The Role of Imaging in the Diagnosis of Primary and Secondary Breast Angiosarcoma: Twenty-Five-Year Experience of a Provincial Cancer Institution.

BACKGROUND: Breast angiosarcoma may arise spontaneously (primary breast angiosarcoma (PBA)) or may arise secondary to a biological insult, such as radiation therapy (secondary breast angiosarcoma (SBA)). We evaluated the imaging findings of patients diagnosed with PBA and SBA within the province of British Columbia, Canada. MATERIALS AND METHODS: This was a multi-center, retrospective study of patients diagnosed with PBA and SBA over a 25-year period. Patients were identified via a provincial database which registers all cases of sarcoma. Patients diagnosed with histologically proven PBA and SBA were eligible for inclusion. Multimodal breast imaging reviewed included mammography, ultrasound, magnetic resonance imaging, and computed tomography. RESULTS: Thirteen patients were diagnosed with PBA and 22 patients were diagnosed with SBA. The median (interquartile range (IQR)) age of patients diagnosed with PBA (45.5 years (19.7 years)) was less than that of patients diagnosed with SBA (75.8 years (13.8 years), P < .001). Patients diagnosed with PBA (90.9%) were more likely to present with a parenchymal mass clinically and radiographically than those with SBA (28.6%, P < .002). Patients diagnosed with SBA (71.4%) were more likely to present with cutaneous findings than patients diagnosed with PBA (0.0%, P < .05). Without specific clinical context, the imaging findings of PBA and SBA were observed to be non-specific. CONCLUSION: This is the only study which evaluated the imaging findings of patients diagnosed with PBA and SBA within a large, defined geographical area. Given non-specific imaging findings, awareness of the disease and clear and timely communication between radiologists and clinicians is required to ensure appropriate diagnosis and management.

Distinct Uroplakin II Staining Pattern in Apocrine Breast Carcinoma.

Uroplakin II (UPII) has been shown as a highly specific marker of urothelial carcinoma; however, it can also stain subtypes of apocrine-differentiated breast carcinoma. Given that urothelium and breast epithelium share other common immunohistochemical markers, such as CK7 and GATA3, this can lead to a potential diagnostic pitfall. We stained a cohort of triple-negative breast cancer with UPII. Compared with the diffuse, cytoplasmic staining in urothelial carcinoma, UPII was positive in 38.9% of apocrine carcinoma (7/18) with a course, granular cytoplasmic staining pattern and negative in all nonapocrine triple-negative breast cancer cases. Furthermore, the same staining pattern was present in all apocrine metaplasia of the breast (4/4) and apocrine sweat glands in normal skin (6/6). This distinct subcellular localization of UPII staining in breast carcinoma can offer a potential solution to the above diagnostic pitfall.

Renal cell tumor with sex-cord/gonadoblastoma-like features: analysis of 6 cases.

Renal tumors are one of the most diverse groups of tumors in pathology. Many emerging and important entities have been described recently. Here, we describe a series of renal tumors occurring in adult patients, with distinct histologic features, and with a striking resemblance to gonadal sex cord-stromal tumors. Patients were three males and three females aged 39-82 years; tumor size ranged from 0.9 to 3.6 cm. Five tumors were organ-confined, while one case had a focal perinephric invasion. No aggressive behavior was noted. Microscopically, all the tumors were composed of loose or compact tubular structures with elongated or angulated shapes. The tumor cells were cylindrical or cuboidal, with pale eosinophilic cytoplasm, irregular nuclear membranes, and ISUP/WHO grade 2-3 nuclei. The stroma showed focal or prominent collagen deposition with prominent basement membrane-like material. In all cases, the tumor cells were positive for PAX8, CD10, and vimentin and retained positivity for FH and SDHB. Cathepsin K and AMACR were variably positive. Tumors were negative for HMB45, Melan A, TFE3, SF1, inhibin, calretinin, ER, PR, CD117, OCT3/4, SALL4, ALK, and WT1. Molecular studies showed no abnormalities in TFEB, TFE3, or FH genes. In 3/4 tested cases, mutation of the NF2 gene was present. In all the tested male cases, loss of the Y chromosome was found. In the relatively short follow-up, these tumors appear to have indolent behavior. This study expands the clinicopathologic diversity of renal cell tumors by describing a series of potentially novel tumors morphologically resembling gonadal sex-stromal tumors, with negativity for sex cord-stromal markers. Potential relationship to recently described biphasic hyalinizing psammomatous renal cell carcinoma is discussed.

Urinary Large Cell Neuroendocrine Carcinoma: A Clinicopathologic Analysis of 22 Cases.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a rare disease. We present a relatively large retrospective cohort of urinary LCNEC, 20 from the urinary bladder, and 2 from the ureter, from a single institution. The patients included 16 men and 6 women with a median age of 74.5 years. Most LCNEC presented at an advanced stage with tumors invading the muscularis propria and beyond (21/22). Eight cases were pure LCNEC, while 14 cases were mixed with other histologic types, including conventional urothelial carcinoma (n=9), carcinoma in situ (n=7), small cell carcinoma (n=6), and urothelial carcinoma with glandular (n=3) features. Most LCNEC expressed neuroendocrine markers synaptophysin (22/22), chromogranin (13/16), CD56 (7/7), TTF1 (8/8), and INSM1 (2/3). They were negative for common urothelial markers including HMWCK (0/3), p40/p63 (0/6), CK20 (0/10), and had variable GATA3 staining (4/8). Ki-67 stained 25% to nearly 100% tumor cell nuclei. Patient survival was associated with cancer stage, and pure LCNEC showed worse survival than mixed LCNEC. Compared with small cell carcinoma at similar stages from a prior study, LCNEC had a worse prognosis only when patients developed metastatic disease. For organ-confined LCNEC, neoadjuvant chemotherapy followed by radical resection is the treatment option to achieve long-term survival.

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.

SOX10 expression in mammary invasive ductal carcinomas and benign breast tissue.

SOX10 immunohistochemistry is used to identify tumors of neural crest origin, including melanocytic neoplasms. SOX10 expression has also been identified in myoepithelial cells of the breast and in a subset of invasive mammary carcinomas. In order to characterize SOX10 expression in ductal carcinomas of the breast, the aim of this study was to characterize the SOX10 in invasive ductal carcinomas according to molecular subtype, DCIS, and benign breast tissue. Forty cases of invasive ductal carcinoma of the breast were retrieved, with ten cases with immunohistochemical profile compatible with luminal A-like, luminal B-HER2-positive, non-luminal HER2-positive, and triple-negative subtypes. Whole tissue sections from each case were stained with SOX10. Six (60%) of ten triple-negative tumors were SOX10+ compared with 1 (3%) of 30 carcinomas of other molecular subtypes. All but one of the positive tumors showed at least moderate expression in at least 40% of tumor cells. All seven cases SOX10+ carcinomas were grade 3 tumors. Of the 13 cases with DCIS available for assessment, one (8%) showed positive SOX10 expression (a case associated with triple-negative carcinoma). Twenty-two cases contained normal breast tissue that showed SOX10 expression in both myoepithelial and luminal cells, predominantly patchy with variable intensity. SOX10 showed incomplete myoepithelial staining compared to other myoepithelial markers. In conclusion, SOX10 IHC cannot reliably differentiate between high-grade triple-negative carcinomas, melanomas, and myoepithelial tumors in the breast. SOX10 is not as robust a myoepithelial marker compared with other established markers.

Metastatic breast carcinoma to the urinary bladder-a report of 11 cases including a tumor to tumor metastasis.

Metastatic breast carcinoma to the urinary bladder is rare. Eleven cases of metastatic breast carcinoma to the bladder are described in this report, including one case with a tumor to tumor metastasis. The patients ranged from 51 to 83 years of age. The time intervals between the diagnosis of primary breast cancer and the occurrence of bladder metastases ranged from 41 to 336 months. There were seven cases of invasive ductal carcinoma and four cases of invasive lobular carcinoma. In one case, a lobular carcinoma of the breast metastasized to a concurrent squamous cell carcinoma of the bladder. The immunophenotypic status of estrogen receptor and Her2 expression of the metastatic carcinomas were all concordant with the primary tumors. In nine patients with follow-up available, seven patients died of the disease ranging from 1 to 23 months after the diagnosis of the bladder metastasis and two patients were alive at 5 months of follow-up. To date, this report is the largest single series of patients with breast carcinoma metastatic to the bladder. It is the first reported instance of lobular carcinoma of the breast metastasizing to a squamous cell carcinoma of the bladder.

Sclerosing Odontogenic Carcinoma with Local Recurrence: Case Report and Review of Literature.

Sclerosing odontogenic carcinoma is a rare locally destructive neoplasm with many histologic mimics. Here the diagnostic challenges are presented of a case of sclerosing odontogenic carcinoma with variable histologic features, including unusual and unexpected negative immunostaining for CK19.

Molecular Profiling of Hyalinizing Clear Cell Carcinomas Revealed a Subset of Tumors Harboring a Novel EWSR1-CREM Fusion: Report of 3 Cases.

We describe a novel gene fusion, EWSR1-CREM, identified in 3 cases of clear cell carcinoma (CCC) using anchored multiplex polymerase chain reaction, a next-generation sequencing-based technique. CCC is a low-grade salivary tumor recently characterized to have EWSR1-ATF1 fusions in the majority of cases. Three cases of malignant tumor presenting in the base of tongue, lung, and nasopharynx were studied. All cases shared a clear cell morphology with hyalinized stroma, presence of mucin and p63 positivity and were initially diagnosed as mucoepidermoid carcinoma but were negative for evidence of any of the expected gene fusions. Anchored multiplex polymerase chain reaction demonstrated a EWSR1-CREM fusion in all 3 cases to confirm a diagnosis of CCC. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. EWSR1-CREM fusions have not been previously reported in CCC and have only rarely been reported in other tumors. We show that the ability to discover novel gene variants with next-generation sequencing-based assays has clinical utility in the pathologic classification of fusion gene-associated tumors.

The Significance of the Stromal Response in Breast Cancer: An Immunohistochemical Study of Myofibroblasts in Primary and Metastatic Breast Cancer.

BACKGROUND: Gene expression profiling of breast cancer has demonstrated the importance of stromal response in determining the prognosis of invasive breast cancer. The host response to breast cancer is of increasing interest to pathologists and may be a future focus for novel pharmacological treatments. METHODS: This study describes the pattern of distribution of stromal myofibroblasts using immunostains for CD10 and smooth muscle actin (SMA) in 50 primary breast cancers and their matched nodal metastases (68.6% nodes positive and 31.4% nodes negative). The stroma within the tumor (intratumoral) and at the advancing tumor edge (peri-tumoral) was studied in both primary and nodal sites. A simple quantitative scoring system was employed for both immunostains. The correlation between expression of these markers by stromal cells and standard pathological prognostic factors of stage, grade, hormone receptor and Her-2 status was analysed. RESULTS: SMA-positive stromal cells were more abundant in peri-tumoral stroma compared with intratumoral stroma in both primary and metastatic lesions. SMA expression in the lymph node metastases showed a significant correlation with tumor stage. SMA expression in peri-tumoral stroma correlated with Her-2 status. CONCLUSION: The results of this study suggest that myofibroblasts, particularly those expressing SMA, might potentiate the progression of the carcinomatous process especially in nodal metastases. Thus these cells may be a potential therapeutic target.

Metastatic non-small cell lung carcinoma a mimic of primary breast carcinoma-case series and literature review.

Metastatic tumors to the breast are rare but constitute a major diagnostic dilemma. Of these, non-mammary carcinomatous metastases to the breast are particularly challenging and, without a clinical history, may be extremely difficult to distinguish from primary breast carcinoma (PBC). We specifically studied metastatic tumors of pulmonary origin, as the lung is one of the major primary sites for carcinomatous metastasis to breast. Sixteen metastatic lung tumors to the breast were identified in our archives between 1996 and 2017 including 12 non-small cell lung carcinomas (NSCLC), one large-cell neuroendocrine, one atypical carcinoid, and two small-cell carcinomas. Adenocarcinoma was the most frequent amongst the NSCLCs (11/14). We retrieved the clinical information of these cases and reviewed the pathological characteristics to provide practical tools for pathologists to aid in their identification. Even in the absence of a clinical history of lung cancer, metastatic pulmonary adenocarcinoma to the breast should be considered in at least one of the following scenarios: (1) single or multiple well-circumscribed lesions of the breast that lack an in situ component and that are accompanied by distant metastases but negative axillary lymph nodes, (2) breast tumors that are triple negative yet not high-grade, or (3) breast tumors presenting as stage 4 disease and/or having an unusually aggressive clinical course on standard breast therapy. Accurate and timely diagnosis of these tumors is mandatory because of treatment and prognostic implications.

Combined Papillary Renal Cell Carcinoma with Neuroendocrine Differentiation and Mucinous Tubular and Spindle Cell Carcinoma.

A unique case of combined papillary renal cell carcinoma (PRCC) and mucinous tubular and spindle cell carcinoma (MTSCC) presenting in a man aged 67 years is reported. The two separate components were distinct on morphological, immunohistochemical (IHC), and genetic grounds, while type 2 PRCC predominated. Three years after the initial diagnosis, the PRCC component metastasized to the lungs where it morphologically mimicked a pulmonary neuroendocrine tumor. Retrospectively focal neuroendocrine differentiation was demonstrated by IHC in the PRCC component of the primary neoplasm.

Large-scale DNA organization is a prognostic marker of breast cancer survival.

Breast cancer is the leading cause of cancer-related deaths among women worldwide. We investigated whether changes in large-scale DNA organization (LDO) of tumor epithelial nuclei are an indicator of the aggressiveness of the tumor. We tested our algorithm on a set of 172 duplicates TMA cores samples coming from 95 breast cancer patients. Thirty-five patients died of breast cancer, and 60 were still alive 10 years after surgery. Duplicates cores were used to create training and test set. The TMA slides were stained with Feulgen-thionin and imaged using our in-house high-resolution Imaging system. Automated segmentation of cell nuclei followed by manual selection of intact, in-focus nuclei resulted in an average of 50 cell nuclei per sample available for analysis. Using forward stepwise linear discriminant analysis, a combination of six features that combined linearly gave the best discrimination between the two groups of cells: cells collected from 'deceased' patients TMA specimens and cells collected from "survivors" patients TMA specimens. Five of these features measure the spatial organization of DNA chromatin. The resulting canonical score is named cell LDO score. A patient LDO score, percentage of cell nuclei with a cell LDO score higher than a predefined cutoff value, was processed for the specimens in the test set, and a cutoff value was defined to classify patients with a low or a high LDO score. Using this binary test, 82.1% of patients were correctly classified are "deceased" or "survivors," with a specificity of 79% and a sensitivity of 88%. The relative risk of death of an individual with a high LDO score was nine times higher than for a patient with a low LDO score. When testing the combination of LDO score, node status, histological grade, and tumor grade to predict breast cancer survival, LDO was the most significant predictor. LDO classification was also highly associated with survival for only grade 1 and 2 patients as well as for only grade 3 patients. Our result confirms the potential of LDO to measure phenotypic changes associated with more aggressive disease and could be evaluated to identify patients more likely to benefit from adjuvant therapies.

Quantification of large scale DNA organization for predicting prostate cancer recurrence.

This study investigates whether Genomic Organization at Large Scales (which we propose to call GOALS) as quantified via nuclear phenotype characteristics and cell sociology features (describing cell organization within tissue) collected from prostate tissue microarrays (TMAs) can separate biochemical failure from biochemical nonevidence of disease (BNED) after radical prostatectomy (RP). Of the 78 prostate cancer tissue cores collected from patients treated with RP, 16 who developed biochemical relapse (failure group) and 16 who were BNED patients (nonfailure group) were included in the analyses (36 cores from 32 patients). A section from this TMA was stained stoichiometrically for DNA using the Feulgen-Thionin methodology, and scanned with a Pannoramic MIDI scanner. Approximately 110 nuclear phenotypic features, predominately quantifying large scale DNA organization (GOALS), were extracted from each segmented nuclei. In addition, the centers of these segmented nuclei defined a Voronoi tessellation and subsequent architectural analysis. Prostate TMA core classification as biochemical failure or BNED after RP using GOALS features was conducted (a) based on cell type and cell position within the epithelium (all cells, all epithelial cells, epithelial >2 cell layers away from basement membrane) from all cores, and (b) based on epithelial cells more than two cell layers from the basement membrane using a Classifier trained on Gleason 6, 8, 9 (16 cores) only and applied to a Test set consisting of the Gleason 7 cores (20 cores). Successful core classification as biochemical failure or BNED after RP by a linear classifier was 75% using all cells, 83% using all epithelial cells, and 86% using epithelial >2 layers. Overall success of predicted classification by the linear Classifier of (b) was 87.5% using the Training Set and 80% using the Test Set. Overall success of predicted progression using Gleason score alone was 75% for Gleason >7 as failures and 69% for Gleason >6 as failures. © 2017 International Society for Advancement of Cytometry.

Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1 This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.

Post-radiation epithelioid angiosarcoma of the urinary bladder and prostate.

Angiosarcoma of the lower urinary tract is exceedingly rare. A minority of cases are associated with local radiotherapy. Epithelioid angiosarcoma is a variant of angiosarcoma composed of large rounded epithelioid endothelial cells that are positive for cytokeratin on immunostaining. There are only two cases of post-radiation epithelioid angiosarcoma reported in the urinary bladder, and none in the prostate gland. We report a case of epithelioid angiosarcoma involving the urinary bladder and prostate in a patient with a history of radiotherapy for prostatic adenocarcinoma. A brief review of literature regarding post-radiation epithelioid angiosarcomas in the lower urinary tract is discussed.