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.

From February 2023 (Volume 23, Issue 1), the title of the Bosnian Journal of Basic Medical Sciences will be changed to Biomolecules and Biomedicine. The new title reflects the increasing number of published research done on subcellular/molecular level as well as translational and clinical research contained in the term Biomedicine. Biomolecules and Biomedicine will continue to be published by the Association of Basic Medical Sciences of the Federation of Bosnia and Herzegovina. Read more in the PDF.

SUMMARY In prostate adenocarcinoma, both tumorous stroma and epithelium have important role in tumor progression. Transforming growth factor beta (TGF- β) 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- β and MMP2 between both epithelium and stroma of prostatic adenocarcinoma and adjacent unaffected parenchyma. The intensity of TGF- β and MMP2 expression in epithelium, tumorous stroma and adjacent unaffected parenchyma was analyzed in 62 specimens of prostatic adenocarcinoma by microarray-based immunohistochemistry. TGF- β 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- β (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- β and MMP2 in prostatic adenocarcinoma progression.

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.

A 65-year-old woman with a negative family history of breast cancer presented with a palpable mass in the left breast’s central portion. Mammography revealed an oval heteroechogenic, partly solid, partly cystic, sharply demarcated mass, measuring 100×90 mm in greatest diameter, classified as BI-RADS 4c, according to ACR BI-RADS Atlas Fifth Edition (Figure 1A-B). Breast MRI showed a lobulated mass with smooth margins appearing hypointense on T1WI and high signal intensity on T2WI (Figure 1C-D). A core needle biopsy revealed a cellular neoplasm, composed of small, closely packed tubules with spindle cell intervening stroma without prominent atypia and mitotic activity, classified as B3 category according to the UK National Coordinating Committee for Breast Screening Pathology (Figure 2A). The multidisciplinary tumor board discussed the case and recommended a wide surgical excision. With the patient’s approval, a left mastectomy was recommended and performed. The axillary clearance was not performed. The 100×90 mm tumor was grossly well-circumscribed, grayish-white, and predominantly solid, with a smaller cystic component, without necrosis and hemorrhage (Figure 2B). Histopathologic examination revealed a well-circumscribed tumor with two distinct components (tubular adenoma and phyllodes tumor) with the transition to one another (Figure 2C). The larger portion of the tumor was composed of closely packed small round to oval tubules with little intervening spindle cell stroma consistent with tubular adenoma. The smaller component showed a biphasic fibroepithelial tumor with leaf-like projections with moderately cellular stroma (Figure 2D-E). The stromal cells exhibited mild to moderate atypia, and their mitotic activity was up to six mitoses/10 hpf (Figure 2F). Stromal overgrowth was absent, while the malignant heterologous elements were not observed despite the exhaustive tumor sampling (25 paraffin blocks). The final diagnosis was a complex fibroepithelial tumor composed of borderline phyllodes and tubular adenoma. Clinical Science

Abstract Rationale: Pheochromocytoma (PHEO) is a rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla. Most pediatric PHEOs are functional tumors, and clinical manifestations are related to catecholamine hypersecretion and/or tumor mass effects. Patient concerns: We report here a case of a 10-year-old boy with a highly functional adrenal PHEO detected after the evaluation of a generalized tonic-clonic seizure in the patient. His vital signs at admission were: blood pressure up to 220/135 mm Hg; pulse, 112 beats/min; temperature, 37.4°C; respiratory rate, 22 breaths/min. Diagnosis: A 24-hour urine collection for catecholamines test showed a marked increase in Vanillylmandelic acid levels (338.9 μmol/L). An abdominal magnetic resonance imaging revealed a well-defined left adrenal gland mass measuring ∼5 cm in its largest dimension. Interventions: The mass was surgically removed, and histopathological examination revealed PHEO with low malignant potential (Adrenal Gland Scaled Score/PASS/ < 4). Outcomes: The patient was discharged on the 10th postoperative day in good condition. At 24-month follow-up, the patient was doing well without complications such as tumor recurrence, elevated blood pressure, and seizure. Lessons: PHEO should be considered in the differential diagnosis of children with seizures presenting in the emergency department. A multidisciplinary approach to the evaluation and treatment of PHEO is also crucial for a successful outcome.

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 BRAF V600E mutation was identified in 62% of our cases, 9 (38%) cases were BRAF WT , and 4 cases were uninformative. Of the 20 tumors with FISH results, two (10%) were positive for KANK1-NTRK3 fusion. Both cases were BRAF WT suggesting mutual exclusivity of BRAF V600E 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 BRAF WT 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.

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. 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. 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). 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.

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.