Jodi M. Carter

Toolbox to Reduce Lumpectomy Reoperations and Improve Cosmetic Outcome in Breast Cancer Patients: The American Society of Breast Surgeons Consensus Conference

BackgroundMultiple recent reports have documented significant variability of reoperation rates after initial lumpectomy for breast cancer. To address this issue, a multidisciplinary consensus conference was convened during the American Society of Breast Surgeons 2015 annual meeting.MethodsThe conference mission statement was to “reduce the national reoperation rate in patients undergoing breast conserving surgery for cancer, without increasing mastectomy rates or adversely affecting cosmetic outcome, thereby improving value of care.” The goal was to develop a toolbox of recommendations to reduce the variability of reoperation rates and improve cosmetic outcomes. Conference participants included providers from multiple disciplines involved with breast cancer care, as well as a patient representative. Updated systematic reviews of the literature and invited presentations were sent to participants in advance. After topic presentations, voting occurred for choice of tools, level of evidence, and strength of recommendation.ResultsThe following tools were recommended with varied levels of evidence and strength of recommendation: compliance with the SSO-ASTRO Margin Guideline; needle biopsy for diagnosis before surgical excision of breast cancer; full-field digital diagnostic mammography with ultrasound as needed; use of oncoplastic techniques; image-guided lesion localization; specimen imaging for nonpalpable cancers; use of specialized techniques for intraoperative management, including excisional cavity shave biopsies and intraoperative pathology assessment; formal pre- and postoperative planning strategies; and patient-reported outcome measurement.ConclusionsA practical approach to performance improvement was used by the American Society of Breast Surgeons to create a toolbox of options to reduce lumpectomy reoperations and improve cosmetic outcomes.

Identification of a novel FN1–FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour‐induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1–FGFR1 fusion gene in three out of four PMTs by next‐generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT‐PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1–FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded proteins oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia‐inducing FGFR1 fusion genes, which are ligand‐independent, the FN1–FGFR1 chimeric protein was predicted to preserve its ligand‐binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis. Copyright

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.

A novel chromogenic in situ hybridization assay for FGF23 mRNA in phosphaturic mesenchymal tumors.

Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT) are very rare tumors of bone and soft tissues. Most patients with PMT have long-standing osteomalacia secondary to production of fibroblast growth factor 23 (FGF23), a hormone that inhibits phosphate reuptake within the renal proximal tubule. Previously, we have reported the detection of FGF23 mRNA in PMT by reverse transcription polymerase chain reaction (PCR); however, the low specificity and risk for nontumoral tissue contamination inherent in PCR-based methodology limit its clinical utility. We evaluated RNAscope as a semiquantitative method of in situ FGF23 mRNA detection in the diagnosis of PMT. Twenty-five PMTs (median 52 y, range 5 to 73 y) occurred in patients with tumor-induced osteomalacia (TIO), manifesting as masses (mean 3.9 cm, range 1.4 to 12 cm) in various bones and soft tissues. FGF23 mRNA was positive in 96% (22/23) informative cases of PMT: 16 cases scored 3+; 5 scored as 2+; 1 scored as 1+. Among these cases, FGF23 mRNA was detected in 3 malignant PMTs along with their metastases. Forty control cases included aneurysmal bone cyst (N=4), chondromyxoid fibroma (N=8), high-grade osteosarcomas (N=8), and (nonfamilial) tumoral calcinosis, as well as miscellaneous cartilage-forming tumors or osteoid-forming tumors and soft tissue tumors. All control cases were negative for FGF23 mRNA in the lesional cells. One aneurysmal bone cyst had rare FGF23 mRNA-expressing osteocytes clustered around remodeled bone. One ovarian serous carcinoma in a patient with disseminated disease, elevated serum FGF23, and TIO was negative for FGF23 mRNA in the neoplastic cells. We conclude that RNAscope is a highly sensitive and specific, semiquantitative in situ hybridization method of FGF23 mRNA detection applicable to formalin-fixed, paraffin-embedded tissues. Detection of FGF23 expression is a valuable diagnostic adjunct, especially in patients with occult TIO. Compared with reverse transcription PCR, this method preserves tissue morphology and reduces “false positives” related to detection of endogenous FGF23 mRNA expression by osteocytes.

Activating GNAS mutations in parosteal osteosarcoma.

Parosteal osteosarcoma is a surface-based osteosarcoma that often exhibits deceptively bland cytologic features, hindering diagnosis in small biopsies or when correlative radiologic imaging is not readily available. A number of benign and malignant fibro-osseous lesions, including fibrous dysplasia (FD) and low-grade central osteosarcoma, fall within the morphologic differential diagnosis of parosteal osteosarcoma. Somatic mutations in GNAS, encoding the &agr;-subunit of the heterotrimeric G protein complex (Gs&agr;), occur in FD and McCune-Albright syndrome but have not been reported in parosteal osteosarcoma. We evaluated GNAS mutational status in parosteal osteosarcoma and several of its histologic mimics to determine its utility in differentiating these entities. Eleven of 14 (79%) FD cases had GNAS mutations within codon 201 (5 R201C and 6 R201H mutations). GNAS mutations were not detected in any cases of adamantinoma or osteofibrous dysplasia. Direct sequencing of 9 parosteal osteosarcomas, including 3 of low grade and 6 with dedifferentiation, revealed activating GNAS mutations in 5 cases (55%), distributed as 4 R201C-mutated tumors and 1 tumor with an R201H mutation. GNAS codon 227 mutations were not detected in any of the cases. There was no association between GNAS mutational status and patient demographics, histologic dedifferentiation, or clinical outcome. To our knowledge, we report the first series of parosteal osteosarcomas harboring activating GNAS mutations. Our data suggest that GNAS mutational status may have limited utility as an ancillary technique in differentiating benign and malignant fibro-osseous lesions of the bone.

Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women

Women with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.

Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients

BackgroundPostmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients.MethodsFormalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS.ResultsCLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone:androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03–0.59). A similar pattern was observed with estradiol:testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04–0.72).ConclusionsCLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens:androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings.

Aberrant intermediate filament and synaptophysin expression is a frequent event in malignant melanoma: an immunohistochemical study of 73 cases

Malignant melanomas are known to express vimentin, among other intermediate filaments. Though anomalous keratin expression by malignant melanoma has been reported, its frequency is not well-established and this phenomenon is not well-known. We have seen in consultation a number of malignant melanomas with anomalous expression of keratin, other intermediate filaments, or synaptophysin, and therefore studied a large group of primary and metastatic melanomas to determine the frequency of these events. About 73 cases of malignant melanoma (22 primaries and 51 metastases) from 71 patients (51 male, 20 female; mean 59 years, range 17–87 years) were retrieved from our archives. Prior diagnoses were confirmed by re-review of hematoxylin and eosin sections and relevant (e.g., S100 protein, HMB45, Melan-A, and tyrosinase) immunohistochemical studies. Available sections were immunostained for keratin (OSCAR and AE1/AE3 antibodies), desmin, neurofilament protein, glial fibrillary acidic protein, synaptophysin, and chromogranin A. Not all cases could be tested for all markers. Cases were predominantly epithelioid (48/73, 66%) or spindle cell/desmoplastic (25/73, 34%). S100 protein, Melan-A, HMB45, and tyrosinase were positive in 60/65 (92%), 34/64 (53%), 30/60 (50%), 25/48 (52%) of cases, respectively. All five S100-protein-negative cases expressed at least one of the other melanocytic markers: Melan-A (two of four, 50%), HMB45 (two of three, 67%), and tyrosinase (one of two, 50%). All cases expressed at least one melanocytic marker. Cases were positive for keratin (OSCAR, 17/61, 28%; AE1/AE3, 16/40, 40%), desmin (11/47, 24%), neurofilament protein (5/31, 16%), glial fibrillary acidic protein (3/32, 9%), and synaptophysin (10/34, 29%), typically only in a minority of cells. Chromogranin was negative (0/32, 0%). Altogether 9/73 cases (12%) showed expression of >1 intermediate filament. All S100-protein-negative melanomas showed anomalous intermediate filament expression (keratin—one case, desmin—three cases, neurofilament protein—one case). Anomalous intermediate filament or synaptophysin expression was more common in epithelioid (intermediate filament, 27/48, 56%; synaptophysin, 7/22, 32%) as compared with spindle cell/desmoplastic (intermediate filament, 8/25, 32%; synaptophysin, 3/12, 25%) melanomas. Overall, 48% (35/73) of cases showed anomalous expression of at least one intermediate filament. Anomalous expression of all intermediate filaments and synaptophysin was found in significant subsets of malignant melanoma, representing potentially serious diagnostic pitfalls. While the inclusion of consultation cases may inflate the frequency of these findings in this series, similar findings were also seen in institutional cases. Malignant melanoma showing anomalous intermediate filament and synaptophysin expression may easily be mistaken for carcinomas, rhabdomyosarcomas, and neuroendocrine tumors. Awareness of this phenomenon, careful histopathological evaluation, and an appropriate melanocytic immunohistochemical panel should facilitate the diagnosis of malignant melanoma with unusual immunophenotypes.

Superficial CD34-positive fibroblastic tumor: report of 18 cases of a distinctive low-grade mesenchymal neoplasm of intermediate (borderline) malignancy

Fibroblastic mesenchymal tumors show a spectrum of biological behavior, from benign to fully malignant. We report our experience of two decades with a distinctive, previously undescribed low-grade fibroblastic tumor of the superficial soft tissues. Eighteen cases were identified within our consultation files, previously coded as ‘low-grade sarcoma, not further classified’ and ‘malignant fibrous histiocytoma, low grade’. The tumors occurred in adults (median age 38 years, range 20–76 years) of either sex (10 males and 8 females), ranged in size from 1.5 to 10 cm (mean 4.1 cm), and were confined to the superficial soft tissues of the thigh (N=5), knee (N=2), and other sites. Histological features included a fascicular growth pattern of the neoplastic spindled cells with striking, often bizarre cellular pleomorphism and variably prominent nucleoli. Necrosis was seen in one case. All cases showed strong, diffuse CD34 positivity and 68% of tested cases demonstrated focal cytokeratin expression. Desmin, ERG, FLI-1, smooth muscle actin, and S100 protein were negative. TP53 overexpression was absent. Fluorescence in-situ hybridization studies for TGFBR3 and/or MGEA5 rearrangements were negative in all tested cases. Clinical follow-up was available in 13 patients (median duration of 24 months; range 1–104 months). Twelve of 13 patients had no disease recurrence. One patient had regional lymph node metastases, 7 years after incomplete excision of the primary tumor. All patients are currently alive and disease free. The unique clinicopathological features of superficial CD34-positive fibroblastic tumor define them as a novel subset of low-grade fibroblastic neoplasms, best considered to be of borderline malignancy.

Myofibromas with atypical features: expanding the morphologic spectrum of a benign entity.

Typical myofibromas are biphasic tumors composed of a central zone of immature spindled to rounded cells arranged in a pericytic pattern and a peripheral zone of myoid nodules. Central necrosis is occasionally seen. A small but undefined subset of myofibromas displays atypical features that may lead to a misdiagnosis of sarcoma. To more completely characterize these tumors and define their behavior, we analyzed our experience with myofibromas having 1 or more atypical features including hypercellularity, absent or inconspicuous, poorly demarcated myoid nodules, infiltrative growth pattern, and perineural invasion. Of 266 cases of myofibromas, 24 cases were retrieved on the basis of pathology reports in which atypical features were mentioned. The tumors presented in 16 male and 8 female individuals (mean age 17 y; range, 2 wk to 62 y) as masses of variable size (mean 3.0 cm; range, 1.5 to 6.5 cm). Fourteen cases arose on the head and neck and 10 cases on the limbs. The referring or suspected diagnosis was sarcoma in 8 cases. The tumors were typically more cellular than ordinary myofibroma with levels of cellularity similar to that expected in fibrosarcoma (22/24). In addition, they displayed inconspicuous, loosely cohesive (22/24) or absent myoid nodules (2/24), infiltrating borders (19/24), intravascular growth (5/24), and perineural invasion/nerve entrapment (6/24). The mean mitotic rate was 5 mitoses/10 high-power fields, but no tumor showed significant cytologic atypia. The tumors were positive for actins (11/11) and CD34 (2/8). Follow-up in 14 patients revealed no distant metastases. We conclude that a small subset of myofibromas shows atypical features that complicate the diagnosis but do not adversely affect outcome.