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
;
Zografski, George
;
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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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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Ovarian mucinous cystadenoma with murale nodule of poorly differentiated squamous cell carcinoma. Report of a case
(Blackwell Publishing Ltd., 2008-10)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
Background. Mural nodules associated with mucinous and serous tumors of the ovary may represent a reactive process, a benign tumor, or a malignant neoplasm. Thus, the prognosis of the ovarian tumor can be dramatically modified by the presence of this nodule. We report the clinicopathologic and immunohistochemical findings of a case of a mural nodule of anaplastic squamous cell carcinoma associated with ovarian mucinous cystic tumor. Case report. The patient was a 66-year-old postmenopausal woman (gravida 1, para 1) with a 6-month history of increasing abdominal fullness. An abdominal ultrasound revealed a multilocular left ovarian cyst with a solid component. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, the diagnosis of a mucinous cystadenoma with a focus of FIGO stage IC anaplastic carcinoma in the left ovary was made. The patient received six courses of chemotherapy; 3 months after completing chemotherapy, she developed rectosygmoidal wall metastases. Despite rectosygmoid resection and additional chemotherapy and radiotherapy, the disease persisted in the pelvis and the patient died 14 months after initial operation. The primary tumor nodule as well as metastatic rectosygmoid tumors were studied by conventional and immunohistochemical methods. Results. The left ovarian tumor measured 8.5 x 8 x 6 cm. On cut sectioning, it was multilocular with a solid 4.5 x 4 x 3 cm mural nodule. Microscopically, the cyst wall was predominantly lined with benign mucinous epithelium, with rare foci of endometriosis found in smaller locules. The solid area of the mural nodule showed nests of spindle or polygonal highly malignant cells with admixed inflammatory cells. Necrosis and hemorrhage were also present. The ovarian capsule was invaded by the pleomorphic tumor cells. In favor of a diagnosis of anaplastic carcinoma were poor circumscription of the nodule with lymph-vascular involvement and absence of a prominent inflammatory reaction with multinucleated giant cells of the epulis type. In addition, the metastatic rectosygmoid tumor showed poorly differentiated squamous cell carcinomatous features. Immunohistochemically, the atypical cells of the nodule as well as a metastatic tumor were uniformly positive for epithelial markers such as pan-cytokeratin, high-molecular weight cytokeratin, cytokeratin 7 and epithelial membrane antigen, negative for carcinoembryonic antigen and focally weakly positive for vimentin. Many of these cells were also immunoreactive for p53 (80-90%) and Ki-67 (40-50%). Conclusion. The occurrence of ovarian mucinous cystic tumor with mural nodule of poorly differentiated squamous cell carcinoma is evidently very uncommon, because we have not found a similar case in the literature. The malignant nodules composed of sarcoma or anaplastic carcinoma such as in our case are associated with an unfavourable outcome and must be distinguished from other sarcoma-like nodules that may also occur in the wall of mucinous ovarian tumours. Therefore, the implementation of strict morphologic criteria supplemented by immunohistochemistry aids in the sometimes difficult differential diagnosis among these types of mural nodules.
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Malignant perivascular epithelioid cell tumor of the uterus with aggressive behaviour: A case report
(Blackwell Publishing Ltd., 2008-10)
Prodanova, Irina
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Kubelka-Sabit, Katerina
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Background. The perivascular epithelioid cell tumor (PEComa) is recognized by the World Health Organization as a mesenchymal neoplasm showing at least partial morphological and immunohistochemical evidence of a putative perivascular epithelioid cell differentiation. This family of tumors includes angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), clear cell sugar tumor of the lung and distinctive clear cell tumors at various other anatomic sites. Occasionally, PEComas are associated with the tuberous sclerosis complex (TSC). Because non-AML/non-LAM PEComas are extremely rare and their nature and prognostic factors undefined, we present a case of uterine PEComa with obviously aggressive behavior. Case report. A 55-year-old (gravida-2, para-2) presented with a large uterine mass palpated during a routine gynaecological examination. The patient did not have any stigmata or family history of TSC, and had no history of melanoma. A transvaginal ultrasound revealed an enlarged uterus with a heterogeneous mass which size was estimated at 9 x 9 cm. The clinical impression of the lesion was a leiomyoma. Total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy was performed 9 months later, and the pathohistological diagnosis was malignant PEComa of the uterus with metastases in the omentum. Three months after the surgical intervention the patient is still receiving adjuvant chemotherapy and there is no evidence of recurrence. Results. The uterine body was enlarged and measured 12 x 14 x 8 cm, with lobulated surface. Within the myometrium there was a poorly demarked gray-ten nodular tumor occupying the fundus, anterior and posterior walls with focally hemorrhagic areas and necrosis on cut surface. The largest diameter of the tumor was 14 cm. In the adipose tissue of the omentum there were numerous nodular tumor masses whose diameters ranged from 1 to 3 cm. Histologically, the tumor demonstrated a tongue-like growth pattern and was composed of large epithelioid cells with clear or eosinophilic cytoplasm, partially arranged around blood vessels The nuclei were mainly round, centrally located, and vesicular, with moderate to severe pleomorphism and hyperchromatism. Extensive cellular atypia, including bizarre multinucleated giant cells with large nuclei and nucleoli, was present as well. Mitotic count was high (15 per 50 HPFs), with prominent coagulative tumor necrosis. The microscopic examination of the nodular tumors from the omentum exhibited the same morphological features. Immunohistochemically, the tumor cells showed positivity for HMB-45 and smooth muscle actin while they were negative for cytokeratins, carcinoembryonic antigen, S-100 protein, CD-10, caldesmon and desmin. Immunoreactivity for vimentin was inconspicuous. The estrogen and progesterone receptors were also negative. A proliferative index of 30% was noted with Ki-67 immunostaining. The morphology and immunohistochemical profile of the lesions was consistent with PEComa. Conclusion. Due to the fact that a vast majority of PEComas has a benign course of disease or is considered to be of uncertain malignant potential, we present this case with evident aggressive behaviour since we believe that the histological features of this tumor can serve as a model for defining of the criteria for potentially malignant PEComas.
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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
;
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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