Faculty of Medicine

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Endometrial adenocarcinoma occuring in young women
(Hellenic Division of International Academy of Pathology, 2003-05)
Kubelka-Sabit, Katerina
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Prodanova, Irina
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Yashar, Genghis
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Zografski, George
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Background: Endometrial adenocarcinoma (EA) primarily occurs in postmenopausal women. Only 1-8% of the cases are diagnosed in women under forty years of age, while this neoplasm is extremely rare in the third decade. Hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy (HSOPL) is the treatment of choice for older or patients with invasive EA. However, in young women with non-invasive well-differentiated EAs, who wish to preserve their fertility, conservative treatment with progestins can be tried. Aims: The purpose of this retrospective study is to present the clinical and morphologic characteristics, as well as the immunohistochemical profile of 3 cases of well-differentiated EAs, that occurred in women in their third decade of life. Since the neoplasms were non-invasive, an attempt to preserve their fertility has been made. Methods and patients: Six of the 1081 cases (0.5%) of EA diagnosed at the Department of Histopathology and Clinical Cytology in the last 14-year period (1989-2002), occurred in patients younger than 35 years. Three of them (1.4%, 3/206), have been diagnosed in the last two years (2001-2002). The youngest of the last three patients (age 21), had a genetic abnormality (45X/47XXX) and experienced prolonged and heavy uterine bleedings that required explorative curettage. The second patient (age 25) had a history of diabetes and infertility. The neoplasm was found in the endometrial biopsy that was taken for evaluation of the endometrial response to hormonal stimulation. In the third patient (age 27) the neoplasm was an accidental finding in the cervical curettage material that was submitted to our department, for histopathologic reevaluation of the previously diagnosed moderate dysplasia of the epithelium of the uterine cervix. The materials, obtained either by dilatation and curettage (3 cases) or HSOPL (one case), were submitted to our department and were routinely processed. Standard hematoxylin and eosin (H&E) stained slides were prepared from paraffin blocks, whereas additional histochemical (PAS, alcian blue, azan, silver by Jones) and immunohistochemical stains (estrogen-ER, progesterone-PgR, p53, Ki-67) were performed on selected paraffin blocks that contained the neoplastic tissue. Results: In the curettage materials of the three patients, fragments of endometrial polyp were identfied, that contained areas of simple, complex and atypical hyperplasia. In each of these cases, only few small (1-3-millimetre in diameter) foci of well-differentiated EA were detected. Fragments of functional endometrium were also present. All three patients had hormone (ER, PgR) responsive neoplasms, whereas Ki-67 proliferative index was significantly higher in the neoplastic tissue (30-40%), compared to the zones of atypical hyperplasia (10-20%). The suppressor gene protein product p53 was negative in all three EAs. Subsequent dilatation and curettage to remove the residual parts of the polyp was performed in two of the patients. Conservative 5-6-month treatment with progestins led to regression of the disease in all patients, documented by endoscopy and curettage in two patients. As for the youngest patient, clinical decision for HSOPL has been made, and multiple sections of the operative material did not show any residual EA. Conclusions: Even though extremely rare, EAS may occur in asymptomatic patient and/or in young women without clinical evidence of polycystic ovary disease. In these patients careful histopathologic evaluation of the curettage material is essential, in order to select the ones to whom conservative fertility-preserving treatment can be offered.
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Malignant diffuse peritoneal leiomyomatosis: A case report
(Expansion Scientifique Publications, 1998-10)
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Ivkovski, Ljube
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Yashar, Genghis
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Veljanovska, Slavica
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Vuzevski, Vojislav
Diffuse peritoneal leiomyomatosis (DPL) is a rare condition characterized by the presence of multiple abdominal smooth muscle nodules. Malignant transformation appears to be extremely rare. This report presents the eighth case with proven malignancy. The patient is a 43 year old, Caucasian, non-pregnant female, with no history of hormonal therapy, presented with a few months old history of intermittent and increasing right lower abdominal pain. In October 1996, explorative laparatomy was performed. Innumerable subperitoneal gray-white masses with firm to rubbery consistency, varying in size from 0.2 to 11.5 cm, were found scattered over the parietal peritoneum, omentum and mesentery. Several of these nodules were removed. Their microscopic appearance was variable. Most of the lesions appeared to consist of subperitonel nodules of benign-appearing smooth muscle cells. Nevertheless, some of them showed malignant characteristics, marked cellularity, and numerous mitoses. Immunohistochemical and ultrastuctural studies proved the smooth muscle origin of the tumors. During the next few months the abdominal tumors increased in size and the patient's condition progressively deteriorated. A second laparotomy was performed in March 1997. More than 40 nodules were removed together with a small bowel segment where inflammatory fistula was found. After receiving three courses of chemotherapy, the patient refused further treatment. In December 1997, the patient was admitted to the hospital with acute abdominal pain due to ileus, and the third laparotomy was performed. This additional case indicates that DPL has a low, but definite malignant potential, and suggests that meticulous examination of histologic material and careful follow up are required.
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Small and large cell neuroendocrine carcinomas of the uterine cervix. A report of 10 cases.
(Springer, 2005-08)
Kubelka-Sabit, Katerina
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Plaseska-Karanfilska, Dijana
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Prodanova, Irina
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Yashar, Genghis
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Hadzi-Nicheva, Biljana
BACKGROUND: Small (SCC) and large cell (LCC) neuroendocrine carcinomas of the uterine cervix are rare and highly aggressive neoplasms. Their association with the integration of human papilloma virus (HPV) DNA of the types 16 or 18 has been documented in many studies. AIMS: The purpose of this study is to present the clinical, histopathological, immunohistochemical characteristics and the presence of HPV DNA in ten cases of SCCs and LCCs of the uterine cervix. METHODS: Seven patients with primary SCCs and three patients with LCCs of the uterine cervix were diagnosed at our department between 1989 and 2004. Clinical data were retrieved from the patients’ files and included age, recurrence and survival. Routinely processed operative and/or biopsy specimens were used for immunohistochemical stains and hybridization procedures. Primary antibodies against several epithelial, neuroendocrine, mesenchimal and proliferative markers were included. The presence of HPV DNA was assessed by conventional in situ hybridization (ISH) using probes for HPV 16/18 and 31/33/51 and polymerase chain reaction (PCR), using three primers (MY09/11, GP5+/GP6+, E6). Six of the patients were surgically treated. Postoperatively, four received chemo and/or radiotherapy, two rejected further treatment and one patient was lost to follow-up. The other four patients underwent conservative treatment due to advanced disease. RESULTS: The patients’ age ranged from 25 to 71 years. Histologically, the tumors showed trabecular, nesting or a sheet-like pattern, with areas of necrosis and frequent mitoses. Their neuroendocrine nature was confirmed by diffuse positive immunostaining for neuron-specific enolase and low-molecular weight cytokeratins. Focal positivity for chromogranin, synaptophysin and S100, together with pancytokeratin and EMA, was evident in the majority of the tumors. Their aggressive potential was confirmed by high Ki-67 proliferative index (50-90%). HPV types 16/18 were found in 4 tumors using ISH, and HPV 16 in additional 3, using PCR (type 16). 3 of the patients developed distant metastases and died 7-48 months after receiving partial or full treatment, while 6 are alive and without evidence of disease after 4-38 months. CONCLUSIONS: SCCs and LCCs are highly aggressive neoplasms. However, early diagnosis and combined therapy may improve survival in some patients. Although mainly a morphologic diagnosis, immunohistochemistry may help in the diagnosis of SCC and LCC.
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Benign and malignant pigmented lesions of the female genital tract (FGT). Report of 15 cases.
(Springer, 2001-09)
Kubelka, Katerina
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Yashar, Genghis
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Prodanova, Irina
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Ivkovski, Ljube
Introduction: Benign and malignant pigmented lesions (PL) of the FGT are uncommon, predominantly affecting the vulva. Methods: We report the clinical and pathological features of the 15 PL of the FGT retrieved in a 12-year, retrospective analysis at our Department. Patient records and archival pathology specimens of 7 benign and 8 malignant PL of the FGT, were reviewed. Results: The mean age of all patients was 47 (range, 28-67). Three patients had vulvar nevi (2 intradermal and 1 dysplastic), while blue nevi ranging 2-10 mm in diameter were accidentally discovered in the endocervix of the hysterectomy specimens in four other patients. Vulvar primary malignant melanomas (PMMs) were uncommon (4 cases), comprising 2.5% of female PMMs and 4.3% of all vulvar malignancies diagnosed between 1989 and 2000. Contrary to other studies, all vulvar PMM in our series were of nodular type, ranging 3-13 mm in depth according to Breslow and III-IV level according to Clark. Within the same period, two patients with malignant PL of the uterine cervix were detected, accounting for 0.13% of all females with malignant cervical neoplasms. One of them had a PMM diagnosed in advanced clinical stage (FIGO III), and the other patient had an unusual pigmented squamous cell carcinoma in liB postoperative stage. There were also 2 cases of delayed unilateral ovarian metastases of cutaneous PMM. The diagnosis in all cases of non-vulvar pigmented lesions was confirmed by immunohistochemistry. Conclusions: Although uncommon, PL especially those affecting rare localizations must be considered as diagnostic possibility in FGT.
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Myoepithelial carcinoma of the breast arising in adenomyoepithelioma. A case report.
(Springer, 2001-09)
Yashar, Genghis
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Ivkovski, Ljube
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Kubelka, Katerina
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Zografski, George
Introduction: Adenomyoepithelioma (AME), and especially myoepithelial carcinoma (MC), the malignant variant of this tumor, is a rare breast neoplasm. This report comprises the pathological features of a breast MC arising in AME with an aggressive clinical course. Case report: A 48-year old woman with a palpable mass in the right breast was admitted in November 1998. A month later following FNAB, surgical excision was performed. During the follow-up period of 17 months, until the patient's death, two local recurrences developed. Despite the aggressive chemotherapy, administrated after the first recurrence, subsequently bone, pulmonary and brain metastases appeared. Results: The primary tumor was an ovoid, white-grey, encapsulated mass measuring 4x3,5x1,5 cm. Microscopically, this biphasic tumor was composed of rare tubules surrounded by interlacing bundles of spindle cells exhibiting mild atypia. It was initially classified as a benign phyllodes tumor. The immunohistochemical analyses performed after the second recurrence proved the myoepithelial origin of the neoplasm (S-100, cytokeratin and alpha-SMA positive cells), with a high mitotic index (11 MF/10 HPF), and an immunophenotype indicating aggressive biological potential (steroid receptor negative, 50% Ki-67 and 30% p53 positive cells). Therefore, it was reclassified as MC arising in spindle cell type of AME. Conclusion: The histopathological diagnosis of AME could be very difficult, especially when a distinction from other spindle cell breast neoplasms must be done. Immunohistochemistry is essential to confirm the diagnosis, having in mind the reported pathological characteristics and the immunohistochemical profile of recurrent and malignant tumors of this type.
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Immunohistochemical study of phyllodes tumor of the breast
(Springer, 1999-09)
Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
Phyllodes tumor ('PT) is a rare, fibroepithelial breast neoplasm with unpredictable prognostic and controversial therapeutic aspects. Aims: The aim of this retrospective study is to evaluate Ki-67 and CD34 antigen expression, as well as estrogen (ER) and progesterone receptor (PgR) status in stromal cells, as additional diagnostic criteria in assessing different types of PT. Methods: Routinely processed, formalin-fixed and paraffin-embedded surgical specimens from 47 cases of PT were stained by immunoperoxidase technique using Ki-67, CD34, ER and PgR monoclonal antibodies. On the basis of histopathological criteria proposed by Azzopardi, 6 malignant, 12 borderline and 29 benign PT have been evaluated. The mean size of the tumour was 9.4 cm (range 2.8-20 era). During the follow-up period (mean 50, range 2-127 months), recurrences were observed in 8 patients (17%). Results: The proliferating index determined by Ki-67 antigen expression was significantly different between histologically benign PT (19%), borderline PT (25%) and malignant PT (50%). There was a difference of the human progenitor cell CD34 antigen expression in malignant PT (50%), borderline PT (50%) and benign PT (30%). As expected, the stromal cells in various types of PT were mostly ER negative and PgR positive. Conclusions: Our preliminary results suggest that CD34 positivity and high proliferative index of Ki-67 antigen in stromal cells are more frequently associated with high grade PT. Therefore, the immunohistochemical features could provide better discrimination between different PT types. The prognostic implications of these observations should be evaluated in additional studies.
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Paravaginal female adnexal tumor of probable Wolffian origin. A case report
(Springer, 1999-09)
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Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
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Stavrik, George
Female adnexal tumor of probable Wolffian origin (FATWO) is a rare neoplasm originating from mesonephric remnants. Approximately 50 cases have been reported, predominantly arising in broad ligament, mesosalpinx, ovarian hilus, and periadnexal region. Aims: The aim of this report is to present the clinical and pathological features of a FATWO occurring in paravaginal area. So far, there have been only two cases reported to occur at this site. Case report: The patient is a 23-year old, nuliparous female, presented with a painless fixed paravaginal tumor. In August 1995, explorative laparatomy was performed. Encapsulated ovoid, tumor, located between urinary bladder and vagina, tightly fixed to vaginal wall connective tissue, was found. The uterus and both adnexa appeared unremarkable. The tumor was removed and biopsy sample from left ovary was taken. The patient had had an uneventful post-operative course and she remained well, without evidence of recurrence, 42 months after laparatomy. Results: The tumor was a solid ovoid mass with smooth surface, measuring 6.7 x 5 x 3.7 cm. On sectioning, the neoplastic tissue was solid, soft, butter yellow in colour; multiple cysts varying up to 3 cm in diameter and hemorrhagic foci were also present. Microscopically, it was well circumscribed and surrounded by fibrous capsule, composed of tumor cells arranged in different patterns: solid, closely packed tubules, and microcystic. The histochemical and immunohistochemical features of the tumor were identical to other cases of FATWO reported in the literature. Conclusions: Although the majority of these tumors are benign, a few cases have shown definite low malignant potential, with metastases and recurrences developing after at least 6 to 16 years following radical surgery. The presented case indicates that in spite of the unusual location, FATWO must be recognized, ensuring a careful and prolonged follow-up.
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Female genital actinomycosis: a review of 24 cases
(Springer, 2006-05)
Kubelka-Sabit, Katerina
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Prodanova, Irina
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Yashar, Genghis
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Zografski, George
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Objectives: The aim of this retrospective study was to present the clinical characteristics of the patients with female genital actinomycosis in correlation with the histopathological findings. Actinomycosis is a relatively rare chronic granulomatous inflammatory disease caused by the bacteria Actinomyces israelii, a normal commensal of the gastrointestinal and genital tract. The abdominal form of the disease is rare, however the incidence of the female genital and pelvic actinomycosis is rising, especially among the intrauterine device (IUD) users (8-20%). Methods: According to the computer database at our department, 965 cases of endometritis, 6,313 cases of cervicitis and 584 cases of pelvic inflammatory disease (PID) were diagnosed in a 15-year period (1991-2005). However, only 21 (2.2%) cases of endometrial, 1 (0.02%) cervical actinomycosis and 2 (0.3%) cases of pelvic actinomycosis were identified in this period. Explorative curettage was performed in 21 patients due to prolonged uterine bleeding and extirpation of an IUD was done in 19 of them. One patient had a biopsy taken for a suspicion of cervical neoplasm, consecutively diagnosed as endometrial adenocarcoma. In the PID group, one patient with a previous history of tubal pregnancy underwent a transabdominal biopsy for a paravesical tumor, two weeks after extirpation of an IUD. The last patient had no IUD and was surgically treated with hysterectomy and bilateral adnexectomy for a suspicion of malignant ovarian tumor. The biopsy, curettage and operative materials were formalin-fixed, routinely processed and paraffin-embedded. 4 microns thin sections were cut and slides were stained using standard hematoxylin–eosin staining procedure. Results: The mean age of the patients was 52.3 ranging from 41 to 68. Macroscopically visible sulfur granules were not identified in any of the cases of disease confined to the uterus. However microscopically, in all the 22 biopsy and curettage materials, elements of chronic granulomatous endometritis and/or cervicitis were seen, together with branching filaments of Actinomyces. In the paravesical tumor, abscesses filled with necrotic debris and scattered Actinomyces colonies were found. Macroscopically visible sulfur granules were identified only in the operative material, where a rough necrotic greyish-yellow area was seen on the serosal surface on the left side and posterior wall of the uterine corpus, measuring 4 × 3 cm. A left tubo-ovarian abscess measuring 4 × 3 × 3 cm was also found. On sectioning, several small and large abscesses filled with puss were present. The histological examination confirmed multiple actinomycotic abscesses in the ovary, paraovarian region and the external third of the left lateral uterine wall. Conclusions: Female genital actinomycosis is a rare and obscure granulomatous disease. It is most prevalent in IUD carriers and easily diagnosed when confined to the uterus. However, the pelvic actinomycosis is often misdiagnosed, simulating malignant pelvic or ovarian tumor. Therefore, unnecessary surgical interventions can be avoided with a careful examination of these patients and a timely identification of the disease.

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