Unclassified sclerosing malignant melanomas with AKAP9-BRAF gene fusion: a report of two cases and review of BRAF fusions in melanocytic tumors.

The current classification of melanocytic tumors includes clinical, pathological, and molecular data. A subset of lesions remains difficult to classify according to these complex multilayer schemes. We report two cases of deeply infiltrating melanomas with a sclerosing background. The first case occurred on the back of a middle-aged man appearing clinically as a dermatofibroma. The architectural and cytological aspects resembled those of a desmoplastic melanoma but the strong expression of both melanA and HMB45, two stainings usually reported as negative in this entity, raised the question of an alternate diagnosis. The second case was a large, slowly growing, perivulvar tumor in a middle-aged woman. The morphology was complex with a central junctional spitzoid pattern associating an epidermal hyperplasia with large nests of large spindled melanocytes. The dermal component was made of deeply invasive strands and nests of nevoid unpigmented melanocytes surrounded by fibrosis; a perineural invasion was present at the periphery of the lesion. In both cases, aCGH found, among many other anomalies, a chromosomal breakpoint at the BRAF locus. RNA sequencing identified in both an AKAP9-BRAF gene fusion. A complementary resection was performed and no relapses have been observed in the respectively 15 and 6 months of follow-up. Both of these melanomas remained unclassified. We further review the variety of melanocytic tumors associated with such BRAF fusions.

Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer.

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.

Breast cancer detection using high-resolution breast PET compared to whole-body PET or PET/CT.

PURPOSE: To compare the performance characteristics of positron emission mammography (PEM) with those of whole-body PET (WBPET) and PET/CT in women with newly diagnosed breast cancer. METHODS: A total of 178 women consented to PEM for presurgical planning in an IRB-approved protocol and also underwent either WBPET (n = 69) or PET/CT (n = 109) imaging, as per usual care at three centers. Tumor detection sensitivity, positive predictive values, and (18)F-fluorodeoxyglucose (FDG) uptake were compared between the modalities. The effects of tumor size, type, and grade on detection were examined. The chi-squared or Fisher's exact tests were used to compare distributions between groups, and McNemar's test was used to compare distributions for paired data within subject groups, i.e. PEM versus WBPET or PEM versus PET/CT. RESULTS: The mean age of the women was 59 ± 12 years (median 60 years, range 26-89 years), with a mean invasive index tumor size of 1.6 ± 0.8 cm (median 1.5 cm, range 0.5-4.0 cm). PEM detected more index tumors (61/66, 92%) than WBPET (37/66, 56%; p < 0.001) or PET/CT (95/109, 87% vs. 104/109, 95% for PEM; p < 0.029). Sensitivity for the detection of additional ipsilateral malignancies was also greater with PEM (7/15, 47%) than with WBPET (1/15, 6.7%; p = 0.014) or PET/CT (3/23, 13% vs. 13/23, 57% for PEM; p = 0.003). Index tumor detection decreased with decreasing invasive tumor size for both WBPET (p = 0.002) and PET/CT (p < 0.001); PEM was not significantly affected (p = 0.20). FDG uptake, quantified in terms of maximum PEM uptake value, was lowest in ductal carcinoma in situ (median 1.5, range 0.7-3.0) and invasive lobular carcinoma (median 1.5, range 0.7-3.4), and highest in grade III invasive ductal carcinoma (median 3.1, range 1.4-12.9). CONCLUSION: PEM was more sensitive than either WBPET or PET/CT in showing index and additional ipsilateral breast tumors and remained highly sensitive for tumors smaller than 1 cm.

Comparative effectiveness of positron emission mammography and MRI in the contralateral breast of women with newly diagnosed breast cancer.

OBJECTIVE: The objective of our study was to compare the performance of positron emission mammography (PEM) with that of MRI in the evaluation of the contralateral breast of women with newly diagnosed cancer. SUBJECTS AND METHODS: Four hundred seventy-two women with newly diagnosed breast cancer offered breast-conserving surgery from September 2006 through November 2008 consented to participate in a multicenter protocol. Participants underwent contrast-enhanced breast MRI and 18F-FDG PEM in randomized order, and the examinations were interpreted independently. The performance characteristics of the imaging modalities were compared using the McNemar test and generalized estimating equations. A retrospective blinded review of PEM images was performed by four experienced observers to understand the reasons for false-negatives. RESULTS: Three hundred sixty-seven women (median age, 58 years; age range, 26-93 years) eligible for analysis completed the appropriate follow-up for study inclusion. Fifteen women (4.1%) were found to have contralateral cancer (11 invasive [mean tumor size, 12 mm; median, 10 mm; range, 1-22 mm] and four ductal carcinoma in situ). Of the 15 cases, both PEM and MRI showed three (20%), only MRI showed 11 (73%), and one (6.7%) was found at prophylactic mastectomy. MRI sensitivity at 14 of 15 (93%; 95% CI, 66-94) was higher than PEM at three of 15 (20%; 95% CI, 5.3-46) (p<0.001). On PEM, three additional cancers were seen prospectively but were considered probably benign and two other cancers were visible in retrospect at the site. Of 352 contralateral breasts without cancer, findings were negative or benign on PEM for 335 (95.2%; 95% CI, 92.2-97.0), which is more than MRI at 315 (89.5%; 95% CI, 85.7-92.4; p=0.002). The positive predictive value (PPV) of PEM-prompted biopsies (3/14 [21%]) was not significantly different from the PPV of MRI (15/54 [28%], p=0.58). On blinded retrospective PEM review of the 15 contralateral cancers, PEM findings for 11 (73%) were considered suspicious. CONCLUSION: Contralateral cancer was found in 15 of 367 women (4.1%), with MRI showing 14 (93%). Eleven contralateral cancers (73%) were visible on PEM, but only three (20%) were recognized prospectively as suspicious. Lesions that are visible on PEM should be viewed as suspicious unless known to be benign by prior breast imaging or biopsy.

Breast cancer: comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast.

PURPOSE: To determine the performance of positron emission mammography (PEM), as compared with magnetic resonance (MR) imaging, including the effect on surgical management, in ipsilateral breasts with cancer. MATERIALS AND METHODS: Four hundred seventy-two women with newly diagnosed breast cancer who were offered breast-conserving surgery consented from September 2006 to November 2008 to participate in a multicenter institutional review board-approved, HIPAA-compliant protocol. Participants underwent contrast material-enhanced MR imaging and fluorine 18 fluorodeoxyglucose PEM in randomized order; resultant images were interpreted independently. Added biopsies and changes in surgical procedure for the ipsilateral breast were correlated with histopathologic findings. Performance characteristics were compared by using the McNemar test and generalized estimating equations. RESULTS: Three hundred eighty-eight women (median age, 58 years; age range, 26-93 years; median estimated tumor size, 1.5 cm) completed the study. Additional cancers were found in 82 (21%) women (82 ipsilateral breasts; median tumor size, 0.7 cm). Twenty-eight (34%) of the 82 breasts were identified with both PEM and MR imaging; 21 (26%) breasts, with MR imaging only; 14 (17%) breasts, with PEM only; and seven (8.5%) breasts, with mammography and ultrasonography. Twelve (15%) cases of additional cancer were missed at all imaging examinations. Integration of PEM and MR imaging increased cancer detection-to 61 (74%) of 82 breasts versus 49 (60%) of 82 breasts identified with MR imaging alone (P < .001). Of 306 breasts without additional cancer, 279 (91.2%) were correctly assessed with PEM compared with 264 (86.3%) that were correctly assessed with MR imaging (P = .03). The positive predictive value of biopsy prompted by PEM findings (47 [66%] of 71 cases) was higher than that of biopsy prompted by MR findings (61 [53%] of 116 cases) (P = .016). Of 116 additional cancers, 61 (53%) were depicted by MR imaging and 47 (41%) were depicted by PEM (P = .043). Fifty-six (14%) of the 388 women required mastectomy: 40 (71%) of these women were identified with MR imaging, and 20 (36%) were identified with PEM (P < .001). Eleven (2.8%) women underwent unnecessary mastectomy, which was prompted by only MR findings in five women, by only PEM findings in one, and by PEM and MR findings in five. Thirty-three (8.5%) women required wider excision: 24 (73%) of these women were identified with MR imaging, and 22 (67%) were identified with PEM. CONCLUSION: PEM and MR imaging had comparable breast-level sensitivity, although MR imaging had greater lesion-level sensitivity and more accurately depicted the need for mastectomy. PEM had greater specificity at the breast and lesion levels. Eighty-nine (23%) participants required more extensive surgery: 61 (69%) of these women were identified with MR imaging, and 41 (46%) were identified with PEM (P = .003). Fourteen (3.6%) women had tumors seen only at PEM.

[Progress report on the Bethesda System]. / Le point sur le Système de Bethesda 2001.

The 2001 Bethesda System is a uniform system of terminology for reporting results of pap smears. It is acknowledged by most cytopathologists worldwide as a standard for cervical cytology reports. In France, several national surveys have confirmed its current utilization. However, more specific analysis have shown that the Bethesda System may be routinely modified by individual laboratories or even individual cytopathologist working within the same department. The aim of this progress report was to emphasize the importance of fully understanding the Bethesda System and applying it in a rigorous and standardized way.