HER2-positive apocrine carcinoma of the breast: a population-based analysis of treatment and outcome.

PURPOSE: Apocrine carcinoma of the breast (APO) expresses HER2 in 30-50% of cases. This study explored the clinicopathological features and outcome of HER2+/APO and matched HER2+/NST cohort. METHODS: We used the SEER database to explore the cohorts. Univariate and multivariate analyses were used to assess the survival. Based on ER and PR [steroid receptors/SR/] and HER2 status, we divided the cohorts to match the intrinsic molecular subtypes for comparisons. RESULTS: We retrieved 259 cases of HER2+/APO. Most HER2+/APO were SR negative (65%). HER2+/APO were more prevalent in the 80+ age group (24.7% vs. 15.7%, p < 0.001). HER2+/SR-/APO had a significantly lower histological grade than the HER2+/SR-/NST (p < 0.001). Breast cancer-related deaths were more prevalent in HER2+/NST (7.8% vs. 3.9%, p = 0.019). This was particularly evident between SR- subgroups (10.4% in HER2+/SR-/NST vs. 4.2% in HER2+/SR-/APO, p = 0.008) and was reaffirmed in breast cancer-specific survival in univariate analysis (p = 0.03). Other than race and SR status, HER2+/APO subgroups did not differ in clinicopathological parameters. CONCLUSIONS: Our study confirms the rarity of the APO and reveals that SR status in APO does not affect these patients' prognosis. HER2+/APO tumors tend to have a less aggressive phenotype and a more favorable outcome despite a markedly lower ER/PR positivity.

Histologic diversity in chromophobe renal cell carcinoma does not impact survival outcome: A comparative international multi-institutional study.

Predicting the clinical behavior and trajectory of chromophobe renal cell carcinoma (ChRCC) by histologic features has so far proven to be challenging. It is known that ChRCC represents a heterogeneous group of neoplasms demonstrating variable, yet distinctive morphologic and genetic profiles. In this international multi-institutional study, we aimed to assess the impact of histologic diversity in ChRCC (classic/eosinophilic versus rare subtypes) on survival outcome. This is an international multi-institutional matched case-control study including 14 institutions, examining the impact of histologic subtypes of ChRCC on survival outcome. The study group (cases) included 89 rare subtypes of ChRCC. The control group consisted of 70 cases of ChRCC including classic and eosinophilic features, age- and tumor size-matched. Most of the rare subtypes were adenomatoid cystic/pigmented ChRCC (66/89, 74.2%), followed by multicystic ChRCC (10/89, 11.2%), and papillary ChRCC (9/89, 10.1%). In the control group, there were 62 (88.6%) classic and 8 (11.4%) eosinophilic ChRCC. There were no statistically significant differences between the study and control groups for age at diagnosis, gender distribution, tumor size, presence of tumor necrosis, presence of sarcomatoid differentiation, and adverse outcomes. No statistically significant differences were found in clinical outcome between the rare subtypes and classic/eosinophilic groups by tumor size, necrosis, and sarcomatoid differentiation. Further, no statistically significant differences were found in clinical outcome between the two groups, stratified by tumor size, necrosis, and sarcomatoid differentiation. Our findings corroborated previous studies that both sarcomatoid differentiation and tumor necrosis were significantly associated with poor clinical outcome in classic/eosinophilic ChRCC, and this was proven to be true for ChRCC with rare histologic subtypes as well. This study suggests that rare morphologic patterns in ChRCC without other aggressive features play no role in determining the clinical behavior of the tumor.

CORRELATION OF EXPRESSION OF TGF- ß AND MMP2 BETWEEN PROSTATIC ADENOCARCINOMA AND ADJACENT UNAFFECTED PARENCHYMA.

In prostate adenocarcinoma, both tumorous stroma and epithelium have important role in tumor progression. Transforming growth factor beta (TGF- ß) is a promotor in advanced stages of prostate cancer. Matrix Metalloproteinase 2 (MMP2), the endopeptidase that degrades extracellular matrix is considered to be overexpressed in prostatic carcinoma related to its growth and aggressiveness. Therefore, the aim was to analyze the expression of proteins TGF- ß and MMP2 between both epithelium and stroma of prostatic adenocarcinoma and adjacent unaffected parenchyma. The intensity of TGF- ß and MMP2 expression in epithelium, tumorous stroma and adjacent unaffected parenchyma was analyzed in 62 specimens of prostatic adenocarcinoma by microarray-based immunohistochemistry. TGF- ß was more expressed in tumorous than in prostate stroma (p =0.000), while no statistical significance in case of MMP2 (p = 0.097) was found. MMP2 was more expressed in tumorous than in prostate epithelium (p =0.000), while no statistical significance in case of TGF- ß (p = 0.096) was observed. The study results indicate that both tumorous stroma and epithelium have a role in tumor progression and support potential role of TGF- ß and MMP2 in prostatic adenocarcinoma progression.

KANK1-NTRK3 fusions define a subset of BRAF mutation negative renal metanephric adenomas.

BACKGROUND: Metanephric adenoma (MA) is a rare benign renal neoplasm. On occasion, MA can be difficult to differentiate from renal malignancies such as papillary renal cell carcinoma in adults and Wilms̕ tumor in children. Despite recent advancements in tumor genomics, there is limited data available regarding the genetic alterations characteristic of MA. The purpose of this study is to determine the frequency of metanephric adenoma cases exhibiting cytogenetic aberration t (9;15)(p24;q24), and to investigate the association between t (9,15) and BRAF mutation in metanephric adenoma. METHODS: This study was conducted on 28 archival formalin fixed paraffin-embedded (FFPE) specimens from patients with pathologically confirmed MA. Tissue blocks were selected for BRAF sequencing and fluorescent in situ hybridization (FISH) analysis for chromosomal rearrangement between KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3), which was previously characterized and described in two MA cases. RESULTS: BRAFV600E mutation was identified in 62% of our cases, 9 (38%) cases were BRAFWT, and 4 cases were uninformative. Of the 20 tumors with FISH results, two (10%) were positive for KANK1-NTRK3 fusion. Both cases were BRAFWT suggesting mutual exclusivity of BRAFV600E and KANK1-NTRK3 fusion, the first such observation in the literature. CONCLUSIONS: Our data shows that BRAF mutation in MA may not be as frequent as suggested in the literature and KANK-NTRK3 fusions may account for a subset of BRAFWT cases in younger patients. FISH analysis for KANK1-NTRK3 fusion or conventional cytogenetic analysis may be warranted to establish the diagnosis of MA in morphologically and immunohistochemically ambiguous MA cases lacking BRAF mutations.

Co-presence of human papillomaviruses and Epstein-Barr virus is linked with advanced tumor stage: a tissue microarray study in head and neck cancer patients.

BACKGROUND: Human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), known oncoviruses, can be co-present and cooperate in the initiation and/or progression of human carcinomas, including head and neck. Based on this fact, we recently reported the prevalence of both HPVs and EBV in cervical and breast cancers. METHODS: We herein explore for the first time the co-prevalence of high-risk HPVs and EBV in 98 head and neck (HN) squamous cell carcinoma (SCC) tissues from Bosnian patients using polymerase chain reaction (PCR) and immunohistochemistry (IHC) analysis, as well as tissue microarray methodology. RESULTS: The majority of these cancer tissue cases were from the oral cavity (68%). We found that high-risk HPVs and EBV are co-present in 34.7% of the SCC samples; with a significant correlation between the various HPV types and EBV co-incidence (p = 0.03). Our data showed that 30.8% of oral SCCs are positive for E6 oncoprotein of high-risk HPVs and 44.6% are positive for LMP1 of EBV. The most commonly expressed HPVs in our HNSCC samples include HPV types 16, 18, 45 and 58. Additionally, 37.5% of oral SCCs are positive for both HPVs and EBV, with statistically significant association between high-risk HPV types and EBV (p < 0.05). More importantly, our data revealed that the co-presence of HPV and EBV is strongly correlated with advanced tumor stage (p = 0.035). CONCLUSION: In this study we show that HPV and EBV oncoviruses are co-present in HNSCC, particularly in oral cancer, where they can cooperate in the initiation and/or progression of this cancer. Thus, further studies are necessary to elucidate the mechanism of this cooperation.

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases.

We profiled nine pure clear cell carcinomas of the breast using massively parallel DNA and RNA sequencing (NGS), in situ hybridization (ISH), and immunohistochemistry (IHC). All cases were primary mammary clear cell carcinomas that were diagnosed in female patients (mean age: 53.4 years; range: 31-69 years). Based on our findings, we conclude that the majority of clear cell carcinomas are ER/PR positive and consequently amenable to anti-ER treatment modalities. A subset of clear cell carcinomas also harbored alterations in PIK3CA/PTEN/AKT pathway, particularly PTEN, indicating a potential benefit of PI3K/Akt/mTOR inhibitors. The status of I-O biomarkers in clear cell carcinomas indicates a limited therapeutic benefit of immune checkpoint inhibitors (against PD-1/PD-L1).

A Successful Treatment of Encapsulating Peritoneal Sclerosis in an Adolescent Boy on Long-term Peritoneal Dialysis: A Case Report.

Encapsulating peritoneal sclerosis (EPS) is a rare life-threatening complication associated with peritoneal dialysis (PD). EPS is characterized by progressive fibrosis and sclerosis of the peritoneum, with the formation of a membrane and tethering of loops of the small intestine resulting in intestinal obstruction. It is very rare in children. We present a case of a 16-year-old adolescent boy who developed EPS seven years after being placed on continuous ambulatory peritoneal dialysis (CAPD) complicated by several episodes of bacterial peritonitis. The diagnosis was based on clinical, radiological, intraoperative and histopathological findings. The patient was successfully treated with surgical enterolysis. During a 7-year follow-up, there have been no further episodes of small bowel obstruction documented. He still continues to be on regular hemodialysis and is awaiting a deceased donor kidney transplant. EPS is a long-term complication of peritoneal dialysis and is typically seen in adults. Rare cases may be seen in the pediatric population and require an appropriate surgical approach that is effective and lifesaving for these patients.

Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer.

Neuroendocrine breast cancer (NEBC) is a group of rare tumors, which could benefit from therapy targeting the somatostatin receptors (SSTRs). In particular, SSTR2A and SSTR5 are potential targets given their consistent expression in gastrointestinal and pancreatic primary and metastatic neuroendocrine cancers. Currently, there are no studies describing the expression of SSTRs in NEBC. The purpose of our study was to characterize the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of NEBC. Thirty-one primary NEBC cases were analyzed, and SSTR2A and SSTR5 immunohistochemistry performed and scored using the modified immunoreactive score proposed by Remmele and Stanger. All patients were females with a mean age of 66.6 years (SD = 14). 77% of cases were histological grade 2. SSTR2A showed a weak positivity in 11 cases (35.5%), moderate positivity in 6 cases (19.4%) and strong positivity in 5 cases (16.1%). Nine cases were negative for SSTR2A (29%). SSTR5 showed a weak positivity in 16 cases (51.6%), moderate positivity in 6 cases (19.4%), while no cases showed strong positivity. Nine cases were negative for SSTR5 (29%). Five cases were negative for both SSTR2A and SSTR5. A weak to moderate SSTR2A and SSTR5 expression was observed in 50-70% of the cases. A subset of NEBCs with strong SSR2A expression may benefit from SSTRs targeted therapy. These results need further validation in a larger series including metastatic NEBC, to provide potential therapeutic targets for patients with advanced disease.

Papillary pattern in clear cell renal cell carcinoma: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 23 cases.

Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype of RCCs, demonstrates a wide spectrum of morphologic features (i.e., low-grade spindle cell, syncytial giant cells, and mucin-producing cells). However, papillary growth pattern in ccRCCs is rather a rare finding, which can present challenges in differential diagnostic work up. The aim of this study was to investigate ccRCCs with predominant papillary features from morphologic, immunohistochemical and molecular genetic perspectives. 23 clear cell renal cell carcinomas with papillary architecture were selected. Tumors were evaluated morphologically, immunohistochemically, and molecularly by next-generation sequencing (NGS). The diagnosis of MiT family translocation RCC was excluded by TFE3 immunohistochemistry. Mean age of patients was 65.2 years (range 42-81 years), and 19/23 were male. Tumor size ranged from 1.6 to 12.8 cm (median 6.5 cm). At a median follow-up of 2.5 years (range 1.5-9 years), 2 patients (8.7%) died of disease, 2 developed metastasis. Areas of papillary pattern accounted for approximately 40-100% of the tumor. CK7 was negative in non-papillary areas in majority of cases (20/23, 87%), and was only focally positive in 3/23 cases (13%). In papillary areas, AMACR was positive/focally positive in 17/23 (73.9%) cases and in the non-papillary areas it was positive/focally positive in 22/23 (95.6%) cases. CAIX was mainly negative in both non-papillary and papillary areas (15/23 [65%] and 16/23 [69.5%], respectively). Molecular analysis of 15 analyzable cases revealed the most frequently mutated gene to be VHL (in 9 cases), followed by PRBM1 (in 2 cases) and 29 other different mutations in various genes. Papillary growth pattern in ccRCC is not an uncommon situation. Papillary RCC with clear cells and MiT family (TFE3) translocation RCCs are the major differential diagnostic considerations in such scenarios. Our NGS molecular analysis supported classifying such tumors as a morphologic variant of ccRCC.

Skeletal Muscle Metastases from Squamous Cell Carcinoma of the Cervix: Report of Two Cases With Literature Review.

Cervical carcinoma is the second most common female malignancy worldwide. It usually spreads by direct local extension or the lymphatic vessels. Hematogenous dissemination with distant skeletal muscle metastases is a rare phenomenon. We report here 2 patients whose recurrent squamous cell carcinomas of the cervix presented with symptomatic skeletal muscle metastases affecting the muscles of the thoracic wall and forearm, respectively. We also discuss the differential diagnosis and comprehensively review the previously published literature on this rare presentation of cervical carcinoma.

Methylation-associated silencing of SFRP1 gene in high-grade serous ovarian carcinomas.

Wnt is a highly conserved signaling pathway responsible for tissue regeneration, maintenance and differentiation of stem cells in adults. Its aberrant activation through reduced expression of Wnt signaling pathway inhibitors, such as proteins from the SFRP family, is commonly seen in many tumors. In the present study we explored SFRP1 protein expression using immunohistochemistry in 11 low-grade serous ovarian carcinomas (LGSC), 42 high-grade serous ovarian carcinomas (HGSC), and 5 normal ovarian tissues (controls). SFRP1 gene methylation was analyzed by methylation-specific PCR in 8 LGSCs, 13 HGSCs and control samples. SFRP1 gene was unmethylated and SFRP1 protein expression was strong in normal ovaries (n=5). Although SFRP1 gene was unmethylated in almost all of the LGSC cases (7/8, 88%), SFRP1 protein expression was significantly lower than in normal ovaries (p<0.05). Seven out of 13 HGSCs (54%) showed SFRP1 gene hypermethylation and protein expression level was also significantly lower than in normal ovaries (p<0.001). Our preliminary data show loss of SFRP1 protein expression caused by the SFRP1 promoter hypermethylation in a subset of HGSCs. SFRP1 protein expression was also lost in LGSCs but different regulatory mechanisms may be involved. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations.

Whorling cellular perineurioma: A previously undescribed variant closely mimicking monophasic fibrous synovial sarcoma.

The authors present a distinctive perineurioma (PN) variant which morphologically strongly resembles monophasic fibrous synovial sarcoma (MSS). The patients were 3 males and 1 female. The age ranged from 15 to 61years (mean: 44years). Locations included the sole, lower jaw, palm and foot. The tumor size ranged from 1.3cm to 2.5cm in the largest dimension (mean 1.8cm). Morphologically, all tumors had an identical, monotonous appearance. The perineurial cells were closely packed and created a confluent cellular whorls and/or sheets in a scarce stroma, with only focally discernible long, slender cytoplasmic processes typical for perineurial differentiation. The nuclei were rounded or slightly elongated to tapered, without nuclear atypia. Mitoses were rare to completely absent. Atypical mitoses, hemorrhage, necrosis or calcifications were not present. The proliferative index (Ki-67) was 1-3%. All analyzed tumors were positive for EMA, Claudin-1, GLUT-1 and negative with S100 protein, CD34, OSCAR, CK7 and TLE-1. Two cases were tested by fluorescence in situ hybridization and neither showed alterations of the SYT gene. One case studied by electron microscopy showed characteristic features of perineurial differentiation. Follow-up was available for two patients both of which showed no evidence of disease at 8years and 6months, respectively. Based on their bland morphology, perineurial features and presumably benign clinical outcome we propose the term "whorling cellular perineurioma" for these tumors, which may represent an extremely cellular variant of sclerosing PN. Awareness of this PN subtype and its distinction from MSS is of utmost clinical significance.

Cystic and necrotic papillary renal cell carcinoma: prognosis, morphology, immunohistochemical, and molecular-genetic profile of 10 cases.

Conflicting data have been published on the prognostic significance of tumor necrosis in papillary renal cell carcinoma (PRCC). Although the presence of necrosis is generally considered an adverse prognostic feature in PRCC, we report a cohort of 10 morphologically distinct cystic and extensively necrotic PRCC with favorable biological behavior. Ten cases of type 1 PRCC with a uniform morphologic pattern were selected from the 19 500 renal tumors, of which 1311 were PRCCs in our registry. We focused on precise morphologic diagnosis supported by immunohistochemical and molecular-genetic analysis. Patients included 8 men and 2 women with an age range of 32-85 years (mean, 62.6 years). Tumor size ranged from 6 to 14 cm (mean, 9.4 cm). Follow-up data were available in 7 patients, ranging from 0.5 to 14 years (mean, 4 years). All tumors were spherical, cystic, and circumscribed by a thick fibrous capsule, filled with hemorrhagic/necrotic contents. Limited viable neoplastic tissue was present only as a thin rim in the inner surface of the cyst wall, consistent with type 1 PRCC. All cases were positive for AMACR, OSCAR, CAM 5.2, HIF-2, and vimentin. Chromosome 7 and 17 polysomy was found in 5 of 9 analyzable cases, 2 cases demonstrated chromosome 7 and 17 disomy, and 1 case showed only chromosome 17 polysomy. Loss of chromosome Y was found in 5 cases, including 1 case with disomic chromosomes 7 and 17. No VHL gene abnormalities were found. Papillary renal cell carcinoma type 1 can present as a large hemorrhagic/necrotic unicystic lesion with a thick fibroleiomyomatous capsule. Most cases showed a chromosomal numerical aberration pattern characteristic of PRCC. All tumors followed a nonaggressive clinical course. Large liquefactive necrosis should not necessarily be considered an adverse prognostic feature, particularly in a subset of type 1 PRCC with unilocular cysts filled with necrotic/hemorrhagic material.

Warthin-like papillary renal cell carcinoma: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 11 cases.

Oncocytic papillary renal cell carcinoma (PRCC) is a distinct subtype of PRCC, listed as a possible new variant of PRCC in the 2016 WHO classification. It is composed of papillae aligned by large single-layered eosinophilic cells showing linearly arranged oncocytoma-like nuclei. We analyzed clinicopathologic, morphologic, immunohistochemical and molecular-genetic characteristics of 11 oncocytic PRCCs with prominent tumor lymphocytic infiltrate, morphologically resembling Warthin's tumor. The patients were predominantly males (8/11, 73%), with an average age of 59years (range 14-76), and a mean tumor size of 7cm (range 1-22cm). Tumors had the features of oncocytic PRCCs with focal pseudostratification in 8/11 cases and showed dense stromal inflammatory infiltration in all cases. Papillary growth pattern was predominant, comprising more than 60% of tumor volume. Tubular and solid components were present in 5 and 3 cases, respectively. Uniform immunohistochemical positivity was found for AMACR, PAX-8, MIA, vimentin, and OSCAR. Tumors were mostly negative for carboanhydrase 9, CD117, CK20, and TTF-1. Immunohistochemical stains for DNA mismatch repair proteins MLH1 and PMS2 were retained in all cases, while MSH2 and MSH6 were negative in 1 case. Tumor infiltrating lymphocytes (TILs) consisted of both B and T cells. Chromosomal copy number variation analysis showed great variability in 5 cases, ranging from a loss of one single chromosome to complex genome rearrangements. Only one case showed gains of chromosomes 7 and 17, among other aberrations. In 4 cases no numerical imbalance was found. Follow up data was available for 9 patients (median 47.6months, range 1-132). In 6 patients no lethal progression was noted, while 3 died of disease. In conclusion, Warthin-like PRCC is morphologically very close to oncocytic PRCC, from which it differs by the presence of dense lymphoid stroma. Chromosomal numerical aberration pattern of these tumors is variable; only one case showed gains of chromosomes 7 and 17. Warthin-like PRCC is a potentially aggressive tumor since a lethal outcome was recorded in 3/9 cases.

The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status.

In the current study, we assessed the prevalence and molecular features of HER2-low phenotype in the apocrine carcinomas of the breast (ApoCa) and its relationship with tumor-infiltrating lymphocytes (TILs). A cohort of 64 well-characterized therapy-naïve ApoCa was used. The TIL distribution was assessed using the hematoxylin and eosin whole slide/scanned images following the international TILs working group recommendations. Next-generation sequencing (NGS) was performed in a subset of HER2-low ApoCa. All patients were women, with a mean age of 62 years. Forty-three carcinomas were pure apocrine carcinoma (PAC; ER-/AR+), and the remaining 21 were classified as apocrine-like carcinomas (ALCs; ER+/-, AR+/-). HER2/neu was positive (score 3+ by IHC and/or amplified by FISH) in 20/43 (47%) PAC and 4/21 (19%) ALC. The prevalence of HER2-low expression (scores 1+ or 2+ without HER2 amplification) in ApoCa was 39% without significant differences between PAC and ALC (P = 0.14); however, the HER2-low phenotype was more prevalent in triple-negative PAC than in ALC (P < 0.001). Levels of TILs were low (≤10%) in 74% of ApoCa (median 5%, range 0%-50%). TIL levels were significantly higher in ALC than in PAC (P = 0.02). HER2 status had no impact on TIL distribution (P = 0.45). The genomic profile of HER2-low ApoCa was similar to other subtypes of ApoCa. ApoCa has predominantly low TIL, particularly PAC. The prevalence of the HER2-low phenotype in ApoCa is high, which should have therapeutic and clinical implications given the recently approved therapies with antibody-drug conjugates (ADCs) for HER2-low breast cancers.

Comprehensive genomic profiling of a metastatic small cell lung carcinoma with a complete and long-term response to atezolizumab: A case report.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with a poor outcome. We present the case of a 57-year-old male patient with extensive-stage (ES-SCLC) treated with chemotherapy and atezolizumab. A complete response was achieved with a long remission of ∼three years. Comprehensive genomic profiling (CGP) of the tumor revealed high tumor mutation burden (13 mutations/Mb) and mutations of TP53, RB1 and ERCC4 genes. This case study confirms that a complete response to chemoimmunotherapy may be achieved in the case of ES-SCLC. It further provides the additional value of CGP and predictive testing in the management of ES-SCLC.

Acinic cell carcinoma of the breast: A comprehensive review.

Acinic cell carcinoma of the breast is a rare special subtype of breast cancer in the category of salivary gland-type tumors. It is morphologically similar to acinic cell carcinomas of salivary glands and pancreas and has a triple-negative phenotype (estrogen receptor-negative, progesterone receptor-negative, and Her-2/neu negative). Its molecular genomic features are more similar to triple-negative breast cancer of no special type than to its salivary gland counterpart. However, the clinical course of the mammary acinic cell carcinoma appears to be less aggressive than the usual triple-negative breast carcinomas. This review comprehensively summarizes the current literature on the clinicopathologic, immunohistochemical, and molecular features of this rare and distinct subtype of breast cancer.