Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone

Implementation of a software application for presurgical case history review of frozen section pathology cases

Background: The frozen section pathology practice at Mayo Clinic in Rochester performs ~20,000 intraoperative consultations a year (~70–80/weekday). To prepare for intraoperative consultations, surgical pathology fellows and residents review the case history, previous pathology, and relevant imaging the day before surgery. Before the work described herein, review of pending surgical pathology cases was a paper-based process requiring handwritten transcription from the electronic health record, a laborious and potentially error prone process. Methods: To facilitate more efficient case review, a modular extension of an existing surgical listing software application (Surgical and Procedure Scheduling [SPS]) was developed. The module (SPS-pathology-specific module [PM]) added pathology-specific functionality including recording case notes, prefetching of radiology, pathology, and operative reports from the medical record, flagging infectious cases, and real-time tracking of cases in the operating room. After implementation, users were surveyed about its impact on the surgical pathology practice. Results: There were 16 survey respondents (five staff pathologists and eleven residents or fellows). All trainees (11/11) responded that the application improved an aspect of surgical list review including abstraction from medical records (10/11), identification of possibly infectious cases (7/11), and speed of list preparation (10/11). The average reported time savings in list preparation was 1.4 h/day. Respondents indicated the application improved the speed (11/16), clarity (13/16), and accuracy (10/16) of morning report. During the workday, respondents reported the application improved real-time case review (14/16) and situational awareness of ongoing cases (13/16). Conclusions: A majority of respondents found the SPS-PM improved all preparatory and logistical aspects of the Mayo Clinic frozen section surgical pathology practice. In addition, use of the SPS-PM saved an average of 1.4 h/day for residents and fellows engaged in preparatory case review

Rapidly fatal SMARCA4-deficient undifferentiated sarcoma originating from hybrid hemosiderotic fibrolipomatous tumor/pleomorphic hyalinizing angiectatic tumor of the foot

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient's death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT

TGFBR3 and MGEA5 Rearrangements in Pleomorphic Hyalinizing Angiectatic Tumors and the Spectrum of Related Neoplasms

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, locally aggressive tumor of the distal extremities with a proclivity for local recurrence. PHATs contain characteristic ectatic, thin-walled vessels, lined by fibrin, and are surrounded by groups of variably pleomorphic spindled to epithelioid neoplastic cells. The putative precursor lesion of PHAT, originally termed "early PHAT" shares many clinicopathologic features with hemosiderotic fibrolipomatous tumor (HFLT). HFLT, myxoinflammatory fibroblastic sarcoma (MIFS), and tumors showing hybrid features of HFLT and MIFS often show TGFBR3 and MGEA5 gene rearrangements. To date, only a small number of PHATs has been tested for either rearrangement; all have been negative. We hypothesized that PHATs contain TGFBR3 and/or MGEA5 rearrangements. Cases of PHAT (all containing areas of HFLT) (N = 10), HFLT (N = 7), MIFS (N = 6), hybrid HFLT/MIFS (N = 3), and PHAT-like undifferentiated pleomorphic sarcomas (N = 7) were retrieved from our institutional and consultation archives and analyzed for TGFBR3 and MGEA5 rearrangements using a break-apart probe strategy for FISH. Six of 10 PHATs harbored TGFBR3 and/or MGEA5 gene rearrangements: 4 cases had both TGFBR3 and MGEA5 rearrangements, and 2 cases contained MGEA5 rearrangements. Two of 7 HFLTs were positive: 1 case had a TGFBR3 rearrangement, and 1 case had an MGEA5 rearrangement. One of 6 MIFSs had an MGEA5 rearrangement. All 3 hybrid HFLT/MIFS cases were positive: 2 cases had both TGFBR3 and MGEA5 rearrangements, and 1 case had a TGFBR3 rearrangement. All PHAT-like undifferentiated pleomorphic sarcomas were negative. We report, for the first time, the presence of TGFBR3 and/or MGEA5 rearrangements in tumors showing mixed features of HFLT and PHAT. The presence of such rearrangements strongly suggests that HFLT is related to both PHAT and MIFS and that the latter 2 tumors may represent morphologic variants of a single, genetically defined entity in which only MIFS has acquired the capacity to metastasize

TGFBR3 and MGEA5 rearrangements are much more common in “hybrid” hemosiderotic fibrolipomatous tumor-myxoinflammatory fibroblastic sarcomas than in classical myxoinflammatory fibroblastic sarcomas: a morphological and fluorescence in situ hybridization study

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma that most often involves the distal extremities of adults. Some MIFSs have been reported to show TGFBR3 and MGEA5 rearrangements. TGFBR3 and MGEA5 rearrangements have also been reported in hemosiderotic fibrolipomatous tumor (HFLT), in pleomorphic hyalinizing angiectatic tumor (PHAT), and in rare tumors allegedly showing features of both HFLT and MIFS (hybrid HFLT-MIFS). These findings have led to speculation that HFLT, MIFS, PHAT, and hybrid HFLT-MIFS are closely related; however, areas resembling HFLTs are only very rarely encountered in previous series of MIFSs. We studied classic examples of these tumors with the goal of clarifying the relationship between MIFS and HFLT-MIFS. Cases of MIFS (n=31), hybrid HFLT-MIFS (n=8), PHAT (n=2), HFLT (n=1), and undifferentiated pleomorphic sarcoma (n=4) were retrieved from our archives, and the diagnoses were verified by 5 soft tissue pathologists. Using previously validated break-apart fluorescence in situ hybridization probes, we analyzed for TGFBR3 and MGEA5 rearrangements. Only 2 of 31 MIFSs harbored MGEA5 rearrangements; all lacked TGFBR3 rearrangements. Six of 8 hybrid HFLT-MIFSs harbored rearrangements of TGFBR3 and/or MGEA5. Both PHATs were positive for rearrangements of TGFBR3 and/or MGEA5. The HFLT was positive for rearrangements of both TGFBR3 and MGEA5. All undifferentiated pleomorphic sarcomas with focal myxoid change were negative. We conclude that (1) TGFBR3 and/or MGEA5 rearrangements are much more common in hybrid HFLT-MIFSs than in classic MIFSs, (2) HFLTs and MIFSs may be unrelated lesions, and (3) hybrid HFLT-MIFSs most likely represent HFLTs with sarcomatous progression, rather than tumors strictly related to classic MIFSs

Spindle Cell Lipomas Arising at Atypical Locations

Objectives: Spindle cell lipomas (SCLs) are benign lipomatous neoplasms that classically arise in the posterior neck, upper back, and shoulders of older male patients. We sought to characterize the occurrence of this entity at nonclassic sites.Methods: All cases of SCL arising at atypical sites were retrieved from our archives.Results: Of 439 total cases of SCL, 57 arose at atypical locations in 32 men and 25 women (age range, 27-79 years). The tumor sites included leg (n=23), buttock/perineum/inguinal (n=10), forearm (n=9), finger (n=9), foot (n=2), toe (n=2), hand (n=1), and flank (n=1). CD34 was positive staining in all cases tested (52/52), while desmin was negative in most tumors (48/50). Thirty-eight of 38 cases tested exhibited loss of Rb expression. No cases showed CPM/MDM2 amplification (0/48). No local recurrences have been reported (n=39).CONCLUSIONS: SCLs may arise in the trunk, lower extremities, and distal upper extremities. While most SCLs arising in classic sites occur in male patients, there is a relatively equal sex distribution in tumors at atypical sites. Pathologists should be aware that SCLs arise at atypical locations to avoid misclassification as other lipomatous neoplasms, including atypical lipomatous tumor