The Impact of BMP-4 Tissue Expression on Progression and Survival in Breast Cancer.

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.

Correlation between numerical and categorical immunohistochemical score of Ki-67 and HER2 with clinicopathological parameters of breast cancer.

Aim To evaluate the relationship between numerical and categorical immunohistochemical score of Ki-67 and human epidermal growth factor of receptor 2 (HER2) with clinicopathological parameters of breast cancer (BC). Methods The study included 311 patients with invasive BC diagnosed at the Department of Pathology, School of Medicine in Sarajevo, Bosnia and Herzegovina, during the period 2015-2019. The expression level of Ki-67 and HER2 was detected by immunohistochemical analysis. Results The expression of Ki-67, as a numerical variable correlated significantly with tumour grade (p=0.025), progesterone receptor (PR) (p=0.034) and categorical score of HER2 (p=0.028). When Ki-67 was categorized into high (>14%) and low (≤14%) level groups, a statistically significant association was found between Ki-67 level groups and HER2 status (categorical and numerical) (p=0.001 and p=0.043, respectively), as well as significant negative linear correlation with PR (p=0.037). The expression of HER2, as a numerical variable, showed a statistically significant correlation with tumour grade (p=0.038), PR (p=0.025) and categorical Ki-67 (p=0.043). Categorical score of HER2 correlated significantly with age (p=0.025), histologic type (p=0.039), tumour grade (p=0.016), estrogen receptor (ER), (p=0.002) progesterone receptor (PR) (p=0.0001), and categorical and numerical value of Ki-67 (p=0.0001 and p=0.0001, respectively). Conclusion The results demonstrated that the categorical immunohistochemical score of HER2 provided a greater association with clinicopathological parameters than numerical score of BC. Furthermore, a slightly better correlation with clinicopathological parameters was shown by the numerical value than by the categorical score of Ki-67 by applying a cut-off value of 14%.

Serum total prostate-specific antigen (tPSA): correlation with diagnosis and grading of prostate cancer in core needle biopsy.

Aim To investigate the impact of pre-treatment serum total prostate-specific antigen (PSA) level on prevalence of prostate carcinoma detection in prostate core needle biopsy, and its correlation with established prognostic factors. Methods Prostate needle biopsy samples of 115 patients with available pre-treatment serum total PSA (tPSA) level were analysed. For all cases where morphology alone was insufficient, immunohistochemistry was performed using p63, CKHMW and AMACR antibody panel in order to confirm or exclude the existence of prostate carcinoma. Results Statistically significant positive correlation between serum total PSA values and prevalence of finding prostate carcinoma in needle biopsy specimens was found (p=0.011), as well as in the case when the patients were classified into groups according to tPSA levels (p=0.028). Serum total PSA values and levels (level groups) showed significant positive correlation with Gleason score (p=0.029 and p=0.036, respectively) and Grade Group of prostate carcinomas (p=0.044 and p=0.046, respectively). Sensitivity of the screening test by using 4 ng/mL as cut off value for tPSA was 94.12% (CI: 80.32-99.28%), specificity 8.64% (CI: 3.55-17.00%), positive predictive value 30.19% (CI: 21.65-39.87%) and negative predictive value 77.78% (CI: 39.99-97.19%). Conclusion The increase of serum tPSA value increases the likelihood of finding prostate cancer on needle biopsy specimens. Due to such findings and its positive correlation with a grade of prostate cancer, our study indicates that tPSA can still be considered as a useful tool both in detecting and predicting aggressiveness of prostate cancer.

Immunohistochemical expression and significance of NM23 suppressor protein in primary gastric adenocarcinoma.

NM 23 protein was originally identified as a metastasis suppressor protein. The expression of NM23 has been correlated with tumour metastatic potential in various human carcinoma, mostly in ductal breast and colorectal carcinomas. Evidence for their expression in gastric cancer is rather contradictory, both for protein expression status and prognostic value. This study was done to analyze the immunohistochemical expression of NM23 in gastric carcinoma, and correlation of the degree of staining with clinicopathological parameters was investigated. In a retrospective immunohistochemical study specimens obtained from 56 gastric cancer patients who had undergone gastrectomy with perigastric lymphadenectomy were analysed, in correlation with classical clinical-pathological parameters of tumours, WHO-, Lauren-, Goseki-, and Ming- classification. NM 23 gene expression was compared in gastric adenocarcinoma and tumour-adjacent non-neoplastic gastric mucosa. A semiquantitative immunostaining evaluation (score 0-3) was used, counting the percentage of stained cells. Statistical analysis was performed using Kolmogorov-Smirnov test, and Spearman rank correlation test. The investigated group consisted of 40 males and 16 females (2.5:1) with a mean age of 63 years (range: 48-81 years). The percentage of positive expression of NM23 (score 3) were in 30 (53.5%) specimens in non-neoplastic mucosa in adjacent gastric carcinoma, and negative (score 0-2) in all 56 (100%) specimens of gastric adenocarcinoma. NM23 expression was higher in non-neoplastic mucosa than in adjacent gastric adenocarcinoma tissue (p<0.0001). NM23 protein expression did not correlate with gender (p=0.115), tumour size (p=0.844), tumour grade (p=0.172), lymphovascular invasion (p=0.606), lymph node metastases (p=0.311), Lauren classification (p=0.426), Goseki classification (p=0.458) and Ming classification (p=0.212). Our series did not show a significant correlation between NM23 expression and analysed clinico-pathological variables, but these results suggest that protein NM23 may have a role in gastric carcinoma pathogenesis.

Interdigitating dendritic cell sarcoma of the liver and lung: a case report with morphohological and immunohistochemical features of tumor.

Interdigitating dendritic cell sarcoma is extremely rare neoplasm that mainly occurs in the lymph nodes. Only 45 cases have been reported in the literature to date. We report a case of this sarcoma arising from the liver and lung, a previosly unreported site for this neoplasm. An 19-year-old girl deteriorated rapidly after artificial abortion and died 4 weeks later. Autopsy showed markedly enlarged liver and lung with numerous nodules up to 0.5 centimeters in diameter. Microscopically, nodules was composed of large pleomorphic cells that were immunohistochemically positive for proteins S-100 and vimentin, some of them expressed positivity to fascin and CD 68, with a rich small CD3 positive T lymphocytic infiltrateite around them. Based of these findings, the present case was diagnosed as interdigitating dendritic cell sarcoma, a neoplasm that remains a diagnostic and clinical challenge, because it can mimic a wide variety of other malignant tumors and tumor-like lesions.

Immunohistochemical expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in invasive breast carcinoma.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a natural inhibitor of matrix metalloproteinases (MMPs). Aim of this study was to assess the immunohistochemical expression of TIMP-1 in invasive breast carcinomas, and to examine its association with classical clinico-pathological parameters, oestrogen receptor, progesterone receptor and Her-2/neu protein expression. Immunohistochemistry was used to determine the expression of TIMP-1 on 38 paraffin-embedded breast tissue specimens - 18 with invasive ductal carcinoma, 10 with invasive lobular carcinoma, and 10 specimens from patients with fibrocystic breast disease. TIMP-1 protein was immunodetected in the carcinoma cells, fibroblasts and inflammatory cells of the stroma in 92,9%, 65,8%, and 65,8% of cases, respectively. TIMP-1 protein expression in carcinoma cells showed positive correlation with TIMP-1 protein expression in peritumoural fibroblasts (p=0,010). Positive peritumoural fibroblast TIMP-1 expression was associated with histological tumour type with higher frequency in ductal carcinomas (p=0,023). Negative association was found between TIMP-1 protein expression in carcinoma cells and HER-2/neu nuclear staining (p=0,005). TIMP-1 may be particularly useful as a predictive marker in breast carcinoma when evaluated along with HER-2/neu protein being a promising indicator of favourable prognosis in breast carcinoma.

Dermal squamomelano-cytic tumor: neoplasm of uncertain biological potential.

We report a case of exceedingly rare cutaneous neoplasm with histological features of malignancy and uncertain biological potential. The nodular, darkly pigmented facial tumor with central exulceration, size 12 x 10 x 7 mm, of the skin 61-year-old man preauricular left was completely exised. Histologically tumor consists of atypical squamous cells, which express signs of moderate to significant pleomorphism, mitotically active, with foci forming of parakeratotic horn cysts ("pearls"). Characteristically tumor also consists of large number of atypical melanocytes with multifocal pattern, inserted between atypical squamous cells, and which contain large amount of dark brown pigment melanin. Immunohistochemically, squamous cells stain positively with keratin (CK116), melanocytes were stained with S -100 protein, HMB 45, and vimentin, but failed to stain with CK 116. To our knowledge this is the sixth reported case in world literature. The follow-up time of four years no evidence of recurrence or metastasis, similar all reported cases, but it is too short period in estimation to guarantee a benign course. However, it appears that this group of neoplasm may have different prognosis from pure squamous carcinoma or malignant melanoma.

Non-small cell lung carcinoma: cyclin D1, bcl-2, p53, Ki-67 and HER-2 proteins expression in resected tumors.

The aim of this study was to investigate expression of cyclin D1, bcl-2, p53, Ki-67 and HER-2 proteins in 14 cases of non-small cell lung cancer and to establish their correlation to classical clinico-pathological findings, and alleged prognostic value to estimate biological potential of tumor. Retrospective pilot study of the surgically treated non-small cell lung cancer biopsy specimen, paraffin embedded, used immunohistochemical method to demonstrate expression of cyclin D1, bcl-2, p53, Ki-67 and HER-2. Protein quantification was performed by the semi-quantitative method. Achieved results were correlated with classical clinico-pathological parameters, like tumor size, histological type, differentiation level, presence of vascular invasion and metastasis in regional lymph nodes. Out of 14 cases of non-small cell lung cancer, squamous cell carcinoma was found in 7 patients, giant cell carcinoma in 3, adenocarcinoma in 2, and 1 case of pleomorphic and mucoepidermoid carcinoma. Expression of cyclin D1 was not found, while expression of HER-2 and bcl-2 protein was established in one cases each. p53 expression was noted in 8 cases (57,1%). Statistically positive significant correlation (p<0,05) was found among: presence of lymphovascular invasion to tumor tissue and appearance of nodal metastasis; proliferation Ki-67 index and level of tumor differentiation, i.e. size of tumor. Other investigated parameters showed no significant statistically dependence. p53 expression was not correlated to any of the investigated parameters what might imply the possibility that there is an independent pathway of this protein expression. Negative expression of bcl-2 protein points out to possibility that it is not included into process of tumor apoptosis, as well as that proteins cyclin D1 and HER-2 are not included into processes of the tumor genesis. Since the proliferative activity of the tumor, measured by the expression of Ki-67, is correlated to the gradus and size of the tumor mass, Ki-67 protein can be of a prognostic value to determine biological potential of non-small cell lung cancer.

Testicular metastasis of gastrointestinal stromal tumor of the jejunum.

Gastrointestinal stromal tumors (GIST) are neoplasm of mesenchymal origin that usually begins in cells of the wall of the gastrointestinal tract. It can be benign or malignant. In this report, we have presented a case of malignant GIST with uncommon site of metastasis. This is of interest because of three reasons. Firstly, metastases to the testis are extremely rare. However, metastases to distally localized organs are not commonly associated with GIST, and finally, to our knowledge this is the first case of malignant GIST metastasis to the testis reported in the world.

Zearalenone-induced lymphophagocytosis (T cell apoptosis) on the rat's thymus.

The effects of nonsteroidal mycotoxin zearalenone on the lymphoid tissue of thymus in a sense of investigating the subacute toxicity Wistar-albino rats have been examined in the course of the study. We analyzed 42 rats' specimens of both gender, treated with three dosage levels: 0,5; 2 and 4 mg/kg of body weight, after oral submission of the compound, and observed during three different time intervals: 10, 20 and 30 days. Microscopically was semiquantitatively determined lymphophagocytosis (apoptosis) and cortical thymic cellularity. It was percepted statistically significant growth of lymphophagocytosis compared to a dosage (p<0,01), as well as combination of dosage and interval (p<0,001), while gender had no statistically significant influence on tested parameter (p>0,05). Changes in cortical thyme cellularity were not percepted. Effects of applied doses of zearalenone on the lymphoid tissue of thymus were very mild and in correlation with estrogenicity. They are probably the result of interaction with estrogenic receptors.

Immunohistochemical evaluation of the HER-2 protein in the infiltrative lobular breast cancer.

AIM OF THE STUDY: To investigate the correlation between the expression of HER-2 membrane protein and basic pathohistological parameters in cases of infiltrative breast cancer. MATERIAL AND METHODS: Sixty-nine cases of lobular infiltrative breast cancer were investigated. Mastectomy with a dissection of axillary's lymph nodes was performed in all cases. Upon standard procedure of formalin fixation, embedding in paraffin and examination of slides stained with hematoxillin-eosin, a semiquantitaive method of evaluation of immunohistochemical expression of the HER-2 protein has been performed in all tissue samples of the tumor. RESULTS: Majority of patients (91,3 %) were above 41 year-of-age. In the majority of cases (44,9 %) cancer's diameter ranged from 20-50 mm (pT2), with a moderate degree of differentiation (46,4 %), no signs of vascular invasion (50,7 %) and no metastases in axillary's lymph nodes (65,2 %). Evaluation of immunohistochemical expression of the HER-2 protein revealed that only the degree of tumor differentiation has been in statistically significant (p=0, 037) correlation with the intensity of the HER-2 protein expression. CONCLUSION: In cases of lobular infiltrative breast cancer, oncogenic effect of the HER-2 protein was associated with the degree of cellular differentiation, while it was not in correlation with other pathological parameters of poorer prognosis, such as the size of tumor, presence of vascular invasion and occurrence of metastases in regional lymph nodes.

[Craniofacial surgical treatment of the gigantic plasmacytoma of the skull base: case report]. / Kraniofacijalni hirurski tretman gigantskog plazmocitoma baze lobanje.

The complex craniofacial surgery of solitary bone plasmacytoma (SBP) of the skull base with excellent postoperative outcome was presented. This surgical management was result of the team approach and strategy of neurosurgeon (KD) and maxillofacial surgeon (TM). SBP of the skull base is very rare condition which should be treated by radical microsurgical resection and postoperative radiotherapy.

Expression of p53, bcl-2, and Ki-67 proteins in the inflammatory regenerative and dysplastic epithelial lesions of flat colonic mucosa.

The aim of the study was to define the distribution of p53, bcl-2 and Ki-67 proteins in the inflammatory-regenerative and dysplastic lesions of the colon mucosa. The relationship between the presentation of p53, bcl-2 and Ki-67 proteins and the intensity of the inflammatory-regenerative and dysplastic lesions in the colon flat mucosa was investigated as well. Biopsy specimens from 270 patients were examined: 74 were classified as inflammatory-regenerative and 196 as dysplastic lesions (108 mild, 58 moderate, and 30 severe dysplasia). The expression of all three proteins was assessed on the basis of location, quantity, and intensity of immunostaining, by counting antigen positive cells, in comparison with normal mucosa and adenocarcinoma. p53 protein appears only in sporadic cases (6.6%) of severe dysplasia. Bcl-2 expression appears significantly (p<0.005) more often in cases of mild dysplasia (61.1%) compared to inflammatory-regenerative mucosa (14.8%). In cases of mild dysplasia, bcl-2 positive cells were spreading from the lower third to the middle third of the crypts. Bcl-2 expression was maintained through the stadiums of moderate and severe dysplasia (75.8%), where antigen positive cells were found all along the crypts. A significant increase (p<0.005) in the expression of nuclear protein Ki-67 was noticed in the stadiums of moderate (labelling index =26.3) compared to mild dysplasia (labelling index=16.7), and severe (labelling index=36.7) compared to moderate dysplasia, where the zone of cellular proliferation was widen along the whole crypt length. In the process of the development of epithelial dysplasia in the flat mucosa of colon a degree of the gene p53 alteration is low and appears only in sporadic cases of severe dysplasia. Mutation of the bcl-2 gene is involved in the genesis of the lesion but not in its progression to carcinoma. Increased expression of Ki-67 protein speaks in favour of an increased cellular proliferation which, together with the above mentioned mechanisms, is involved in the process of occurrence and progression of epithelial dysplasia in the flat mucosa of colon.

[Hemangiopericytoma malignum pelvis]. / Hemangiopericitoma malignum pelvis.

Haemangiopericytoma is an uncommon tumour of vascular origin. We report a case of one of the rarer sites of this tumour in man: pelvic paravesical site. We report case of 47 years old man with pelvic hemangiopericytoma and discuss imaging studies and pathohystological findings. Although modern imaging techniques have provided useful information concerning the hypervascular and clearly demarcated appearance of this tumour which displaces but does not invade adjacent organs, its diagnosis can only be established by histology. Its degree of malignancy and its invasive potential are unclear. The risk of local recurrence and metastases in more than one half of cases justifies wide surgical excision, possibly combined with adjuvant radiotherapy, and long-term follow-up. That is to say, that hemangiopericytoma malignum pelvis is the very rare sites of this tumour and till now it is not reported in Bosnia and Herzegovina.

Giant cell fibroblastoma in a 4-year-old boy: a case report and review of the literature.

Giant cell fibroblastoma (GCF) is a rare type of fibroblastic tumor, first described as a juvenile form of dermatofibrosarcoma. Although recurrences are common after local surgical resection, metastasis is not reported.We report a case of a 4-year-old boy with giant cell fibroblastoma, in which the neoplasm was characterized histologically by a proliferation of spindle-shaped cells intermixed with pseudovascular channels called "angiectold spaces". The spaces were lined by large cells with pleomorphic nuclei intermixed with multinucleated cells. Immunohistochemically, the tumor stained diffusely for vimentin and CD34, but negative for S 100 protein. Since the initial description in 1982, less than 100 cases of GCF have been reported. This patient's presentation is particularly interesting because present the first case reported in Bosnia and Herzegovina.

Correlation of the HER-2 protein expression and other clinicopathological features of ductal infiltrative breast cancer.

The aim of the study was to investigate the relationship between the expression of the HER-2 membrane protein and other clinical-pathological parameters such as: histological size of the tumor, degree of the tumor's differentiation, presence of vascular invasion and presence of metastases in regional lymph nodes, in cases of ductal infiltrative breast cancer. We have investigated 56 cases of ductal infiltrative breast cancer. In all patients a mastectomy with a dissection of axillary lymph nodes has been performed. All tissue samples, taken by biopsy, were embedded in the paraffin, stained by hematoxylin-eosin technique and screened, and evaluation was performed by using a semiquantitative method of the immunohistochemical expression of the HER-2 protein. A decrease of the protein HER-2 expression was noticed in cases of an increase of the tumor's diameter above 50 mm. Increased expression of the HER-2 protein was noticed in cases of moderate (grade II) and poor (grade III) differentiation of carcinoma, as well as in cases where there was no metastases in the regional lymph nodes. No relationship has been observed between the expression of HER-2 and occurrence of vascular invasion. In cases of ductal infiltrative breast cancer the expression of HER-2 protein is in correlation with the size and degree of tumor's differentiation, as well as with the presence of metastases in regional lymph nodes.

[Inverted papilloma of the urinary bladder]. / Invertni papilom mokracne besike.

The inverted papilloma is relatively rare urothelial benign tumor. In 1980 was described only 108 cases of this benign proliferative lesions of bladder. Papillary fronds project into the fibrovascular stroma of the bladder rather than into the bladder lumen. The lesion is usually covered by a thin layer of normal urothelium. In Our case, tumor was found during the open adenomectomy, although patient was examined by ultrasound, before surgical treatment. One year after surgical treatment, control cystoscopic examine shows no recidive benign lesion.

Anti-cytokeratin 7: a positive marker for epithelial dysplasia in flat bowel mucosa.

The aim of this paper is to establish by immunohistochemistry the expression of keratin 7 in inflammatory-regenerative flat bowel mucosa and in different grades of epithelial dysplasia regarding the sub-units expressed in normal and carcinomatous colonic mucosa. Biopsy specimens from 270 patients were examined: 74 were classified as inflammatory-regenerative changes and 196 as dysplastic lesions. There were 108 cases of mild dysplasia, 58 cases of moderate and 30 cases of severe dysplasia, respectively). Demonstration of location and intensity of cytokeratin 7 staining was performed by immunohistochemistry using monoclonal antibody (anti-cytokeratin 7). Findings of cytokeratin 7 in dysplastic lesions were compared with those in normal mucosa, inflammatory -regenerative mucosa and adenocarcinoma. Cytokeratin 7 is not found in normal colonic mucosa. In inflammatory-regenerative mucosa it was found in solitary cells in small number of cases. It is found in all cases of epithelial dysplasia and its expression showed no difference regarding moderate and severe dysplasia. In few cases of adenocarcinoma, cytokeratin 7 is found in traces and showed minimal staining intensity. Having in mind that cytokeratine 7 is primarily found in dysplastic lesions of the flat colonic mucosa it can be a valuable diagnostic tool in the histological interpretation of epithelial dysplasia.

Type IV collagen immunoreactivity of basement membrane in inflammatory-regenerative and dysplastic lesions of the flat colonic mucosa.

UNLABELLED: The aim of this research is to establish by immunohistochemistry if there is a change in the expression of collagen type IV, as a substitute of basement membrane, in development of epithelial dysplasia in chronically inflamed colon mucosa. METHODS: Biopsy specimens from 270 patients were examined: 74 were classified as inflammatory-regenerative and 196 as dysplastic lesions. There were 108 cases of mild dysplasia, 58 cases of moderate and 30 cases severe dysplasia, respectively. Visualisation of collagen IV and its way of expression within basement membrane of glandular crypts was performed by immunohistochemistry and then compared with findings in normal colon mucosa and colon adenocarcinoma tissue. RESULTS: Changes in the expression of collagen IV comprised of its focal irregularities, diffuse thinning and/or thickening, focal interruptions or its complete absence. Significant changes in the expression of collagen IV in relation to normal mucosa already occur in inflammatory-regenerative mucosa. In mild dysplasia, these changes are more intensive in relation to those in inflammatory altered mucosa as well as at severe dysplasia in relation to moderate dysplasia. Changes in the expression of collagen IV in severe dysplasia are significantly more serious than in moderate dysplasia but are identical to those in colon adenocarcinoma tissue. CONCLUSION: These findings suggest that change in the expression of collagen IV is in correlation to a degree of epithelial dysplasia that developed in flat chronically inflamed colon mucosa.