Abstract Introduction: Bones, lungs, brain and liver are the most common metastatic sites of breast carcinoma, although invasive lobular carcinoma can give metastases to less common sites, such as the gastrointestinal tract and the female genital tract. Case presentation: We present the case of a 57-year-old female with colic abdominal pain that was sent to surgery for cholecystectomy. Histopathology revealed a poorly cohesive individual or in single file neoplastic cells infiltrating all layers of the gallbladder. Immunohistochemistry revealed these cells to be CK 116, CK7, GCDFP-15, ER and PR positive, and CK20, HER-2, S-100 and E-cadherin negative. PET/CT showed numerous lytic bone lesions, but ultrasound, mammography, MRI and PET/CT revealed no breast mass. Conclusion: Although rare and poorly understood, metastases of invasive lobular carcinoma to gallbladder do exist in a minor percentage of patients, presenting usually as exacerbated cholecystitis. The problem are silent cases and patients with no history of breast carcinoma. This case is unique in that even after the diagnosis of metastatic lobular breast carcinoma to the gallbladder, the primary tumour of the breast was not detected.

Abstract Objective of this study was to identify the histopathological patterns and their frequency in testicular biopsy specimens from azoospermic patients and to categorize it according to Modified Johnsen scoring system. Methods: Testicular biopsies from male patients with clinical diagnosis of azoospermia were included in this study. All tissue samples were fixed in buffered 10% formalin, routinely processed and stained with Hematoxylin and Eosin. All cases were examined microscopically and categorized according to the histopathological patterns and Modified Johnsen scoring system. Results: Total 219 cases of testicular biopsies from 125 azoospermic male patients were evaluated, with 94 cases of bilateral testicular biopsy. The most prevalent age group was of 30-39 years (66.2%). The most common histological pattern was of Sertoli cell only syndrome (58.4%) while the least represented pattern was germ cell maturation arrest, seen in 4.6% cases. The most common Modified Johnsen score was 2 (66.7%). There was discordance in histologic pattern in both testes in 12.76% of patients who had bilateral testicular biopsy. Conclusion: Our study gives an insight on the most common histopathological patterns of azoospermic patients and emphasizes the need for a better national statistics and epidemiological studies of this entity. It also points out the significance of the bilateral testicular biopsy, as both, diagnostic and therapeutic procedure.

Introduction: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin malignancies in the heterogeneous group of non-melanoma skin cancers (NMSC). Due to their increasing incidence, these tumors remain a significant health problem worldwide. The aim is to analyze the relative frequency of primary cutaneous BCC and SCC and to correlate it with the available pathological and clinical features. Methods: We conducted a retrospective analysis to evaluate the incidence of NMSCs in our institution from 2003 to 2022 and to correlate it with patient’s age and sex, together with available pathological and clinical features: Anatomical location, histopathological subtypes of prognostic implications, and size (local stage) of the tumor. Results: We noticed that the incidence of NMSC increased between 2018 and 2022 ( p < 0.01). Among 1570 patients diagnosed with NMSC, BCC represented 77.9% of cases. BCC was a constantly more common type of NMSC, with a statistically significant difference in the period from 2003 to 2005 and in the period from 2017 to 2022 ( p < 0.01). Nodular subtype of the BCC was the most common, affecting primarily face. Superficial BCC occurred most commonly on trunk ( p < 0.01), affecting younger patients than the other histological subtypes (61.29 ± 13.47 years), p < 0.01. BCCs were predominantly smaller tumors (<2 cm) in contrast to SCCs, with the highest incidence in the pT2-pT4 group ( p < 0.01). SCC patients were older (mean age 72.89 ± 9.7) than BCC patients (mean age 65.15 ± 12.80), p < 0.01. Conclusion: To improve prevention strategies and prevent further increases in the incidence of NMSCs, there is a need to develop current and exact registries of these malignancies, especially separately for the most common types – BCC and SCC.

Background: Bone morphogenetic protein -4 (BMP-4) plays important role in many aspects of carcinogenesis but is also involved in progression and metastasis of breast cancer where its precise role is yet to be elucidated. Objective: Since the majority of studies related to BMP-4 expression in breast cancer were conducted on cell lines of mouse models, we aimed to investigate BMP-4 tissue expression in primary human breast cancer and to correlate it with standard pathological factors for breast cancer, progression and survival. Methods: We analyzed immunohistochemical expression of BMP-4 in primary breast cancer tissue of 97 patients, correlated it with standard pathological factors for breast cancer and investigated its impact on progression and survival. Results: BMP-4 expression was positive in 74.23% breast cancer tissue specimens. We found that hormone positive breast tumors are more likely to show BMP-4 strong granular staining pattern (p<0.01; p=0.029, respectively). There was significant association between stage group and BMP-4 expression in order that stage III breast cancer group were predominantly BMP-4 positive tumors (p=0.046). Although the most common site of distant metastases in patients with BMP-4 positive tumors were bones, we found no significant association (p>0.05). Patients with BMP-4 positive breast cancer showed longer overall and progression-free survival, but the results did not reach statistical significance (p>0.05). Conclusion: The results of our study in some extent can confirm the current available data and suggest that the role of BMP-4 in breast cancer is ambiguous, acting both as tumor suppressor and tumor promoter in breast cancer. For final elucidation of its impact on survival and progression in breast cancer, multicentric studies on larger sample size are required.

Introduction: Tumor microenvironment plays a significant role in tumor progression. Tumor stroma is one of the strongest modifiers of tumor cell response, cancer behavior, and cancer progression. This study aimed to investigate the correlation of matrix metalloproteinase-9 (MMP-9) expression and tumor-stroma ratio (TSR) with standard clinicopathological parameters in different molecular subtypes of breast cancer.Methods: Ninety biopsy samples of primary breast cancer diagnosed at the Department of Pathology, School of Medicine, Sarajevo, were selected for this study. The molecular subtype was determined based on the immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. Stromal and tumoral MMP-9 immunohistochemical expression and the TSR were determined for each tumor.Results: Tumoral MMP-9 expression correlated positively with the presence of lymphovascular invasion (p= 0.016). TSR showed significant association and correlation with tumor grade (G) (p= 0.031; p= 0.049) and tumor size (pT) (p = 0.049;p= 0.021, respectively). Stromal MMP-9 expression correlated with histologic type, histologic grade of tumor, and lymphocytic inflammatory infiltrate (p= 0.021;p= 0.047, p= 0.038, respectively). A higher percentage of stromal MMP-9 expression correlated with the strongest lymphocytic response (p = 0.007). Significant correlation was observed between molecular subtypes and histologic grade of the tumor (p= 0.032).Conclusion: Our results, to some extent, confirm the significance of the tumor microenvironment in breast cancer, especially when it is about stromal MMP-9 expression. Although we observed significant association, without linear correlation, we found no significant correlation between molecular subtypes of breast cancer and MMP-9 expression.

Objective: To investigate a possible association between peritumoral lymphatic vessel density (LVD) and adipose tissue invasion (ATI) of cancer cells at the tumor margin and their correlation with other prognostic parameters in breast cancer, including lymph node status. Material and methods: Data of 75 patients with breast carcinoma were evaluated through combination of peritumoral LVD and ATI at the tumor margin and compared with clinicopathological parameters. Peritumoral LVD was assessed by immunostaining for D2-40 using the Chalkley counting method. Marginal ATI was defined as either the presence of more than 20 cancer cells in direct contact with the adipose tissue or as the presence of cancer cells in the adipose tissue. Cases were evaluated concerning to patient’s age, tumor size using the TNM staging system, histological type, histological grade (Nottingham histological score, Elston and Ellis), lymphovascular invasion, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), HER2/neu status and Ki-67. Results: The relationship was identified between LVD and marginal ATI but without statistical significancy (r = -0,207; p=0,113). There was a significant correlation of the marginal ATI with Ki-67 expression (r=0,250; p =0.03). The regression model (all variables according to ATI) showed a significant total effect (p <0.05), where Ki-67 was an only independent indicator of ATI. Conclusion: The present study suggests that adipose tissue invasion of cancer cells at the tumor margin can be a better predictive biologic indicator of aggressiveness than peritumoral lymphatic vessel density in breast carcinoma. Keywords: breast carcinoma, peritumoral lymphatic vessel density, marginal adipose tissue invasion.

Objectives : The main objective of the study was to determine whether the distribution fsaand th Gastric cancer progression in correlation with distribution and density of T-lymphocytes e level of fsa: The main objective of the study was to determine whether the distribution and the level of density of tumor infiltrating CD4+ and CD8+ T-lymphocytes correlates with standard prognostic factors for gastric cancer and whether it has impact on tumor progression. Methods: The study included 60 tissue samples of operable gastric carcinomas of known regional lymph node status, stained by standard hematoxylin eosin and immunohi Objectives: The main objective of the study was to determine whether the distribution and the level of density of tumor infiltrating CD4+ and CD8+ T-lymphocytes correlates with standard prognostic factors for gastric cancer and whether it has impact on tumor progression. Methods: The study included 60 tissue samples of operable gastric carcinomas of known regional lymph node status, stained by standard hematoxylin eosin and immunohistochemical method in order to determine standard pathologic prognostic factors for gastric cancer and to evaluate distribution and density of tumor infiltrating T- lymphocytes. Results: CD8+ T lymphocytes were predominantly distributed along the margin of carcinoma infiltration, while inside the cancer tissue there were generally few. CD4+ lymphocytes were few in almost all three analyzed zones (margin of carcinoma infiltration, cancer stroma and cancer tissue). The density of CD8+ showed significant positive correlation with CD8+ T lymphocytes within the cancer’s stroma. There was statistically significant difference in density of CD4+ T lymphocytes distributed along the margin of carcinoma infiltration and histological tumor grade, as well as in tumor grade according to Goseki. Conclusion: CD8+ T lymphocytes are densely arranged along the margin of carcinoma infiltration and they correlate with histological grade of gastric carcinoma. Keywords: gastric cancer, tumor microenvironment, T- lymphocytes stochemical method in order to determine standard pathologic prognostic factors for gastric cancer and to evaluate distribution and density of tumor infiltrating T- lymphocytes. Results: CD8+ T lymphocytes were predominantly distributed along the margin of carcinoma infiltration, Gastric cancer progression in correlation with distribution and density of T-lymphocytes while inside the cancer tissue there were generally few. CD4+ lymphocytes were few in almost all three analyzed zones (margin of carcinoma infiltration, cancer stroma and cancer tissue). The density of CD8+ showed significant positive correlation with CD8+ T lymphocytes within the cancer’s stroma. There was statistically significant difference in density of CD4+ T lymphocytes distributed along the margin of carcinoma infiltration and histological tumor grade, as well as in tumor grade according to Goseki. Conclusion: CD8+ T lymphocytes are densely arranged along the margin of carcinoma infiltration and they correlate with histological grade of gastric carcinoma. Keywords: gastric cancer, tumor microenvironment, T- lymphocytes density of tumor infiltrating CD4+ and CD8+ T-lymphocytes correlates with standard prognostic factors for gastric cancer and whether it has impact on tumor progression. Methods : The study included 60 tissue samples of operable gastric carcinomas of known regional lymph node status, stained by standard hematoxylin eosin and immunohistochemical method in order to determine standard pathologic prognostic factors for gastric cancer and to evaluate distribution and density of tumor infiltrating T- lymphocytes. Results : CD8+ T lymphocytes were predominantly distributed along the margin of carcinoma infiltration, while inside the cancer tissue there were generally few. CD4+ lymphocytes were few in almost all three analyzed zones (margin of carcinoma infiltration, cancer stroma and cancer tissue). The density of CD8+ showed significant positive correlation with CD8+ T lymphocytes within the cancer’s stroma. There was statistically significant difference in density of CD4+ T lymphocytes distributed along the margin of carcinoma infiltration and histological tumor grade, as well as in tumor grade according to Goseki. Conclusion : CD8+ T lymphocytes are densely arranged along the margin of carcinoma infiltration and they correlate with histological grade of gastric carcinoma. Keywords : gastric cancer, tumor microenvironment, T- lymphocytes

Introduction: Tumor-associated macrophages (TAM) are the most common inflammatory cells in the tumor microenvironment (TM). As a response to microenvironmental signals, they polarize into tumor resisting M1 or promoting M2 macrophages. TAM and tumor-associated dendritic cells (TADC) can either promote tumor growth and tissue invasiveness or have anti-tumor activity. The aim of the study was the examination of prognostic value in the individual cell population in TM and their correlation with clinicopathological parameters of gastric cancer. Materials and Methods: The study analyzed 60 samples of gastric cancer, known status of regional lymph nodes and without dissemination at the time of diagnosis. The control group was normal gastric tissue samples. Traditional parameters of biological aggressiveness, tumor size, histological grade, and lymphovascular invasion, are determined after standard hematoxylin-eosin staining. TAM and TADS have been evaluated using the immunohistochemical method with CD68 (TAM), TNFa (TAM-M1), CD163 (TAM-M2), and S100 (TADC) antibodies. Expression evaluation of the tissue antigen was carried out by semiquantitative methods. Results: There were statistically significant differences of TAM density (P 0.05). Conclusion: TAMs and TADC have shown potential as biomarkers for evaluating the gastric cancer staging and progression. They showed promising prediction in depth of invasion, histological grade of tumor and tumor size. Keywords: gastric cancer, tumor microenvironment, TAM, TAM-M1/M2, TADC

Introduction: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in the progression of several tumors, including breast cancer. Our aim was to investigate the association of immunohistochemical expression of protein MMP-2, and -9 and tissue inhibitors TIMP-1,-2,-3 by tumoral cells in the process of angiogenesis and to define their relation with clinicopathological features for breast cancer. Methods: Immunohistochemical analysis of MMP-2,-9, TIMP-1,-2,-3, endoglin/CD105, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status was performed on 79 tissue samples of breast cancer with axillary lymph node dissection. Results: Statistically significant difference was found between mean age of patients and tissue inhibitors of metalloproteinase (TIMP-1) expression status (p=0.008), i.e., women with TIMP-1 negative tumors were on average younger (mean age 46.5) compared to women with TIMP-1 positive tumors (mean age 58.1); TIMP-2 expression status showed association with ER status (p=0.017), while TIMP-3 negative tumors were on average more frequently ER and PR negative (p=0.016; p=0.027). Status of protein expression of MMP-9 was associated with TIMP-1 protein expression status (p=0.033), i.e., breast cancers with overexpression of protein MMP-9 were more frequently TIMP-1 protein positive. Conclusion: Only TIMPs were associated with clinicopathological features for breast cancer. TIMP-2 expression was associated with worse (TIMP-2 positive tumors were frequently ER-negative), while TIMP-3 expression in tumoral cells was associated with better clinicopathological features for breast cancer (TIMP-3 positive tumors were frequently ER and PR positive).