-, 5-, and 10-year overall survival rates were 81%, 40%, and 28%, respectively, for subungual acral lentiginous melanoma and 94%, 59%, and 38%, respectively, for nonsubungual acral lentiginous melanoma (P = .04); risk of death was significantly higher for subungual tumors (hazard ratio [95% confidence interval] = 1.59 [1.02-2.50]; P = .04). The 1-, 5-, and 10-year disease-specific survival rates were 94%, 56%, and 48%, respectively, for subungual acral lentiginous melanoma versus 96%, 69%, and 55%, respectively, for nonsubungual acral lentiginous melanoma (P = .18). By multivariable analysis, independent poor prognostic factors included older age and ulceration for overall survival and greater Breslow thickness and sentinel lymph node positivity for overall survival and disease-specific survival. Subungual anatomic site was not an independent prognostic factor for overall or disease-specific survival. CONCLUSIONS.­: Subungual anatomic site is not an independent prognostic factor for acral lentiginous melanoma.

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.

Luna stain: a simple and cost-effective diagnostic tool helps in detecting eosinophilic granules deposition of flame figures and aids in diagnosing eosinophilic cellulitis "Wells Syndrome".

We report a rare case of Wells syndrome in which a 61-year-old Caucasian male presented with three distinct skin lesions including a cutaneous bulla, an erythematous plaque, and a linear streak located on the patient's left anterior thigh, left dorsal wrist, and left anterior forearm, respectively. Histologic examination revealed diffuse and interstitial eosinophilic infiltrate admixed with lymphocytes and macrophages that predominantly involve the dermis. Nodular aggregates of eosinophils surrounding dermal collagen fibers suggestive of 'flame figures' were identified. Luna histochemical stain was used and highlighted the deposition of eosinophilic granules over the collagen bundles confirming the presence of flame figures. Laboratory workup revealed peripheral eosinophilia, but a comprehensive clinical evaluation failed to reveal a systemic disease and ultimately the diagnosis of eosinophilic cellulitis 'Wells Syndrome' was rendered. After a short course of immunosuppressive therapy, the patient experienced a complete resolution of the skin lesions on his last follow-up visit several weeks from the initial diagnosis. This case highlights the various clinical forms that Wells syndrome may present with and may serve as a good example for the use of Luna stain as a simple and cost-effective diagnostic tool that can help to arrive at the accurate diagnosis and inform therapy.

Third Line Eribulin for Triple-negative Metastatic Breast Ductal Carcinoma Resulting in Extended Progression-free Survival of 57 Months.

Eribulin is a non-taxane microtubule inhibitor approved for the treatment of metastatic breast carcinoma after two prior chemotherapeutic regimens. We report a patient with extended progression-free survival (PFS) of more than 57 months with metastatic breast carcinoma treated with eribulin in the third-line setting. A 48-year-old lady was diagnosed with stage IIA (pT2N0M0), high grade, triple-negative, invasive ductal carcinoma (IDC) of the left breast on core needle biopsy. She underwent neoadjuvant chemotherapy with adriamycin, and cyclophosphamide followed by a negative sentinel lymph node (SLN) biopsy. Subsequent mastectomy and axillary lymph node dissection revealed a 2.5 cm, high grade, triple-negative IDC with three additional lymph nodes negative for metastatic carcinoma, consistent with the initial diagnosis. Eight months into the surveillance program, the patient developed a 2.8 cm right lower lobe (RLL) lung mass with standard uptake value (SUV) of 27 on positron emission tomography-computed tomography (PET/CT). Core needle biopsy of the lung lesion revealed sheets of poorly differentiated carcinoma, immunophenotypically compatible with the initial diagnosis of breast pathology. She then commenced single-agent paclitaxel in the 1st line metastatic setting with a significant decrease in RLL lung mass to less than 1 cm with an SUV of 1.7 noted. The patient developed progression after seven months and started 2nd line gemcitabine noting initial improvement and subsequent stable disease for a period of 12 months. Eventual progression of RLL lung nodule measuring 2.1 cm with SUV of 10 noted. Initiated 3rd line eribulin with a notable response on imaging studies within three months and with no evidence of disease (NED) on scans over the subsequent 57 months. Eribulin related mild neuropathy superimposed on previous paclitaxel associated grade 2 neuropathy required a 20% eribulin dose reduction. The patient is currently clinically and radiographically stable with plateaued serum tumor markers. Our patient has shown excellent response and tolerance to eribulin with PFS of over 57 months (nineteen times the norm) which is rare.

Cutaneous neoplasms composed of melanoma and carcinoma: A rare but important diagnostic pitfall and review of the literature.

We report two cases of combined cutaneous tumors composed of melanoma and carcinoma. The first tumor presented as a 5-mm pink-blue macule over the right zygomatic arch in an 85-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of melanoma (highlighted by SOX10 and MART-1, with high Ki-67 proliferative index) intermixed with nodular basal cell carcinoma (highlighted by pan-cytokeratin and Ber-EP4). The neoplastic melanocytes were confined to the basal cell carcinoma nodules, and a diagnosis of combined melanoma in situ and basal cell carcinoma was rendered. After therapeutic excision, the patient was disease-free at 9 months after the initial diagnosis. The second tumor presented as a 6-mm pink-brown crusted papule on the right forehead in an 89-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of malignant melanoma (MM) (highlighted by S100 and MART-1) intermixed with squamous cell carcinoma (SCC) (highlighted by cytokeratin and p63), and a diagnosis of combined MM-SCC was rendered. These two cases highlight the importance of recognizing these rare types of melanocytic-epithelial cutaneous neoplasms to arrive at an accurate diagnosis that may inform appropriate disease stage and therapy.

Immunohistochemical and Molecular Features of Melanomas Exhibiting Intratumor and Intertumor Histomorphologic Heterogeneity.

Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to tumor genetic heterogeneity rather than tumor morphology. Therefore, understating the molecular characteristics of such melanomas become indispensable. In this study, DNA was extracted from 11 morphologically distinct regions in eight formalin-fixed, paraffin-embedded melanomas. In each region, mutations in 50 cancer-related genes were tested using next-generation sequencing (NGS). A tumor was considered genetically heterogeneous if at least one non-overlapping mutation was identified either between the histologically distinct regions of the same tumor (intratumor heterogeneity) or among the histologically distinct regions of the paired primary and metastatic tumors within the same patient (intertumor heterogeneity). Our results revealed that genetic heterogeneity existed in all tumors as non-overlapping mutations were detected in every tested tumor (n = 5, 100%; intratumor: n = 2, 40%; intertumor: n = 3, 60%). Conversely, overlapping mutations were also detected in all the tested regions (n = 11, 100%). Melanomas exhibiting histomorphologic heterogeneity are often associated with genetic heterogeneity, which might contribute to tumor survival and poor response to therapy.

Acquired cutis laxa associated with cutaneous mastocytosis.

Cutis laxa is characterized by dramatic wrinkling of skin that is lacking in elasticity due to inherent defects in dermal elastic fibers. Cutis laxa can be caused by genetic and metabolic disorders. It can also be acquired, possibly resulting from inflammatory processes with destruction of elastic fibers. This report describes a 26-year old woman who developed acquired cutis laxa and cutaneous mastocytosis leading to premature aging. She represents a unique co-occurrence of these two separate disease entities. To our knowledge, there has been only one published case report of acquired cutis laxa occurring in association with urticaria pigmentosa in a 4-year old girl. Our case would be a second case that exhibits the coexistence of these two disorders in an adult female.