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

Hypoxia inducible factor-1α correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>The role of angiogenesis in the pathogenesis of renal cell carcinoma is well recognized, however, the influence of tumor cells in this activity has not yet been fully clarified. The aim of this study was to analyze the expression of hypoxia inducible factor-1α (HIF-1α), a regulatory factor of angiogenic switch, in comparison to vascular endothelial growth factor A and C (VEGF-A and VEGF-C), recognized to be involved in blood and lymph vessel neoangiogenesis, with potential association in the prognosis of patients with renal cell carcinoma.</p> <p>Methods</p> <p>Ninety-four patients with diagnosis of clear cell renal cell carcinomas (CCRCC), all clinicopathological characteristics and overall survival were unrolled in this study. Immunohistochemicaly VEGF-A, VEGF-C, HIF-1α and Ki67 were detected on tumor cells and the staining was performed on tissue microarrays (TMA). The staining was evaluated as a percentage of cytoplasmic or nuclear positive tumor cells.</p> <p>Results</p> <p>Variable expression of all three proteins was confirmed. Both angiogenic factors demonstrated perimembranous or diffuse cytoplasmic staining, with diffuse pattern positively associated (p < 0.001). Nuclear HIF-1α expression (nHIF-1α) showed inverse correlation with diffuse cytoplasmic VEGF-A (p = 0.002) and VEGF-C (p = 0.053), while cytoplasmic HIF-1α expression (cHIF-1α) showed positive correlation with diffuse staining of both angiogenic factors (p < 0.001; p < 0.001, respectively). In comparison to clinicopathological characteristics, a higher nuclear grade (p = 0.006; p < 0.001, respectively), larger tumor size (p = 0.009; p = 0.015, respectively), higher stage (p = 0.023; p = 0.027, respectively) and shorter survival (p = 0.018; p = 0.024, respectively) were associated with overexpression of cHIF-1α and diffuse cytoplasmic VEGF-A expression. In contrary, overexpression of nHIF-1α was associated with better diagnostic parameters i.e. lower nuclear grade (p = 0.006), smaller tumor size (p = 0.057), and longer survival (p = 0.005).</p> <p>Conclusion</p> <p>Overexpression of VEGF-A and cHIF-1α in tumor cells highlights a more aggressive subtype of CCRCC that might have some clinical implications. The significance of nHIF-1α expression associated with better differentiated tumors should be further elucidated.</p

Combined evaluation of bone marrow aspirate and biopsy is superior in the prognosis of multiple myeloma

<p>Abstract</p> <p>Background</p> <p>Estimation of plasma cell infiltrates in bone marrow aspirates (BMA) and bone marrow biopsy (BMB) is a standard method in the diagnosis and monitoring of multiple myeloma (MM). Plasma cell fraction in the bone marrow is therefore critical for the classification and optimal clinical management of patients with plasma cell dyscrasias. The aim of the study was to compare the percentage of plasma cells obtained by both methods with the patient clinical parameters and survival.</p> <p>Methods</p> <p>This retrospective study included BMA and BMB of 59 MM patients. The conventional differential count was determined in BMA to estimate the percentage and cytologic grade of plasma cells. The pattern of neoplastic infiltration and percentage of plasma cells were estimated on CD138 immunostained BMB slides microscopically and by computer-assisted image analysis (CIA).</p> <p>Results</p> <p>Significantly higher values of plasma cell infiltrates were observed in pathologist (47.7 ± 24.8) and CIA (44.1 ± 30.6) reports in comparison with cytologist analysis (30.6 ± 17.1; <it>P </it>< 0.001 and <it>P </it>< 0.0048, respectively). BMB assessment by pathologist counting and using CIA showed strongest correlation (r = 0.8; <it>P </it>< 0.0001). Correlation was also observed between the pathologist and cytologist counts (r = 0.321; <it>P </it>= 0.015) as well as comparing the percentage of plasma cells in BMA and CIA (r = 0.27; <it>P </it>= 0.05). Patients with clinical stage I/II had a significantly lower CIA plasma cell count than those with clinical stage III (<it>P </it>= 0.008). Overall survival was shorter in patients with more than 25% of atypical plasma cell morphology estimated in BMA (<it>P </it>= 0.05) and a higher percentage of tumor cell infiltrates estimated by the pathologist and CIA (<it>P </it>= 0.0341 and <it>P </it>= 0.013, respectively).</p> <p>Conclusion</p> <p>Study results suggested the combined analyses to be useful as a routine procedure to achieve more accurate and informative diagnostic data.</p

Impact of bone marrow angiogenesis, expression of osteopontin and vascular endothelial growth factor on myeloma patient response to the first line therapy

Cilj: Istražiti utjecaj angiogenih parametara, izražaja osteopontina (OPN) i vaskularnog endotelnog čimbenika rasta (VEGF; engl. vascular endothelial growth factor) u koštanoj srži na odgovor na prvu liniju terapije u pacijenata s multiplim mijelomom (MM). Ispitanici i metode: U istraživanje je uključeno 68 pacijenata s MM-om, liječenih na Odjelu hematologije Kliničkog bolničkog centra u Rijeci. Za kvantifikaciju angiogenih parametara uz klasičnu metodu utvrđivanja gustoće krvnih žila (MVD; engl. microvessel density) koristili smo i računalno potpomognutu analizu slike koja nam je omogućila izračunavanje broja krvnih žila po mm2, površine krvnih žila po mm2, srednjeg promjera krvnih žila i ukupne vaskularne površine (TVA; engl. total vascular surface) na bioptičkim uzorcima koštane srži obojanim s anti-CD34. Za određivanje izražaja OPN-a i VEGF-a u plazma stanicama korištena je dvostruka imunohistokemijska metoda CD138+OPN i CD138+VEGF. Rezultati: Utvrđeno je da su viši angiogeni parametri, MVD (P = 0,004) i broj krvnih žila po mm2 (P = 0,028) značajni negativni prognostički pokazatelji odgovora na prvu liniju terapije u pacijenata s MM-om. Zaključak: Objektivna metoda procjene angiogeneze u uzorcima koštane srži mogla bi postati dio rutinske patohistološke obrade pacijenata koja bi pomogla u prepoznavanju podskupina pacijenata s eventualnim agresivnijim tijekom i lošijim odgovorom na terapiju.Objective: To investigate the effect of angiogenic parameters, expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow in order to predict response to first-line therapy in patients with multiple myeloma (MM). Patients and Methods: The study included 68 patients with MM, treated at the Department of Hematology, Clinical Hospital Centre in Rijeka. For quantification of angiogenic parameters besides the classical method of determining microvessel density (MVD) we used a computer assisted image analysis which enabled us to calculate the number of blood vessels per mm2, the surface of blood vessels per mm2, an average diameter of blood vessels and total vascular surface (TVA) in the bone marrow biopsies stained with anti-CD34. To determine the expression of OPN and VEGF in plasma cells we used double staining immunohistochemistry method, CD138+OPN and CD138+VEGF. Results: We found that a higher angiogenic parameters, the MVD (P = 0.004) and the number of blood vessels per mm2 (P = 0.028), were significantly negative prognostic indicator of response to the first-line therapy in patients with MM. Conclusion: An objective method of the assessment of angiogenesis in the bone marrow samples could become a part of the routine histopathological analysis which could help to identify a subgroup of patients with possible aggressive course and poor response to the therapy

The association between the recurrence of solitary nonmuscle invasive bladder cancer and tumor infiltrating lymphocytes

Aim To evaluate whether tumor infiltrating lymphocytes (TIL) in biopsy specimens are associated with the clinical outcome of non-muscle invasive bladder cancer. Methods We retrieved tumor specimens from 115 patients with solitary papillary non-muscle invasive bladder cancer treated between 1996 and 2006 and constructed tissue microarrays. Patients were divided in two groups: those with recurrent disease (N = 69) and those without recurrent disease (N = 46) during the follow up of minimum 5 years. All patients were treated with initial transurethral resection and none received adjuvant therapy. Immunhistochemical staining was performed with anti-CD3, CD4, CD8, and Granzyme B (GrB). The CD4+:CD8+ and GrB+:CD8 ratios were determined. Results Tumor infiltrating lymphocytes were predominantly observed within cancer stroma, and only rare individual cells were observed intraepithelially. The group without recurrent disease had lower levels of CD3+ and CD8+ lymphocytes than the group with recurrent disease (P = 0.0001, P = 0.0002, respectively). The CD4+:GrB+ and GrB+:CD8+ ratios were significantly higher in patients without recurrent disease (P = 0.0002, P = 0.039, respectively). Conclusion This study revealed a possible connection between TIL number and bladder cancer recurrence. TIL subset ratio showed different patterns in recurrent and nonrecurrent tumors, which is why it could become a useful a prognostic clinical index if our findings are confirmed in randomized trials

Expression of cyclin D1 in bone marrow of multiple myeloma patients before and after bortezomib treatment

Cilj: Imunohistokemijski procijeniti ekspresiju ciklina D1 na mijelomskim stanicama u koštanoj srži pacijenata s multiplim mijelomom (MM), liječenih bortezomibom te dobivene podatke usporediti s kliničko-patološkim parametrima i odgovorom na terapiju. Ispitanici i metode: Ekspresija ciklina D1 analizirana je ubioptičkim uzorcima koštane srži 24 pacijenta s MM-om prije i nakon provedene terapije bortezomibom. Za određivanje ekspresije ciklina D1 na mijelomskim stanicama korištena je dvostruka imunohistokemijska metoda koja omogućava istovremeno bojanje uzorka s dva protutijela (u ovom slučaju s CD138 za identifikaciju plazma stanica i ciklinom D1). Pozitivnom reakcijom smatralo se nuklearno obojenje naciklin D1, bilo kojeg intenziteta, u ≥ 10 % plazma stanica. Rezultati su potom korelirani s kliničko-patološkim podacima pacijenata ispitivane skupine. Rezultati: Nuklearna ekspresija ciklina D1 u plazma stanicama oboljelim od MM-a prije terapije nađena u je 9/24 pacijenta, a ukupno negativnih pacijenata bez ikakvog nuklearnog bojanja 13/24 ili s bojanjem na ciklin D1 u < 10 % stanica 2/24 bilo je 15/24. Nakon terapije bortezomibom 5/24 pacijenta bilo je pozitivno na ciklin D1, dok je ukupno 19/24 pacijenata bilo negativno, tj. bez ikakvog nuklearnog bojanja 17/24 ili je imalo < 10 % tumorskih stanica 2/24 pozitivno na ciklin D1. U ovoj studiji nije nađena statistički značajna razlika u ekspresiji ciklina D1 prije i nakon provedene terapije bortezomibom (p = 0,084) niti s nekim od kliničko-patoloških parametara. Zaključak: Rezultati i razina ekspresije ciklina D1 uvelike variraju unutar različitih ispitivanih skupina, a također ovise i o terapiji koju su pacijenti dobivali, stoga je za utvrđivanje značaja ciklina D1 na prognozu i korelaciju s kliničko- -patološkim karakteristikama potrebna veća i homogenija skupina pacijenata.Objective: To evaluate, immunohistochemically expression of cyclin D1 in myeloma cells in the bone marrow of multiple myeloma (MM) patients treated with bortezomib and compare obtained data with clinico-pathological parameters and response to therapy. Patients and methods: Twenty four patients with MM treated with bortezomib were included in this study. To determine the expression of cyclin D1 in the bone marrow prior to and after bortezomib treatment, we used double immunohistochemical method, which allows simultaneous staining of the sample with two antibodies (in this case with CD138 (plasma cell marker) and cyclin D1). A positive reaction was considered when ≥ 10% plasma cells showed cyclin D1 nuclear staining, at any intensity. The results were correlated with patient’s clinicopathological data. Results: The nuclear expression of cyclin D1 in the plasma cells of patients with MM before therapy was found in 9/24 cases and there was 15/24 negative patients, including patients without any nuclear staining 13/24 or with nuclear staining for cyclin D1 but in < 10% of plasma cells 2/24. After bortezomib tretament, 5/24 patients were positive for cyclin D1 while 19/24 patients were negative, including patients without any nuclear staining 17/24 or they had < 10% of cyclin D1 positive tumor cells 2/24. In this study there was no statistically significant difference in the expression of cyclin D1 before and after bortezomib treatment (p = 0.084) as well as any correlation with some of the clinical or pathological parameters. Conclusion: The results and the level of expression of cyclin D1 vary within different study groups and depend as well on the prior treatment patients received. Therefore to determine the prognostics significance of cyclin D1 expression and its correlation with clinico-pathological features a larger and more homogeneous group of patients is required

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

Unusual presentation of plasmablastic lymphoma involving ovarian mature cystic teratoma: a case report

Abstract Background: Plasmablastic lymphoma (PBL) is relatively new clinical entity described as a distinct subtype of diffuse large B-cell lymphoma (DLBCL). It is characterized by its aggressive nature and proliferation of large neoplastic cells resembling immunoblasts including cells with more obvious plasmacytic differentiation. In this case report, we describe an unexpected finding of PBL associated with a mature cystic teratoma of the ovary in a young immune competent woman. Case presentation: A 19-year old woman was admitted to the hospital with generalized lymphadenopathy, a pelvic tumor mass measuring 35 × 30 cm and a 4 cm lump in her right breast. She underwent a right salpingo-oophorectomy, lymphadenectomy, splenectomy, omentectomy, and a right breast lumpectomy. On macroscopic examination the right ovary was replaced by a thick-walled multilocular cystic tumor. Upon incision, the cysts were filled with thick, greasy sebaceous material and hair and there were several solid nodules within the cyst walls. Histological examination revealed a mature cystic teratoma and malignant non- Hodgkin lymphoma (NHL) within the solid nodules. Tumor tissue from the right breast, spleen and lymph nodes, all had the same histological, NHL morphology. After extensive immunostaining, a diagnosis of PBL was made. Following surgery, the patient was treated with different chemotherapy regimens, without any significant regression of the disease, and died of multiple organ failure. Conclusions: Primary NHL of the ovary is relatively rare occurrence while secondary involvement by lymphoma is much more common. PBL is a rare lymphoma, primarily reported in the jaw and oral mucosa, but also documented in extra-oral sites. To the best of our knowledge, this is the first case described in a mature ovarian cystic teratoma. Although the patient was HIV-negative and immune competent, she had progressive disease and died despite aggressive chemotherapy 11 months after the initial diagnosis

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

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