Whole-Genome Sequencing Analysis of Male Breast Cancer Unveils Novel Structural Events and Potential Therapeutic Targets.

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly because of its low incidence rate, accounting for only 0.5% to 1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of 10 MaBC cases (n = 10) were delineated and correlated with clinical and histopathologic characteristics. Using fluorescence in situ hybridization, an additional cohort of 18 patients was interrogated to supplement WGS findings. The genomic landscape of MaBC uncovered significant genetic alterations that could influence diagnosis and treatment. We found common somatic mutations in key driver genes, such as FAT1, GATA3, SMARCA4, and ARID2. Our study also mapped out structural variants that impact cancer-associated genes, such as ARID1A, ESR1, GATA3, NTRK1, and NF1. Using a WGS-based classifier, homologous recombination deficiency (HRD) was identified in 2 cases, both presenting with deleterious variants in BRCA2. Noteworthy was the observation of FGFR1 amplification in 21% of cases. Altogether, we identified at least 1 potential therapeutic target in 8 of the 10 cases, including high tumor mutational burden, FGFR1 amplification, and HRD. Our study is the first WGS characterization of MaBC, which uncovered potentially relevant variants, including structural events in cancer genes, HRD signatures, and germline pathogenic mutations. Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this understudied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer.

The "Halo Appearance" of Shear Wave Elastography in the Setting of Fat Necrosis: A Potentially Useful Sonographic Discriminator.

OBJECTIVE: To describe the morphologic sonographic appearances and frequency of the "halo sign" in the setting of fat necrosis on shear wave elastography (SWE). METHODS: Patients with clinically suspected fat necrosis were prospectively scanned using SWE in addition to standard gray-scale and Doppler images. Cases were qualitatively grouped into one of three sonographic appearances: focal hypoechoic lesion with increased internal tissue stiffness ("focal stiffness"), focal hypoechoic lesion with isoechoic or hyperechoic periphery demonstrating increased tissue stiffness relative to the central hypoechoic lesion ("halo stiffness"), heterogeneously echogenic lesion with diffusely increased stiffness ("heterogeneous stiffness"). RESULTS: Exactly 19 patients met inclusion criteria (female n = 14; male n = 5). Shear wave velocities were recorded and retrospectively evaluated. The mean clinical follow-up was 11.4 months (range 3.0-25.5). Lesions demonstrated higher average tissue stiffness than background tissue (overall mass shear wave velocity 3.26 m/s, background 1.42 m/s, P < .001; lesion Young's modulus 40.85 kPa vs background 7.22 kPa, P < .001). The halo sign was identified in 10/19 (55%) patients. CONCLUSION: The halo sign is a potentially useful sign in the setting of fat necrosis seen in the majority of clinically suspected cases.

Sclerosing well-differentiated liposarcoma: two diagnostically challenging mimicker cases and a literature review.

Liposarcoma is a malignant soft tissue tumor with several subtypes, the most common of which is well-differentiated liposarcoma (WDL) or atypical lipomatous tumor (ALT). WDL/ALTs are further divided into three histological subtypes, including lipoma-like, sclerosing, and inflammatory. While the majority of these tumors are predominantly fatty, the sclerosing variant demonstrates diverse histologic and radiographic characteristics, including variable amounts of fibrosis and fat. Because of this histological variability and relative rarity, the sclerosing WDL/ALT can present diagnostic dilemmas. We present two cases of sclerosing WDL/ALT, both of which demonstrated high degrees of fibrosis and a paucity of fat, mimicking desmoid fibromatosis and other fibrotic soft tissue tumors. Thus, it is important for radiologists to be aware of the subtypes of liposarcoma and their unique characteristics, and to consider sclerosing WDL/ALT in cases of fibrotic soft tissue tumors.

Dedifferentiated Chondrosarcoma: Diagnostic Controversies and Emerging Therapeutic Targets.

PURPOSE OF REVIEW: The pathogenesis of dedifferentiated chondrosarcoma is controversial, and no genetic abnormality has consistently been identified in the disease. Focusing on the diagnostic challenges encountered in dedifferentiated chondrosarcoma, the following review aims at summarizing the tumor's active neoplastic pathways while highlighting therapeutic modalities that could potentially be explored to enhance patient survivorship. RECENT FINDINGS: Owing to the challenging examination of small needle biopsy sampling as well as the disease's overlapping morphological and immunohistochemical features with other bone and soft-tissue sarcomas, the diagnosis of dedifferentiated chondrosarcoma can be problematic. While combined doxorubicin- and cisplatin-based regimens remain the first-line systemic chemotherapy in the disease, ~50% of tumors carry EXT1/2 or IDH1/2 mutations, advancing EXT or IDH inhibitors as potential alternative therapies, respectively. Despite systemic chemotherapy, dedifferentiated chondrosarcoma remains an aggressive tumor with dismal prognosis and limited survival. A multidisciplinary collaboration across multiple cancer centers is warranted to yield an accurate diagnosis, understand the disease's underlying pathogenesis, develop adequate treatment, and improve patient survivorship.

Intraductal Papilloma of the Breast: Prevalence of Malignancy and Natural History Under Active Surveillance.

BACKGROUND: The optimal management of intraductal papillomas (IPs) without atypia diagnosed on needle core biopsy (NCB) is unclear. This study analyzed the malignancy risk of immediately excised IPs and characterized the behavior of IPs under active surveillance (AS). METHODS: We retrospectively reviewed the pathology and imaging records of patients diagnosed with IPs without atypia on NCB during a 10-year period (1999-2019). The malignancy upgrade rate was assessed in patients who had an immediate surgical excision, and the rates of both radiographic progression and development of malignancy were assessed in a cohort of patients undergoing AS. RESULTS: The inclusion criteria were met in 152 patients with 175 IPs with a mean age of 51 ± 13 years. The average size of the IPs on initial imaging was 8 ± 4 mm. Most of the lesions (57%, n = 99) were immediately excised, whereas 76 (43%) underwent AS with interval imaging with a median follow-up period of 15 months (range, 5-111 months). Among the immediately excised IPs, surgical pathology revealed benign findings in 97% (n = 96) and ductal carcinoma in situ in 3% (n = 3). In the AS cohort, 72% (n = 55) of the IPs remained stable, and 25% (n = 19) resolved or decreased in size. At 2 years, 4% had increased in size on imaging and were subsequently excised, with ductal carcinoma in situ (DCIS, n = 1) and benign pathology (n = 1) noted on final pathology. CONCLUSIONS: In a large series of breast IPs without atypia, no invasive carcinoma was observed after immediate excision, and 96% of the lesions had not progressed on AS. This suggests that patients with IP shown on NCB can safely undergo AS, with surgery reserved for radiographic lesion progression.

Does Magnetic Resonance Imaging After Diagnostic Ultrasound for Soft Tissue Masses Change Clinical Management?

OBJECTIVES: To evaluate whether a follow-up magnetic resonance imaging (MRI) scan performed after initial ultrasound (US) to evaluate soft tissue mass (STM) lesions of the musculoskeletal system provides additional radiologic diagnostic information and alters clinical management. METHODS: A retrospective chart review was performed of patients undergoing initial US evaluations of STMs of the axial or appendicular skeleton between November 2012 and March 2019. Patients who underwent US examinations followed by MRI for the evaluation of STM lesions were identified. For inclusion, the subsequent pathologic correlation was required from either a surgical or image-guided biopsy. Imaging studies with pathologic correlations were then reviewed by 3 musculoskeletal radiologists, who were blinded to the pathologic diagnoses. The diagnostic utility of MRI was then assessed on the basis of a 5-point grading scale, and inter-reader agreements were determined by the Fleiss κ statistic. RESULTS: Ninety-two patients underwent MRI after US for STM evaluations. Final pathologic results were available in 42 cases. Samples were obtained by surgical excision or open biopsy (n = 34) or US-guided core biopsy (n = 8). The most common pathologic diagnoses were nerve sheath tumors (n = 9), lipomas (n = 5), and leiomyomas (n = 5). Imaging review showed that the subsequent MRI did not change the working diagnosis in 73% of cases, and the subsequent MRI was not considered to narrow the differential diagnosis in 68% of cases. There was slight inter-reader agreement for the diagnostic utility of MRI among individual cases (κ = 0.10) between the 3 readers. CONCLUSIONS: The recommendation of MRI to further evaluate STM lesions seen with US frequently fails to change the working diagnosis or provide significant diagnostic utility.

Adenomyoepithelial tumors of the breast: molecular underpinnings of a rare entity.

Adenomyoepitheliomas (AMEs) of the breast are uncommon and span the morphologic spectrum of benign, atypical, in situ, and invasive forms. In exceptionally rare cases, these tumors metastasize to regional lymph nodes or distant sites. In the era of genomic characterization, data is limited regarding AMEs. The aim of this study was to provide insight into the molecular underpinnings of a spectrum of AMEs. Seven cases of AMEs of the breast (benign-1, atypical-2, in situ-1, invasive-3) were identified in our files. The seven samples were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Two atypical AMEs and the malignant in situ AME harbored the same gain-of-function PIK3CA mutation. The malignant in situ AME also showed EGFR amplification, not described previously. Both a benign AME and a malignant invasive AME shared the same gain-of-function AKT1 variant. The benign AME also showed a GNAS mutation. Moreover, the same gain-of-function HRAS mutation was present in an atypical AME and a malignant invasive AME. We also identified co-occurring HRAS and PIK3CA mutations in an ER-positive atypical AME, which has not been previously described. No fusion drivers were detected. We describe the molecular characteristics of the spectrum of AME tumors of the breast, which harbor alterations in the PI3K/AKT pathway. Our findings are clinically relevant with respect to the current options of targeted therapy in the rare instances where malignant AME tumors of the breast progress.

Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity.

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.

Fibroepithelial Lesions (FELs) of the Breast: Is Routine Excision Always Necessary?

BACKGROUND: When needle core biopsies (NCBs) of the breast reveal fibroepithelial lesions (FELs), excision is often performed to rule out a phyllodes tumor (PT), despite low malignancy rates. Consequently, the natural history of observed FELs is not well described. We analyzed the malignancy risk in excised FELs and the natural history of FELs undergoing active surveillance (AS). METHODS: We retrospectively studied the pathology and imaging records of 215 patients with FELs (n = 252) diagnosed on NCB. Incidence of growth was determined by Kaplan-Meier method. RESULTS: Of 252 FELs, 80% were immediately excised and 20% underwent AS. Of the excised FELs, 198 (98%) were benign: fibroadenoma (FA) or benign breast tissue in 137 (68%), benign PT in 59 (29%), or LCIS in 2 (1%). Borderline PT or malignant lesions were found in 4 (2%). On ultrasound, malignant and borderline PTs were larger than benign lesions [median 3.9 vs 1.3 cm, p = 0.006]. Fifty FELs underwent AS, with a median follow-up of 17 (range 2-79) months. The majority remained stable or decreased in size: at 2 years, only 35% increased in volume by ≥ 50%. Of those tumors undergoing AS that were later excised (n = 4), all were benign. CONCLUSIONS: Almost all FELs (98%) were benign on surgical excision, and the majority undergoing AS remained stable, with benign pathology if later excised. Most FELs on NCB can be safely followed with US, with surgery reserved for patients with FELs that are large, symptomatic, or growing. This could spare most women with FELs unnecessary surgery.

Human T cell lymphotropic virus type-1 associated lymphoma presenting as an intramuscular mass of the calf.

Adult T cell leukemia/lymphoma (ATLL) is a mature T cell neoplasm caused by the human oncogenic retrovirus human T lymphotropic virus type-1 (HTLV-1). While several musculoskeletal manifestations have been described in ATLL, skeletal muscle involvement is unusual, with only four cases reported in the English-language literature. We present a rare case of ATLL manifesting as an intra-muscular calf mass in a 58-year-old man who immigrated to the USA from West Africa. While skeletal muscle involvement by lymphoma is uncommon, it remains important to consider within the differential diagnosis when there are suggestive imaging findings because it entails important technical biopsy considerations as well as treatment implications. This case report also raises awareness of ATLL presenting outside of typical HTLV-1 endemic areas, related to current population migration patterns. ATLL should therefore be considered in patients with appropriate risk factors.

Fibrous Dysplasia-like Lacrimal Sac Tumor Associated With Dacryocystitis.

A 72-year-old woman who presented with right-sided epiphora and conjunctivitis underwent a probing and irrigation procedure with normal results. She improved with antibiotic-steroid drops. A swelling in the medial canthal region completely resolved. One year later, she returned with symptoms of dacryocystitis. An external dacryocystorhinostomy was performed. Characteristic dacryoliths were removed from the sac lumen, and biopsy of the sac wall showed spicules of lamellar bone within a fibrous stroma. Diagnosed as fibrous dysplasia of the lacrimal sac, this rare entity represents the second such case in the literature.The histopathology of an ossified lacrimal sac resembled fibrous dysplasia of bone and exemplifies the second case of this rare entity in the literature.

Hereditary Susceptibility for Triple Negative Breast Cancer Associated With Western Sub-Saharan African Ancestry: Results From an International Surgical Breast Cancer Collaborative.

OBJECTIVE: To investigate subtype-specific risk of germline alleles associated with triple negative breast cancer (TNBC) in African ancestry populations. BACKGROUND: Breast cancer (BC) mortality is higher in African American (AA) compared to White American (WA) women; this disparity is partly explained by 2-fold higher TNBC incidence. METHODS: We used a surgically maintained biospecimen cohort of 2884 BC cases. Subsets of the total (760 AA; 962 WA; 910 West African/Ghanaian; 252 East African/Ethiopian) were analyzed for genotypes of candidate alleles. A subset of 417 healthy controls were also genotyped, to measure associations with overall BC risk and TNBC. RESULTS: TNBC frequency was highest in Ghanaian and AA cases (49% and 44% respectively; P < 0.0001) and lowest in Ethiopian and WA cases (17% and 24% respectively; P < 0.0001). TNBC cases had higher West African ancestry than non-TNBC (P < 0.0001). Frequency of the Duffy-null allele (rs2814778; an African ancestral variant adopted under selective pressure as protection against malaria) was associated with TNBC-specific risk (P < 0.0001), quantified West African Ancestry (P < 0.0001) and was more common in AA, Ghanaians, and TNBC cases. Additionally, rs4849887 was significantly associated with overall BC risk, and both rs2363956 and rs13000023 were associated with TNBC-specific risk, although none as strongly as the Duffy-null variant. CONCLUSIONS: West African ancestry is strongly correlated with TNBC status, as well as germline variants related to BC risk. The Duffy-null allele was associated with TNBC risk in our cohort.

Surface-type chondromyxoid fibroma in an elderly patient: a case report and literature review.

Chondromyxoid fibroma (CMF) is a rare benign bone neoplasm that typically occurs in young adults. Juxtacortical or surface-type CMF are rarer still and we present the case of a surface-type CMF in a 78-year-old woman, with only one other case described in a patient of a similar age previously. This patient was an otherwise healthy woman who presented for evaluation of a palpable lump in the anterior proximal tibia. Initial radiographs obtained demonstrated a focal soft tissue fullness immediately anterior to the anterior cortex of the proximal tibia, which contained faint chondroid-like matrix internally. There was associated scalloping of the anterior tibial cortex. MRI confirmed the presence of a juxtacortical, enhancing lesion. Subsequent excisional biopsy was performed and histopathology demonstrated features, which was consistent with surface-type CMF. At a 6-month follow-up the patient remained free of recurrence. In a patient of this age, paraosteal chondrosarcoma should be excluded. Surface-type CMF, although rare, has been described in older patients and while it is unlikely to feature in a list of differential considerations on initial imaging, awareness of the entity is important.

Pyogenic granuloma: A tumor that mimics infection.

This article describes a patient whose cutaneous pyogenic granuloma was mistaken for infection after injury from a fractured smartphone screen. Clinicians should suspect pyogenic granuloma in patients with these types of injuries so that patients can avoid unnecessary procedures, antibiotics, and discomfort.

Metastatic Breast Carcinoma in Cerebrospinal Fluid: A Cytopathological Review of 15 Cases.

The incidence of metastatic carcinoma to the meninges ("meningeal carcinomatosis" [MC]) is increasing due to longer survival of patients and improved imaging techniques. Currently, MC is best diagnosed by cytopathological evaluation of cerebrospinal fluid (CSF). Breast primaries are the commonest cause of MC; although cytopathological features thereof have not been, as yet, fully characterized. In this study of meningeal mammary carcinomatosis, relevant clinicopathological data and archived cytopathological preparations of all "suspicious" and "positive" CSF specimens (1992-2015), from patients with a history of breast carcinoma, were retrieved and reviewed. Twenty-three "positive" CSF specimens, derived from 15 patients formed the basis of this study. All specimens were processed as Cytospin preparations, and stained by Papanicolaou and Diff-Quik techniques. All patients were female, with a mean age of 57 (range: 32-85) years. Mean interval between initial diagnosis of breast carcinoma and "positive" CSF was 32 (range 6-84) months. All 23 specimens (100%) were "cellular" (>10 carcinoma cells). Eighteen (78%) specimens showed only isolated nonclustered cells, and 5 (22%) specimens showed both cell clusters and isolated cells. In most "positive" cases, metastatic breast carcinoma cells showed variation in cell size, with hyperchromatic nuclei, irregular nuclear membranes, prominent nucleoli and cytoplasmic vacuolization. The background in some CSF samples showed red blood cells and fibrin admixed with rare lymphocytes and histiocytes. One specimen showed necrotic debris. Papanicolaou and Diff-Quik-stained Cytospin preparations were equally diagnostic, as the aforementioned findings were present in both types of preparation.

A Phase II Trial Exploring the Success of Cryoablation Therapy in the Treatment of Invasive Breast Carcinoma: Results from ACOSOG (Alliance) Z1072.

BACKGROUND: Cryoablation is a well-established technique to treat fibroadenomas. Pilot studies suggest this could be an effective non-surgical treatment for breast cancer. American College of Surgeons Oncology Group Z1072 is a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers. METHODS: The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion. A secondary objective was to evaluate the negative predictive value of magnetic resonance imaging (MRI) to determine residual IBC or DCIS. Eligible patients included those with unifocal invasive ductal breast cancer ≤2 cm, with <25 % intraductal component and tumor enhancement on MRI. A total of 19 centers contributed 99 patients, of which 86 patients (87 breast cancers) were evaluable for data analysis. RESULTS: Final pathology results, regardless of whether residual IBC/DCIS was in the targeted ablation zone or elsewhere in the breast, showed successful ablation in 66/87 (75.9 %) cancers. The 90 % confidence interval for the estimate of successful cryoablation was 67.1-83.2, with the one-sided lower-sided 90 % CI of 69.0. The negative predictive value of MRI was 81.2 % (90 % CI 71.4-88.8). When multifocal disease outside of the targeted cryoablation zone was not defined as an ablation failure, 80/87 (92 %) of the treated cancers had a successful cryoablation. CONCLUSION: Further studies with modifications on the Z1072 protocol could be considered to evaluate the role for cryoablation as a non-surgical treatment of early-stage breast cancer.

Myoepithelial Carcinoma: The Role of Radiation Therapy. A Case Report and Analysis of Data From the Surveillance, Epidemiology, and End Results (SEER) Registry.

PURPOSE/OBJECTIVE: The role of radiation therapy in the treatment of myoepithelial carcinoma (MC) is unknown. We present a case of a high-grade soft-tissue MC in a pediatric patient and retrospectively examine the effect of postoperative radiation on survival in patients with MC. MATERIALS AND METHODS: Our patient was treated with 4 cycles of ifosfamide, cisplatin, and etoposide followed by 3 cycles of ifosfamide vincristine and etoposide. Radiation was delivered to a total dose of 5580 cGy in 180 cGy/fraction to the surgical bed with a 2 cm margin starting after the third cycle of chemotherapy. The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for cases of surgically resected MC. Retrospective analysis was performed with the endpoint of overall survival (OS). RESULTS: Two hundred thirty-four cases of MC were identified; for 62 of these cases, the grade of the tumor wasidentified. Of these 62 patients, 27 received postoperative radiation. OS was improved with adjuvant radiation therapy in patients with grade III or IV MC (P<0.01) as determined by the log-rank test. CONCLUSIONS: This analysis of SEER data showed an OS benefit with adjuvant radiation therapy in the treatment of high-grade MC. Physicians should report all cases of MC to improve clinical decision making in the treatment of this rare disease.

Squamous Cell Carcinoma In Situ of the Breast: Report of a Case.

We present the case of a 73-year-old woman with pure squamous cell carcinoma in situ of the left breast. This non-invasive malignancy exhibited pure squamous type of architectural and cytologic features without any evidence of glandular differentiation either in the initial needle core biopsy or in the subsequently performed excisional biopsy and simple mastectomy. The tumor spanned 1.6 cm, involved numerous ducts and terminal ducts and extended into lobules, and was characterized by keratinizing squamous cells with intermediate-grade nuclei. Intercellular bridges extended between the malignant squamous cells. Keratinous debris with "pearl" formation was evident in most involved glands. No invasive carcinoma was identified. There was no evidence of metastatic disease in the ipsilateral sentinel lymph nodes. Thus far, only three cases of squamous cell carcinoma in situ of the breast have been reported in one series-none of which showed any evidence of recurrent or metastatic disease at last follow-up. In our case, treated exclusively by surgery, there was no evidence of disease 11 years after diagnosis.