Tumor Budding as a Prognostic Marker in Primary Colon Cancer - A Single Center Experience.

Introduction: Tumor budding (TB) is considered to be a morphological and prognostic factor relevant to colon cancer (CC). The aim of our study is to assess the TB and to evaluate its relationship to clinicopathological findings within stage II and III CC patients as a single center experience. Materials and methods: A total of 120 CC patients operated between 2018 and 2021 at the University Clinic of Digestive Surgery in Skopje, the Republic of North Macedonia were included in this retrospective, single center study. TB was evaluated by the magnification of 200x along the invasive front of the primary tumor on H&E and CKAE1/AE3 immunohistochemically stained sections. Two grades were used: low grade (TB1, 0-4 TBs) and high-grade, which includes intermediate (TB2, 5-9 TBs) and high grade (TB3 ≥10TBs) of TBs. Results: A statistically significant correlation has been identified between high-grade TB and age (p=0.05) of the patients. There was also a significantly higher occurrence of high-grade TB in patients within stage III CC. Statistically significant correlations were also found in lymph node status (p<0.01), vascular invasion (p<0.05), lymphatic invasion (p<0.01), postoperative relapse (p<0.01), and death (p<0.01). Tumor relapse and death were significantly more frequent in patients with high-grade TB than those with low-grade TB. Patients with registered high-grade TB demonstrated significantly lower relapse-free survival (RFS) and overall survival (OS) rates than patients with low-grade TB over the observation period (RFS: 53.8% vs. 98.5%, p<0.001; OS: 65.4% vs. 97.1%, p<0.001, respectively). Patients with lung and liver postoperative relapses had higher percentage of cases with high-grade TB (94.1%). Conclusion: Our results are highly suggestive that TB should be included as a histological biomarker in the pathology report of patients with stage II and stage III CC, because of its prognostic value.

Low-grade malignancy glomus tumor of the abdominal wall: a case report and literature review.

Glomus tumors are painful neoplasms arising from the glomus body (responsible for body temperature and blood pressure regulation) in the skin. Although mostly present in the interdigital areas, glomus tumors can arise elsewhere. The vast majority of them are benign. Rarely, malignant variants are reported and are associated with the potential for local infiltration and metastatic dissemination. The abdominal wall location of glomus tumors is extremely rare regardless of whether they present as benign or malignant. We present a case of a 58-year-old female patient with a low-grade malignancy infiltrative glomus tumor of the abdominal wall.

Ultrasound-guided Biopsy of Musculoskeletal Soft-tissue Tumors: Basic Principles, Usefulness and Limitations.

The aim of this article is to provide a short review of the literature concerning the basic principles, usefulness and limitations of ultrasound-guided biopsy of musculoskeletal soft-tissue tumors, with particular focus on core needle biopsies. Musculoskeletal soft-tissue tumors represent a rare and complex group of heterogeneous lesions. Prompt diagnosis of these uncommon lesions can improve the outcome and increase the patient survival rate. A biopsy examination of soft-tissue tumors with imaging modalities is necessary in all cases of aggressive or undetermined lesions. Although fine needle aspiration can be helpful for the biopsy of certain tumor types, core needle biopsy is a standard procedure in most tertiary sarcoma centers. It has a high diagnostic accuracy, low complication rate and lower price in comparison to open biopsy, and can replace it in the majority of cases of soft-tissue tumor assessment. However, the examining physician has to be familiar with the technique, and the strengths and potential difficulties in performing ultrasound-guided biopsy, as well as possible solutions to obstacles. Several recently developed ultrasound techniques can be helpful and improve the outcome of imaging-guided biopsies of musculoskeletal lesions.

Signet ring cell carcinoma of rectum metastasizing to synchronous renal cell carcinoma: a case report.

BACKGROUND: Rectal signet ring cell carcinoma is a rare type of colorectal adenocarcinoma characterized by an aggressive biological behavior and poor prognosis. The co-occurrence of colorectal carcinoma and renal cell carcinoma (RCC) has found in many hundreds of patients, many of whom also have additional malignancies. Cancer to cancer metastasis is rare and an uncommon phenomenon in malignancy, especially at the time of initial diagnosis, suggesting a genetic susceptibility. CASE PRESENTATION: We present the case of a 66-year-old Macedonian man with synchronous rectal signet ring cell carcinoma and RCC with tumor to tumor metastasis feature. He underwent a left nephrectomy and anterior rectal resection after complaining of constipation for 3-4 months and the appearance of synchronous tumors on the imaging studies. Morphology and immunohistochemical analysis of specimens from the RCC revealed signet ring cells identical to the rectal signet ring cell carcinoma. The next-generation sequencing study revealed mutations in TP53 and ERBB2, and microsatellite stable signet ring cell carcinoma was determined by deoxyribonucleic acid (DNA) sequencing. CONCLUSIONS: Cancer to cancer metastasis, although rare, needs to be considered in synchronous tumors. RCC, when diagnosed in multiple synchronous tumors, should be examined carefully. The paucity of reported cases indicates the need for advanced research in imaging methods for metastasis and new therapeutic approaches.

A Rare Case of Soft Tissue Erdheim Chester Disease: Diagnostic Dilemma and Management.

BACKGROUND: Erdheim Chester disease (ECD) is a rare form of non-Langerhans histiocytosis that still presents a diagnostic and clinical dilemma. CASE PRESENTATION: We present a rare case of ECD, young 31 male with atypical localisation and soft tissue presentation and no bone involvement. He started clinical investigations due to subcutaneous tumour mass in the lumbar spine that caused severe back pain. Skin biopsy revealed ECD with Immunohistochemistry CD68+, CD10+, CD11c+, vimentin+, S100A4+. Activating BRAFV600E mutation was positive from the tumour tissue. The patient was referred to the haematology department. PET CT was performed for initial disease staging. Treatment was started with corticosteroids (methylprednisolone 0.5 mg/kg per day), and after 7 days, a significant clinical improvement was noticed in terms of pain disappearance with no need for pain killers. After two weeks, treatment with interferon Alfa (IFN-α) was started in a dose of 3 million units 3 times per week. After 4 months of interim treatment PET, CT revealed a significant reduction of the tumour mass. Therapy with IFN-α was continued, and the patient is still clinically in good condition. CONCLUSION: It can be concluded that shortening the time of diagnosis of ECD is essential in treatment outcome of this disease. Still, large studies have to confirm the best treatment of this rare condition.

Standardization and optimization of fluorescence in situ hybridization (FISH) for HER-2 assessment in breast cancer: A single center experience.

Accurate assessment of human epidermal growth factor receptor 2 (HER-2) is crucial in selecting patients for targeted therapy. Commonly used methods for HER-2 testing are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Here we presented the implementation, optimization and standardization of two FISH protocols using breast cancer samples and assessed the impact of pre-analytical and analytical factors on HER-2 testing. Formalin fixed paraffin embedded (FFPE) tissue samples from 70 breast cancer patients were tested for HER-2 using PathVysion™ HER-2 DNA Probe Kit and two different paraffin pretreatment kits, Vysis/Abbott Paraffin Pretreatment Reagent Kit (40 samples) and DAKO Histology FISH Accessory Kit (30 samples). The concordance between FISH and IHC results was determined. Pre-analytical and analytical factors (i.e., fixation, baking, digestion, and post-hybridization washing) affected the efficiency and quality of hybridization. The overall hybridization success in our study was 98.6% (69/70); the failure rate was 1.4%. The DAKO pretreatment kit was more time-efficient and resulted in more uniform signals that were easier to interpret, compared to the Vysis/Abbott kit. The overall concordance between IHC and FISH was 84.06%, kappa coefficient 0.5976 (p < 0.0001). The greatest discordance (82%) between IHC and FISH was observed in IHC 2+ group. A standardized FISH protocol for HER-2 assessment, with high hybridization efficiency, is necessary due to variability in tissue processing and individual tissue characteristics. Differences in the pre-analytical and analytical steps can affect the hybridization quality and efficiency. The use of DAKO pretreatment kit is time-saving and cost-effective.

Endometrioid Adenocarcinoma Arising in Adenomyoma in a Woman with a Genital Prolapse - Case Report.

BACKGROUND: Endometrial cancer is the third-ranked genital malignancy in women and includes 3% of cancer deaths. There is a 2.8% chance of a woman developing endometrial cancer during her lifetime. Low-grade endometrioid adenocarcinomas are often seen along with endometrial hyperplasia, but high-grade endometrioid adenocarcinomas have more solid sheets of less-differentiated tumour cells, which are no longer organised into glands, often associated with surrounded atrophic endometrium. CASE REPORT: We present an unusual case of endometrial adenocarcinoma arising in adenomyoma in 74-year old woman presented with genital prolapse, without other clinical symptoms. Ultrasound evaluation revealed endometrium with 4 mm-thickness and atrophic ovaries. The cervical smear was normal. The patient underwent a total vaginal hysterectomy. The histopathology of the anterior uterine wall revealed an intramural adenomyoma of 4 mm in which some endometrial glands with malignant transformation of well-differentiated endometrioid adenocarcinoma without infiltration in surrounding myometrium and lymphovascular invasion were present. The endometrium lining the uterine cavity was predominantly atrophic, and only one focus of simplex and complex hyperplasia was found, with cell-atypia. According to AJCC/FIGO 2010, the tumour was classified: pTNM = pT1B pNX pMX G1 R0 L0 V0 NG1, Stage I. On dismiss, the near-future oncological consultation was recommended. CONCLUSION: We would like to point out the rare occurrence of such type of malignancy and the importance of meticulous histopathology evaluation, even after reconstructive surgery for genital prolapse.

Thyroid cancer detection rate and associated risk factors in patients with thyroid nodules classified as Bethesda category III.

Background Ultrasound guided fine-needle aspiration (FNA) is a standard procedure for thyroid nodules management and selecting patients for surgical treatment. Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS), as stated by The Bethesda System for Reporting Thyroid Cytopathology, is a diagnostic category with an implied malignancy risk of 5-15%. The aim of our study was to review cytology and histopathology reports, as well as clinical and ultrasound data, for thyroid nodules reported as AUS/FLUS, in order to evaluate the malignancy rate and to assess factors associated with malignant outcome. Patients and methods A total of 112 AUS/FLUS thyroid nodules in 105 patients were evaluated, of which 85 (75.9%) were referred to surgery, 21 (18.8%) were followed-up by repeat FNA and 6 nodules (5.3%) were clinically observed. Each was categorized in two final diagnostic groups - benign or malignant, which were further compared to clinical data of patients and ultrasonographic features of the nodules. Results Final diagnosis of malignancy was reached in 35 cases (31.2%) and 77 (68.8%) had benign lesions. The most frequent type of cancer was papillary thyroid carcinoma (PTC) - 58.1% PTC and 25.8% had follicular variant of PTC. Patients' younger age, smaller nodule size, hypoechoic nodule and presence of calcifications were shown to be statistically significant risk factors for malignancy. Conclusions The rate of malignancy for the AUS/FLUS diagnostic category in our study was higher than estimated by the Bethesda System. Clinical and ultrasound factors should be considered when decision for patient treatment is being made.

Correlation of Immunohistochemistry and Fluorescence in Situ Hybridization for HER-2 Assessment in Breast Cancer Patients: Single Centre Experience.

BACKGROUND: Accurate assessment of HER-2 is imperative in selecting patients for targeted therapy. Most commonly used test methods for HER-2 are immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH). We evaluated the concordance between FISH and IHC for HER-2 in breast cancer samples using Food and Drug Administration approved tests. MATERIAL AND METHODS: Archived paraffin tissue blocks from 73 breast cancer patients were used. HER-2 immunostaining was performed using Ventana anti-HER-2 monoclonal antibody. The FISH assay was performed using PathVysion™ HER-2 DNA Probe Kit. RESULTS: Of the 73 cases 68.5% were IHC 0/1+, 15.07% were IHC 2+ and 16.44% were IHC 3+. Successful hybridisation was achieved in 72 cases. HER-2 FISH amplification was determined in 16.67% cases. Ten IHC 3+ and two IHC 2+ cases were FISH positive. Two of the IHC 3+ cases were FISH negative. Concordance rate was 100%, 18.18% and 83.33% for IHC 0/1+, 2+ and 3+ group, respectively. Total concordance was 84.72%, kappa 0.598 (p < 0.0001). The sensitivity of IHC in detecting IHC 2+ and IHC 3+ cases was 16.7% and 83.3%, and the specificity was 85% and 96.67%, respectively. CONCLUSION: The consistency between the methods was highest for IHC negative and lowest for IHC equivocal cases. The immunohistochemistry showed high sensitivity for IHC 2+/3+ cases and high specificity for IHC 3+ cases. Our results support the view that false-positive rather than false-negative IHC results are a problem with HER-2/IHC testing, and that IHC should be used as an initial screening test, but IHC 2+/ 3+ results should be confirmed by FISH.

Factors That Influence Surgical Margin State in Patients Undergoing Cold Knife Conization - A Single Center Experience.

AIM: To evaluate the factors that influence the surgical margin state in patients undergoing cold knife conization at the University Clinic of Gynecology and Obstetrics in Skopje, Republic of Macedonia Materials and methods: We have retrospectively analyzed the medical records of all patients that underwent a cold knife conization at our Clinic in 2015. We cross-referenced the surgical margin state with the histopathological diagnosis (LSIL, HSIL or micro-invasive/invasive cancer), menopausal status of the patients, number of pregnancies, surgeon experience, operating time and cone depth. The data was analyzed with the Chi square test, Fisher's exact test for categorical data and Student's T test for continuous data and univariate and multivariate logistical regressions were performed. RESULTS: A total of 246 medical records have neen analyzed, out of which 29 (11.79%) patients had LSIL, 194 (78.86%) had HSIL and 23 (9.34%) patients suffered micro-invasive/invasive cervical cancer. The surgical margins were positive in 78 (31.7%) of the patients. The average age of the patients was 41.13 and 35 (14.23%) of the patients were menopausal. The multivariate logistic regression identified preoperative forceps biopsy of micro-invasive SCC, HSIL or higher cone specimen histology and shorter cone depth as independent predictors of surgical margin involvement in patients undergoing cold knife conization. CONCLUSION: In the current study, we have found no association between the inherent characteristics of the patient and the surgeon and the surgical margin state after a CKC. The most important predictors for positive margins were the severity of the lesion and the cone depth.

Survival of Advanced Stage High-Grade Serous Ovarian Cancer Patients in the Republic of Macedonia.

AIM: The primary objective of the study was to evaluate the overall survival of women with advanced stage (Stage IIIA-IV) high-grade serous ovarian cancer in Macedonia. MATERIALS AND METHODS: The study was a cross-sectional medical record review of patients diagnosed with advanced stage HGSC. Patients were deemed eligible for inclusion if they were diagnosed with an advanced stage (Stage IIIA-IV) HGSC of the ovary, fallopian tube or peritoneum between 2009 and 2015. The data were analyzed in a descriptive fashion and summary statistics were provided, as appropriate. Survival was calculated using the Kaplan-Meier method. RESULTS: A total of 81 eligible patients were identified and included in the study. The average overall survival in the studied cohort was 46.59 months (95%CI = 39.11-54.06). Patients that were optimally debulked and patients that had a platinum-free interval larger than 12 months had significantly longer survival in the current series (p < 0.001). CONCLUSION: the average overall survival of advanced stage HGSC patients in the studied series was 46.59 months (95%CI = 39.11-54.06). Patients aged 65 years or younger tended to live approximately ten months longer than patients older than 65 years, but this difference was not statistically significant. There was no difference in HGSC survival in the groups of patients with grade 2 and grade 3 disease. However, optimal surgical debulking and platinum sensitivity were associated with significantly better overall survival.

[The possible pathogenesis of AA type amyloidosis in a patient with ulcerative colitis and renal cell carcinoma]. / Sistemna amiloidoza tipa AA u bolesnika s ulceroznim kolitisom i bubreznim karcinomom.

A 43-year-old male with a two-month history of ulcerative colitis and nephrectomy due to a renal cell carcinoma performed a month before was admitted to University Department of Nephrology for nephrotic syndrome and chronic renal failure. Biopsy of the remnant kidney revealed secondary AA amyloidosis with deposits in the glomeruli and walls of intrarenal blood vessels. Re-evaluation of the nephrectomized kidney also showed amyloid deposits both in the renal tissue free from malignant cells and in tumor tissue. In this case the amyloid deposition may have been the result of two coexisting disorders, ulcerative colitis and renal cell carcinoma, both known to be stimulators of amyloid deposition. The remnant kidney function worsened during the follow up and the patients started chronic dialysis after 6 months.

Non-Tumor Cystic Lesions of the Adrenal Gland.

UNLABELLED: Adrenal cystic lesions are uncommon but due to the improved radiologic imaging techniques their appearance seems to increase. MATERIAL AND METHODS: We analyzed the clinical and radiological findings of 10 patients with adrenal cysts and the pathological features of the operative material. Standard dissection procedure and paraffin embedded tissue sections were made, stained by HE and immunohistochemically with CD34, CD 31, Factor 8, Podoplanin, CKWS and AE1/AE3 RESULTS: The mean age of the patients was 40.6 years; female to male ratio was 2.3:1. All the cysts were diagnosed as cystic lesions radiologically except one. The most present clinical symptom was abdominal pain. The diameter of the cysts measured from 2 to 7 cm. Four of the cysts were diagnosed as pseudocysts and six as endothelial. Six cysts were lined by CD34(+) and CD31(+) cells, four were lined by Factor 8(+) and podoplanin(+) cells and four had no lining. CONCLUSION: Endothelial cysts were more common cysts in our study and the immunohistochemical results suggested common vascular origin to all endothelial cysts and supported additional separation of angiomatous and lymphangiomathous adrenal vascular cysts.

Incidence of urinary tract tumours in a two-year period (2010-2011) at the Institute of Pathology, Faculty of Medicine, Skopje, Macedonia.

We performed a retrospective analysis of tumours of the kidneys and the lower urinary tract diagnosed at the Institute of Pathology, Faculty of Medicine, Ss. Cyril and Methodius University, Skopje, Macedonia, in a two-year period (2010-2011), with the aim of highlighting the main morphological characteristics and to present the statistical features of these tumours. All the cases were diagnosed on paraffin sections from surgical specimens routinely stained with H&E, and immunohistochemically with a panel of monoclonal antibodies. The analysis revealed a total of 755 cases, of which 166 (14%) were located in the kidney including the renal pelvis, and 649 (86%) were tumours of the urinary bladder. Twelve of the renal tumours (11.3%) were benign, and the rest were malignant tumours. Most of them were adenocarcinomas (n=77; 72.6%) and 17 cases (16%) were transitional cell carcinomas originating from the renal pelvis. The analysis of the lower urinary tract tumours showed a strong prevalence of malignant urothelial tumours (96%), with a male to female ratio of almost 4:1. Low grade morphology was a predominant feature (71.7%) and 51 cases (22.9%) were of high grade. The percentage of urothelial tumours of the kidney in our series is higher than in most of the reported series, which should lead to an expanded analysis.

Histomorphometric analysis of fibrosis in the renal interstitial compartment.

The interstitium is the extravascular intertubular space of the renal parenchyma, which provides structural support to the functional renal units and is included at the same time in nearly all renal functions. Alterations to this renal compartment have been found in almost all glomerular diseases. During the last thirty years the studies of a few groups of investigators have shown that the degree of the renal dysfunction is strongly correlated with the changes in the tubulointerstitial compartment. We made a morphometric study of a group of 10 renal biopsies, previously diagnosed as IgA nephropathy or membranoproliferative glomerulonephritis. For morphometric analysis we made colour extraction of the interstitial area on tissue sections stained with trichrom Masson using the LUCIA M-NIKON image analysing system with integrated software for statistical analysis of the data. We measured the surface of the marked fields and the results were expressed as a percentage of the total scanned area. The results were correlated with the serum creatinine at the time of biopsy. We found fibrosis occupying more than 10% of the tubulointerstitial surface in all 10 patients. Six of them had a moderate level of fibrosis, occupying more that 20% of the tubulointerstitial space. The statistical analysis of these results showed a significant correlation between the degree of the interstitial expansion and the serum creatinine. The results showing the correlation between these parameters will enable the quantitative histological analyses to be included in the process of the nephropathological diagnosis in order to evaluate the histological risk factors in glomerular diseases.