Vol 45, No 4 (2017)

Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that catalyze the degradation reactions of the extracellular matrix components. In humans, 23 enzymes of this family are known, which are subdivided into 6 groups based on their structure and substrate types: collagenases, gelatinases, stromelysins, matrilizines, MMP membrane type and other MMPs. MMP functions are diverse, and an imbalance of their activity may be one of the etiological factors of various diseases. The review considers classification, regulation of activity and genetic polymorphism of matrix metalloproteinases in health and in various pathological processes in the human body. A list of the most studied polymorphic variants of MMP genes is given, their functional effects are described and the results of associative studies are presented.

Background: Despite comparatively favorable clinical course and satisfactory prognosis of endometrial cancer, the increase of its incidence observed in the last years both in this country and abroad requires the development of new approaches to early diagnostics, prognostic assessment and the choice of personalized postoperative management. Therefore, exploration of biological markers for fundamental tumor characteristics, such as invasion, metastasizing, proliferative activity, sensitivity to endogenous and exogenous regulators, are still on the agenda. The family of matrix metalloproteinases (MMPs) degrading the majority of extracellular matrix components and involved in all stages of tumor progression comprise a rich source of such markers.

Aim: Comparative evaluation of MMP-2, 7, 9 and their type 1 and 2 tissue inhibitors (TIMP) levels in the serum of patients with endometrial cancer and benign endometrial disease and in healthy women, and the analysis of its associations with the main clinical and pathologic characteristics of cancer for evaluation of their potential diagnostic and prognostic value.

Materials and methods: Ninety four patients with endometrial cancer and 53 women with benign endometrial lesions (28 with polyps, 25 with various degree of hyperplasia) were enrolled into the study. The age of cancer patients was 36 to 78 (median 60) years, of those with benign lesions, 20 to 79 (median 54) years. The control group involved 77 practically healthy women aged 19 to 75 (median 46) years. The concentrations of the markers studied were measured by direct enzyme immunoassay (ELISA) kits (Quantikine, R&D Systems, USA).

Results: A significant increase of MMP-7 and TIMP-2 levels was demonstrated both in cancer patients (median values 5.5 and 96.9 ng/ml, respectively) and in those with benign endometrial lesions (median values 5.7 and 73.2 ng/ml, respectively) as compared to the control (median values 2.1 and 60.7 ng/ml, respectively). The ROC curve allowed to establish a cutoff level for MMP-7 (3.5 ng/ml) with good sensitivity/specificity ratio for endometrial cancer (88% and 87% respectively); however, it did not allow for differentiating between benign and malignant endometrial lesions. On the contrary, MMP-2, MMP-9 and TIMP-1 levels were 1.2-1.3-fold decreased in patients with cancer and benign endometrial diseases as compared to the control; MMP-9 and TIMP-1 levels in cancer patients were also lower than in those with endometrial polyps and hyperplasia. There were no significant associations between the levels of the markers studied and the indices of progression, histological type and grade of endometrial cancer. Also, no differences between the marker levels in serum of patients with polyps or various endometrial hyperplasias were identified.

Conclusion: MMPs and TIMPs assessed in this study cannot be considered as potential diagnostic markers of endometrial cancer; however, they might be useful for disease monitoring, prognosis assessment and evaluation of sensitivity to targeted therapy.

Background: The results of immunohistochemical (IHC) assessment in breast cancer may determine not only the outcome, but also the main directions of antitumor treatment.

Aim: To study the results of IHC diagnosis of breast cancer in the Grodno region in 2010 to 2015, to determine the frequency of the BRCA1 gene mutations in triple-negative breast cancer.

Materials and methods: 2008 cases of estrogen receptor and/or progesterone receptor positive and 2445 cases of HER2/neu expressing breast cancer were extracted from the database and IHC laboratory journals of the Grodno Regional Clinical Bureau for Pathological Anatomy. Standard DAKO kits (Denmark) were used for IHC. Molecular genetic studies of DNA samples for the presence of the BRCA genes mutations were done by polymerase chain reaction in 449 women with breast cancer. BRCA1 mutation was assessed in 39 cases of triple-negative breast cancer.

Results: HER2/neu overexpression (3+) was found in 25.5% (622/2445) of all breast cancer cases, whereas of estrogen receptor and progesterone receptor positive tumors in 50.05% (1105/2008) of cases. Triple negative breast cancer was diagnosed in 19.8% (398/2008) of cases, and the mean age of the patients at the diagnosis was 56.2 years. The BRCA1 gene mutations were identified in 5 of 39 (12.8%) cases of triple negative breast cancer, which is significantly more often than in women with breast cancer without consideration of their hereditary predisposition (17/449, or 3.8%; χ2 = 4.87, p = 0.0274). Histological examination showed that among the tumors with the BRCA1 mutations, there were 3 cases with invasive ductal cancer (one G2 and two G3), one with medullary and one with undifferentiated G3 cancer. One patient had a metachronous bilateral lesion.

Conclusion: In the region of Grodno, 50% of breast cancer patients would need hormonal therapy, 25% would need treatment with trastuzumab, and 20% with cytostatic agents. The prevalence of the BRCA1 mutation in triple negative breast cancer is higher compared to that in breast cancer patients without consideration of their hereditary predisposition.

Background: Treatment of large basaliomas may be problematic, because relapses after the use of various treatment modalities are frequent.

Aim: To assess the efficacy of interferon therapy for primary solitary T2N0M0 basalioma.

Materials and methods: We retrospectively analyzed the results of treatment of 72 patients with primary solitary basalioma T2N0M0. The patients from the main group (n = 35) were treated with injections of recombinant interferon alfa 2b into the lesion at a dose of 2 to 3 Mio IU (total dose for the treatment course from 18 to 27 Mio IU). The reference group included 37 patients treated by cryodestruction. The results were assessed at 8 weeks after the end of interferon therapy and at 3 months after cryotherapy. The cure was confirmed cytologically at 3 months after clinical reconvalescence (formation of the scarring atrophy area or re-epithelization).

Results: The treatment was effective in 100% (35/35) of the patients from the main group. Twenty nine (82.9%) cases of basalioma required two courses of interferon therapy, 5 (14.3%) cases 3 courses, and one case (2.8%) 4 courses. In the reference group, 94.6% (35/37) of patients were cured. The difference between the proportions of the cured patients between the two groups was 5.4% (confidence interval (CI) -5.2–17.7%). Within the next 3 years of the follow-up there were no relapses in the main group, whereas the relapses were diagnosed in 9 (24.3%) of the patients from the reference group. The difference of the proportions between the two groups was 24.3% (CI 9.6–40%).

Conclusion: Based on the short- and long-term results, the efficacy of intralesional interferon administration in basalioma T2N0M0 was 100%. For tumors of more than 2 cm², an increase of the single and the total cumulative dose of recombinant interferon alfa 2b is necessary, as well as several courses of interferon treatment. Interferon therapy is more effective than cryodestruction based on the 3-year relapse-free survival.

Rationale: Prevalence of neoplasms in patients with acromegaly and the effects of various risk factors on their development have been insufficiently studied.

Aim: To assess the prevalence of thyroid, gastric and colon neoplasms in patients with newly diagnosed acromegaly, depending on their age, gender, duration and activity of the underlying disease.

Materials and methods: We retrospectively analyzed data extracted from out- and in-patient medical files of 108 patients with acromegaly (25 male, 93 female). Their median age was 50.5 [range 39.3 to 59] years, median duration of acromegaly 5 [range 2 to 10] years (starting from the first appearance of the first physique abnormalities). Thyroid ultrasound was performed in 96 patients, gastroscopy in 92, and colonoscopy in 89.

Results: Benign thyroid nodules were found in 50% (48/96) of patients, malignant thyroid nodules in 6.2% (6/96). Insulinlike growth factor 1 (IGF-1) levels (calculated as a percentage above upper limit of the normal range) in patients with thyroid cancer was 2.3-fold higher than in patients without nodular thyroid disease and 2-fold higher than in patients with benign thyroid nodules (р < 0.012 and p < 0.03, respectively). Malignant neoplasms were more often seen in the elderly (above 60 years of age), compared to younger adults (45 to 60 years) (30.8% and 4.3% of patients, respectively, p = 0.01). Male patients had higher prevalence of thyroid cancer than female (11.1% and 5.1%, respectively). Benign gastrointestinal neoplasms were observed in 51.7% of patients (18% had gastric polyps and 37% colon polyps). Age and duration of acromegaly in patients with gastric neoplasms were higher, than in those without them (р = 0.015 and p = 0.036, respectively). Colon neoplasms consisted of hyperplastic polyps (33.7%) and colon cancer (3% of patients). Patients with colon neoplasms were 11 years older than those without it (p = 0.015).

Conclusion: Gastrointestinal tract and thyroid gland should be diagnostically assessed in all patients at diagnosis of acromegaly, because of the higher risk of the neoplasms in these patients. The association of higher IGF-1 levels with thyroid cancer indicates that this factor may contribute to carcinogenesis and requires further studies.

In addition to abdominal ultrasound and chest X-ray, positron emission tomography combined with computed tomography (PET/CT) has been increasingly used to diagnose metastatic disease in patients with uveal melanoma. We present two clinical cases of the second malignancy (synchronous polyneoplasia, colon cancer) that was eventually found during PET/CT in uveal melanoma patients performed to exclude dissemination of the neoplasm. It was shown that hybrid PET/CT is the most informative method in the diagnosis and monitoring of uveal melanoma patients. During one diagnostic procedure it enables to diagnose early stages of secondary malignancies, in addition to the assessment of metastatic dissemination.