Recent concepts of ovarian cancer

Karcinom jajnika je vodeći uzrok smrti među zloćudnim novotvorinama ženskog spolnog sustava. Usprkos pokušajima razvoja programa probira s ciljem ranog otkrivanja bolesti, kao i novim terapijskim pristupima, mortalitet nije značajno smanjen. Jedan od razloga ovog neuspjeha bio je slabo razumijevanje patogeneze karcinoma jajnika koji je smatran jedinstvenom bolešću. Nove spoznaje pokazuju da je karcinom jajnika vrlo heterogena bolest, koja se na temelju kliničkopatoloških karakteristika te molekularnih i genetičkih promjena može podijeliti u dvije skupine: tip 1 i tip 2 tumori. Ovaj novi model patogeneze karcinoma jajnika danas ima važan klinički i terapijski značajOvarian cancer is the most lethal gynecologic malignancy. Efforts to develop screening methods and new therapeutic approaches to reduce mortality have been unsuccessful. One of the main reasons for this is our lack of knowledge of the origin and pathogenesis of ovarian cancer. This led to the postulate that it is a single disease. Recent studies have shown that ovarian cancer is a heterogeneous disease composed of diverse types of tumors that can be classified based on clinicopathologic and molecular genetic features into two broad groups designated type 1 and type 2. This new model of pathogenesis of ovarian cancer has significant clinical and therapeutic implication

Cervical Cytology and HPV Test in Follow-up after Conisation or LLETZ

The patients treated with conservative surgical therapy for cervical intraepithelial neoplasia (CIN) have an increased risk to develop invasive cervical carcinoma compared to the general population. Cervical cytology and HPV test are included in the protocols for the detection of treatment failure. The purpose of the study was to analyse cytology-histology correlation after conisation or Large Loop Excision of the Transformation Zone (LLETZ), resection margin status, compliance to the follow-up protocol and evaluation of cervical cytology and HPV testing in two year period after surgical treatment. We retrospectively reviewed 251 cases of conisation or LLETZ performed between January and December, 2006. Conventional cervical smears were analysed and abnormal cytology was defined as atypical squamous cells of undetermined significance or worse (ASCUS+). The digene Hybrid capture 2 test was used for detection of high-risk HPV types. Histology analysis demonstrated CIN1+ lesion in 234 cases (93.2%) with cytology-histology correlation in 97.9% of cases. A preoperative HPV test was made in 142 histologically confirmed CIN1+ lesions and 137 (96.5%) tested positive. The resection margins were involved in 48 (20.8%) cases. In 24 (10.3%) cases the margins were difficult to determine. Abnormal cytology was found in 33 (15.2%) cases of the 217 (86.5%) patients that attended the post-treatment visits. The post-treatment HPV test was performed on 159 women and it was positive in 25 (15.7%) cases. The complete follow-up control cytology, with at least three Pap smears in the subsequent two years or with second treatment, was registered in only 146 (58.2%) patients. 14/217 (6.5%) patients underwent second treatment with histologically confirmed treatment failure. In all patients with control smear, repeated cytology found HSIL. On six women, the control HPV test was performed. In five cases, it was positive and in one case with histological diagnoses of VAIN2, it was negative. Our study confirms the important role of cervical cytology in the diagnosis of cervical intraepithelial lesions and monitoring after treatment. In the future we will have to improve compliance to the follow-up protocols and use of the HPV test in the selection of women at risk of treatment failure

Cervical Cytology and HPV Test in Follow-up after Conisation or LLETZ

The patients treated with conservative surgical therapy for cervical intraepithelial neoplasia (CIN) have an increased risk to develop invasive cervical carcinoma compared to the general population. Cervical cytology and HPV test are included in the protocols for the detection of treatment failure. The purpose of the study was to analyse cytology-histology correlation after conisation or Large Loop Excision of the Transformation Zone (LLETZ), resection margin status, compliance to the follow-up protocol and evaluation of cervical cytology and HPV testing in two year period after surgical treatment. We retrospectively reviewed 251 cases of conisation or LLETZ performed between January and December, 2006. Conventional cervical smears were analysed and abnormal cytology was defined as atypical squamous cells of undetermined significance or worse (ASCUS+). The digene Hybrid capture 2 test was used for detection of high-risk HPV types. Histology analysis demonstrated CIN1+ lesion in 234 cases (93.2%) with cytology-histology correlation in 97.9% of cases. A preoperative HPV test was made in 142 histologically confirmed CIN1+ lesions and 137 (96.5%) tested positive. The resection margins were involved in 48 (20.8%) cases. In 24 (10.3%) cases the margins were difficult to determine. Abnormal cytology was found in 33 (15.2%) cases of the 217 (86.5%) patients that attended the post-treatment visits. The post-treatment HPV test was performed on 159 women and it was positive in 25 (15.7%) cases. The complete follow-up control cytology, with at least three Pap smears in the subsequent two years or with second treatment, was registered in only 146 (58.2%) patients. 14/217 (6.5%) patients underwent second treatment with histologically confirmed treatment failure. In all patients with control smear, repeated cytology found HSIL. On six women, the control HPV test was performed. In five cases, it was positive and in one case with histological diagnoses of VAIN2, it was negative. Our study confirms the important role of cervical cytology in the diagnosis of cervical intraepithelial lesions and monitoring after treatment. In the future we will have to improve compliance to the follow-up protocols and use of the HPV test in the selection of women at risk of treatment failure

Relapsed ovarian high-grade serous carcinoma with long-term survival associated with synchronous primary squamous cell carcinoma of the colon

High-grade serous ovarian cancer (HGSOC) is the most common and also the most aggressive subtype of ovarian cancer while squamous cell carcinoma (SCC) of the colon is an extremely rare histologic subtype of all colonic malignancies with poor prognosis. Here we report a unique case of synchronous primary SCC of the colon and second recurrence of HGSOC in a patient with 15-years survival. Our patient developed two recurrent HGSOCs with disease-free survival time of five and nine years, respectively. The second recurrence of HGSOC was associated with the synchronous primary SCC of the ascending colon and was further complicated with the patient′s development of platinum resistance. Awareness of this unusual occurrence should emphasize the need for adequate sampling of tumor tissue in patients with relapsing ovarian cancer. Reports of more cases of SCC of the colon would possibly help to establish appropriate management modality and strategies for treatment

Raynaud’s phenomenom as a first manifestation of high grade serosus carcinoma – case report

Cilj: Prikazati slučaj pacijentice s Raynaudovim fenomenom kao prvom manifestacijom seroznog karcinoma visokog gradusa te dijagnostički i terapijski postupak. Prikaz slučaja: Pacijentica stara 47 godina upućena je na Odjel za reumatologiju i kliničku imunologiju zbog pozitivnih antinuklearnih antitijela i Raynaudova fenomena. Kliničkim pregledom i laboratorijskom obradom isključena je sistemska bolest vezivnog tkiva. Ultrazvukom abdomena uočena je cistična tvorba u području zdjelice. Tumorski markeri CA-125, HE-4 bili su povišeni. PET/CT analizom (pozitronska emisijska tomografija / kompjutorizirana tomografija) uočeno je pojačano nakupljanje radiofarmaka u supra/retroklavikularnim limfnim čvorovima, zdjelično i paraaortalno. Citološka punkcija limfnog čvora na vratu upućivala je na metastatski slabodiferencirani adenokarcinom. Učinjena je laparoskopija desnog i lijevog jajnika, obostrana salpingektomija te zdjelična limfadenektomija. Patohistološka analiza potvrdila je da se radi o intraepitelnom seroznom karcinomu visokog gradusa jajovoda. Nakon dijagnostičke obrade provedeno je 6 ciklusa kemoterapije (Paklitaksel i Carboplatina). Na kontrolnom CT-u nije bilo znakova diseminacije osnovne bolesti. Pacijentica je trenutno dobrog općeg stanja i liječi se Olaparibom. Raynaudov fenomen je u značajnom poboljšanju. Zaključak: Serozni karcinom visokog gradusa može se prezentirati na atipičan način. Iznenadna pojava Raynaudova fenomena kod mlađih osoba treba pobuditi sumnju na moguću malignu bolest.Aim: To present a case of a patient with Raynaud’s phenomenom as the first manifestation of a high grade serosus carcinoma. Case report: A 47-year-old female has been referred to the Department of Rheumatology and Clinical Immunology due to the positive antinuclear antibodies and Raynaud’s phenomena. Both clinical examination and laboratory treatment excluded systemic connective tissue disease. Abdominal ultrasound revealed cystic formation in the pelvis area. Tumor markers CA-125, HE-4 were elevated. PET / CT analysis (positron emission tomography/computed tomography) observed increased radiotracer uptake involving supra/retroclavicular lymph nodes, pelvic and paraortal. The cytology of the lymph node at the neck indicated a metastatic weak-bound adenocarcinoma. Left and right ovarian laparoscopy, double salpingectomy and pelvic lymphadenectomy were performed. The pathological analysis confirmed that it was intraepithelial serous high grade fallopian tube cancer. The patient went to 6 cycles of chemotherapy (Paclitaxel and Carboplatin). Follow up CT didn’t show any signs of dissemination of the underlying disease. The patient is currently in a good general condition and treated with Olaparib. Raynaud’s phenomenon is significantly improved. Conclusion: Serous high-grade cancer can be presented in an atipic manner. The sudden occurrence of Raynaud’s phenomena in younger people should raise doubts about possible malignancy

Papillary Thyroid Carcinoma Arising within a Mature Cystic Teratoma of the Ovary: A Report of Two Cases with Long-Term Follow Up

Objectives: To report two patients with papillary thyroid carcinoma arising within mature cystic teratoma with long term follow-up. Methods: The cases are compared with previous reports of similar entities, with special reference to the treatment modalities and management options in follow-up of these patients. Results: Final diagnosis of both tumors was established after the initial surgery. Both tumors were histologically classified as the malignant transformation of the thyroid tissue within the mature cystic teratoma, both were papillary type and confined to one ovary. We presented two similar cases, but our therapeutic approach was surgically different. Both patients were treated with surgery alone and are alive with no evidence of the disease after 10 and 5 years, respectively. Conclusion: Preoperative and intraoperative frozen section diagnosis of malignant transformation within teratoma is very difficult, so optimal management of the patients has not yet been established. Treatment of this tumor should be individualized, but a contour of treatment modalities and management options are visible and our cases may contribute in this achievement

The role of cytology in preoperative assessment od primary fallopian tube carcinoma: case report

Cilj: Prikazati slučaj pacijentice s primarnim seroznim karcinomom jajovoda, opisati dijagnostički postupak te analizirati ulogu citološke dijagnostike u detekciji ovog tipa tumora. Prikaz slučaja: Pedesetogodišnja pacijentica prethodno je obrađivana u drugoj ustanovi zbog bolova u trbuhu i radiološki dokazanih uvećanih supraklavikularnih, aortokavalnih i ilijačnih limfnih čvorova. Nakon učinjene laparoskopske ekstirpacije limfnih čvorova zbog sumnje na limfoproliferativnu bolest, patohistološkom i imunohistokemijskom analizom utvrđeno je da se radi o metastatskom adenokarcinomu, vjerojatno podrijetla iz ginekološkog sustava ili dojke. Radiološkom obradom dojki nisu pronađene promjene suspektne na malignitet. PET/CT analizom (pozitronska emisijska tomografija/kompjutorizirana tomografija) uočeno je pojačano nakupljanje radiofarmaka u predjelu vrata i tijela maternice. U preoperativnoj obradi učinjena je citološka punkcija uvećanog supraklavikularnog limfnog čvora te je imunocitokemijskom analizom utvrđeno da se radi o metastatskom seroznom adenokarcinomu. U Papa-testu pronađene su maligne stanice jednake morfologije, bez tumorske dijateze, što je upućivalo na ekstrauterini adenokarcinom, a sugerirano je podrijetlo jajnika ili jajovoda. Učinjena je eksplorativna kiretaža, ali je patohistološki nalaz bio uredan. Pacijentica je predviđena za histerektomiju s obostranom adnekstektomijom. Tijekom operativnog zahvata uočeno je proširenje desnog jajovoda tumorskim tkivom koje je probijalo stijenku jajovoda. Učinjena je lavaža peritonealne šupljine u kojoj su pronađene maligne stanice adenokarcinoma. Patohistološka analiza potvrdila je da se radi o primarnom seroznom karcinomu jajovoda s metastazama u jajnicima. Zaključak: Zahvaljujući brzini i preciznosti primijenjenih citodijagnostičkih pretraga dijagnostičko-terapijski postupak pravilno je usmjeren i pravovremeno proveden. Prikazani slučaj potvrđuje da citološka analiza može pridonijeti dijagnostici tumora s neuobičajenom kliničkom prezentacijom ili tumora nejasnog podrijetla.Aim: To report a case of a patient with primary serous carcinoma of the fallopian tube, describe the diagnostic pathway and analyze the role of cytology in the detection of this tumor type. Case report: A 50-year-old patient was previously treated in another hospital for abdominal pain and radiologically confirmed enlargement of supraclavicular, aortocaval and iliac lymph nodes. A lymphoproliferative disorder was suspected and laparoscopic lymph node excision was performed. Histopathological and immunohistochemical analysis revealed a metastatic adenocarcinoma probably of gynecologic or breast cancer origin. Radiographic examination of the breast did not confirm any lesion suspicious for malignancy. Positron emission tomography/computed tomography observed increased radiotracer uptake involving the uterine cervix and corpus. Preoperative fine-needle aspiration cytology and immunocytochemical analysis of an enlarged supraclavicular lymph node was done and metastatic serous adenocarcinoma was confirmed. In the Pap smears malignant cells of equal morphology were found without tumor diathesis indicating an extra-uterine adenocarcinoma. It was suggested to consider a tumor of ovarian or fallopian tube origin. A total hysterectomy with bilateral salpingo-oophorectomy was performed. During surgery an enlargement of the was observed due to tumor growth extending through the tubal wall. The presence of malignant adenocarcinoma cells was found in the peritoneal washing. Histopathological analysis confirmed a primary serous carcinoma of the fallopian tubes with metastatic spread to the ovaries. Conclusion: Applying fast and precise cytology and immunocytochemistry techniques a correct diagnostic and therapeutic approach can be performed and implemented on time. The present case confirms that cytology is a wellestablished and widely accepted method for diagnosing tumors with unusual clinical presentation or unknown origin

Adult Granulosa Cell Tumors of the Ovary: A Retrospective Study of 36 FIGO Stage I Cases with Emphasis on Prognostic Pathohistological Features

Objective . Adult granulosa cell tumors (AGCTs) represent 2% – 5% of all ovarian malignancies. The aim of this study was to analyze clinical and pathohistological parameters and their impact on recurrence, overall, and disease-free survival in FIGO stage I AGCT patients. Methods. The tumor specimens analyzed in this retrospective study were obtained from a total of 36 patients with diagnosis of ovarian AGCT surgically treated at the Department of Gynecology, Rijeka University Hospital Centre, between 1994 and 2012. Clinical, pathological, and follow-up data were collected. Results. The mean age at diagnosis was 54.5 years with a range of 24 – 84. The majority of the patients, 30 (83%), were in FIGO stage IA, 3 (8%) in stage IC1, 1 (3%) in stage IC2, and 2 (6%) in stage IC3. During follow-up period (median 117.5 months, range 26 – 276), recurrence occurred in 4 patients (12%) with 2 deaths of the disease recorded. In univariate analysis, the 5-year survival rates were signi fi cantly shorter in patients with FIGO substage IC ( p =0 019 ), with positive LVSI ( p =0 022 ), with presence of necrosis ( p =0 040 ), and with hemorrhage ( p =0 017 ). In univariate analysis, the 5-year disease-free survival rates were signi fi cantly shorter in patients treated with fertility surgery ( p =0 004 ), with di ff use growth pattern ( p =0 012 ), with moderate and severe nuclear atypia ( p =0 032 ), and with presence of hemorrhage ( p =0 022 ). FIGO substage IC proved to be independent predictor for recurrence (OR = 16.87, p =0 015 , and OR = 23.49, p =0 023 , resp.) and disease-free survival ( p =0 0002 ; HR 20.84, p =0 02 ) at the uni- and multivariate analyses. Conclusions. FIGO substage IC is predictive of recurrence and disease-free survival in patients with early-stage AGCTs. LVSI, presence of necrosis and hemorrhage, di ff use growth pattern, and nuclear atypia in AGCTs seem to be associated with overall and disease-free survival, so these pathological features should be taken into consideration when managing patients with AGCT

Međuovisnost razvijenosti krvožilja i ekspresije tenascina u astrocitnim tumorima mozga : doktorska disertacija

Cilj: 1. Utvrditi način raspodjele tenascina-C u astrocitnim tumorima mozga 2. Istražiti povezanost načina raspodjele 1 intenziteta ekspresije tenascina sa stupnjem angiogeneze u ovim tumorima. Materijal i metode rada: Ispitivanje je provedeno na 103 astrocitna tumora (14 pilocitičkih astrocitoma, 12 difuznih astrocitoma, 15 anaplastičnih astrocitoma i 62 glioblastoma). Na svim tumorima primijenjeno je imunohistokemijsko bojenje na tenascin-C, CD31, VEGF i Ki67. Na glioblastomima je primijenjeno i antitijelo za marker aktiviranih endotelnih stanica, endoglin (CD105). Statistička analiza urađena je statističkim programom Statistica 6.1. Kao statistički značajni prihvaćeni su rezultati s razinom značajnosti p<0,05. Rezultati: Ekspresija teascina-C rasla je s rastom gradusa tumora. U svim gradusima tenascin-C se pojavljivao u dvije lokalizacije- oko krvnih žila (perivaskulrano) i između tumorskih stanica (intercelularno). U intercelularnom prostoru razlikovala se žarišna i difuzna raspodjela tenascina-C. U nižim gradusima tumora ekspresija tenascina-C nije bila jasno povezana s rastom gustoće krvnih žila (MVD) kao što je to bio slučaj u najmalignijim astrocitnim tumorima, glioblastomima. Rast perivaskularne ekspresije tenascina-C u glioblastomima pokazivao je jasnu povezanost s rastom gustoće krvnih žila, bilo da su one bile prikazane s anti-CD31 antitijelom (Spearman p=0,512 p<0,001), bilo anti-CD105 antitijelom (Spearman p=0,589 p<0,001). Također je utvrđena povezanost ekspresije perivaskularnog tenascina-C i VEGF ekspresije u glioblastomima (Spearman p=0,370 p=0,005). Štoviše, utvrđeno je da je MVD znatno veći kod tumora s jakom VEGEF 1 jakom tenascin-C ekspresijom u odnosu na tumore s jakom VEGF ali slabom ili umjerenom tenascin-C ekspresijom (p=0,002). Porast intercelulrne ekspresije tenascina-C povezan je s većom proliferativnom aktivnošću tumorskih stanica (Spearman p=0,388 p=0,001). Također, proliferativna aktivnost je bila veća u tumorima s difuznom raspodjelom tenascina-C nego u tumorima koji su imali žarišnu raspodjelu tenascina (p=0,008). Međutim, preživljenje bolesnika s difuznom raspodjelom tenascina bilo je znatno dulje nego preživljenje bolesnika sa žarišnom raspodjelom tenascina (p=0,039). Nadalje, žarišna raspodjela tenascina povezana je s češćom pojavnosti glomeruloidnih kapilara u glioblastomima (p=0,015). Posebno treba istaknuti da je manji MVD bio povezan s duljim preživljenjem bolesnika kad su se krvne žile prikazale anti-CD105 antitijelom (p=0,045), dok ta povezanost nije dobivena kad su se krvne žile prikazale anti-CD31 antitijelom. Zaključak: Rast tenascin-C ekspresije u perivaskularnoj lokalizaciji značajno je povezana s rastom gustoće krvnih žila u glioblastomima. Tenascin-C pojačava angiogeni učinak VEGF-a. Tenascin-C u intercelularnoj lokalizaciji povezan je s većom proliferativnom aktivnošću tumorskih stanica. Osim intenziteta ekspresije, s proliferativnom aktivnošću povezan je i način raspodjele tenascina u intercelularnom prostoru. Naročito je važno istaknuti da je način raspodjele povezan s duljinom preživljenja bolesnika s glioblastomom. Također treba istaknuti da je endoglin bolji pokazatelj angiogeneze u glioblastomima te predstavlja i potencijalni prognostički čimbenik

Međuovisnost razvijenosti krvožilja i ekspresije tenascina u astrocitnim tumorima mozga : doktorska disertacija

Cilj: 1. Utvrditi način raspodjele tenascina-C u astrocitnim tumorima mozga 2. Istražiti povezanost načina raspodjele 1 intenziteta ekspresije tenascina sa stupnjem angiogeneze u ovim tumorima. Materijal i metode rada: Ispitivanje je provedeno na 103 astrocitna tumora (14 pilocitičkih astrocitoma, 12 difuznih astrocitoma, 15 anaplastičnih astrocitoma i 62 glioblastoma). Na svim tumorima primijenjeno je imunohistokemijsko bojenje na tenascin-C, CD31, VEGF i Ki67. Na glioblastomima je primijenjeno i antitijelo za marker aktiviranih endotelnih stanica, endoglin (CD105). Statistička analiza urađena je statističkim programom Statistica 6.1. Kao statistički značajni prihvaćeni su rezultati s razinom značajnosti p<0,05. Rezultati: Ekspresija teascina-C rasla je s rastom gradusa tumora. U svim gradusima tenascin-C se pojavljivao u dvije lokalizacije- oko krvnih žila (perivaskulrano) i između tumorskih stanica (intercelularno). U intercelularnom prostoru razlikovala se žarišna i difuzna raspodjela tenascina-C. U nižim gradusima tumora ekspresija tenascina-C nije bila jasno povezana s rastom gustoće krvnih žila (MVD) kao što je to bio slučaj u najmalignijim astrocitnim tumorima, glioblastomima. Rast perivaskularne ekspresije tenascina-C u glioblastomima pokazivao je jasnu povezanost s rastom gustoće krvnih žila, bilo da su one bile prikazane s anti-CD31 antitijelom (Spearman p=0,512 p<0,001), bilo anti-CD105 antitijelom (Spearman p=0,589 p<0,001). Također je utvrđena povezanost ekspresije perivaskularnog tenascina-C i VEGF ekspresije u glioblastomima (Spearman p=0,370 p=0,005). Štoviše, utvrđeno je da je MVD znatno veći kod tumora s jakom VEGEF 1 jakom tenascin-C ekspresijom u odnosu na tumore s jakom VEGF ali slabom ili umjerenom tenascin-C ekspresijom (p=0,002). Porast intercelulrne ekspresije tenascina-C povezan je s većom proliferativnom aktivnošću tumorskih stanica (Spearman p=0,388 p=0,001). Također, proliferativna aktivnost je bila veća u tumorima s difuznom raspodjelom tenascina-C nego u tumorima koji su imali žarišnu raspodjelu tenascina (p=0,008). Međutim, preživljenje bolesnika s difuznom raspodjelom tenascina bilo je znatno dulje nego preživljenje bolesnika sa žarišnom raspodjelom tenascina (p=0,039). Nadalje, žarišna raspodjela tenascina povezana je s češćom pojavnosti glomeruloidnih kapilara u glioblastomima (p=0,015). Posebno treba istaknuti da je manji MVD bio povezan s duljim preživljenjem bolesnika kad su se krvne žile prikazale anti-CD105 antitijelom (p=0,045), dok ta povezanost nije dobivena kad su se krvne žile prikazale anti-CD31 antitijelom. Zaključak: Rast tenascin-C ekspresije u perivaskularnoj lokalizaciji značajno je povezana s rastom gustoće krvnih žila u glioblastomima. Tenascin-C pojačava angiogeni učinak VEGF-a. Tenascin-C u intercelularnoj lokalizaciji povezan je s većom proliferativnom aktivnošću tumorskih stanica. Osim intenziteta ekspresije, s proliferativnom aktivnošću povezan je i način raspodjele tenascina u intercelularnom prostoru. Naročito je važno istaknuti da je način raspodjele povezan s duljinom preživljenja bolesnika s glioblastomom. Također treba istaknuti da je endoglin bolji pokazatelj angiogeneze u glioblastomima te predstavlja i potencijalni prognostički čimbenik