Uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma : Epidemiological, clinical and prognostic aspects

Uterine carcinosarcoma (CS), leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS) have historically been considered as main subtypes of uterine sarcomas (USs). Depending on the classification, 3% to 9% of malignancies of the uterine corpus and about 1% of all female genital tract malignancies are USs. However, it has been estimated that USs account for nearly one third of deaths from uterine malignancies. The aims of these studies were to assess clinical behavior, survival, prognostic markers and epidemiological aspects of uterine CS, LMS and ESS. In a retrospective study we analyzed survival and prognostic markers (both clinical and immunohistochemical) in patients treated from 1990 to 2001 at Helsinki University Central Hospital (HUCH). In the epidemiological studies the incidence and occupational risk of uterine LMS and ESS were examined by using the NORDCAN and Nordic Occupational Cancer Study (NOCCA) databases. A cohort of 8606 cases of USs from 13 cancer registries was used to evaluate the risk of a second primary malignancy after the first primary US. This study was co-ordinated by the International Agency for Research on Cancer (IARC). The age-adjusted incidence of LMS was about 0.4 0.5 per 100 000 and that of ESS about 0.2 per 100 000 in Iceland, Denmark, Finland and Norway during the study period 1978 2007. Age-specific incidences were highest around menopause for both subtypes of USs. Shoe and leather workers, farmers and teachers showed elevated standardized incidence ratios (SIRs) as regards LMS. However, no occupations were associated with increased SIRs in connection with ESS. One hundred patients with uterine CS (n = 40), LMS (n = 39) and ESS (n = 21) were treated in our institution during 1990 2001. The 2-, 5-, and 10-year disease-specific survival rates were 64%, 56% and 38% for all subtypes grouped together and 5-year survival rates for each subtype separately were 49% (CS), 57% (LMS) and 65% (ESS). Stage, age, tumor size and delivery status were independently associated with survival when all subtypes were combined. Immunohistochemical (IHC) analysis (n = 65) of ten markers showed that estrogen receptor-α (ER-α) and progesterone receptor (PR) positivity were associated with statistically significantly better disease-specific survival times and p53 positivity with worse disease-specific survival in patients with LMS. The risk of a second primary cancer after the first primary US was analyzed in a cohort of 8606 cases of USs, in which 499 cancer cases were observed. Women with a primary US had a 26% increased risk (SIR 1.26, 95%CI 1.16 1.38) of developing a second primary cancer. SIRs were elevated as regards cancers of the mouth and pharynx (2.16, 95%CI 1.15 3.69), colorectum (1.60, 95%CI 1.28 1.98), lung (1.73, 95%CI 1.27 2.29), breast (1.25, 95%CI 1.05 1.49), urinary bladder (1.74, 95%CI 1.02 2.79), kidney (2.00, 95%CI 1.24 3.06), thyroid gland (2.74, 95%CI 1.42 4.79), and soft tissue sarcoma (5.23, 95%CI 2.51 9.62). In conclusion, the incidences of LMS and ESS showed constant trends in Nordic countries during the study period. Overpresentation of uterine LMS in shoe and leather workers and farmers might be associated with the etiology of LMS and this should be clarified in the future. Our institutional survival rates in cases of uterine CS, LMS and ESS were comparable with or even better than in earlier reports, and stage, age, tumor size, and delivery status of the patient emerged as the main prognosticators. Immunohistochemical expression of ER-α, PR and p53 were associated with survival of patients with LMS. After diagnosis of US there is an elevated risk of a second primary malignancy. Excesses of colorectal and urinary bladder cancers may reflect the effects of earlier treatments of US (radiotherapy and chemotherapy). The elevated risk of mouth and pharynx, lung and urinary bladder cancers after USs might be associated with common etiological factors such as smoking. The excesses of breast cancer in US patients may be related to a shared hormonal etiology.Kohtusarkoomat ovat huonoennusteisia ja harvinaisia gynekologisia kasvaimia: vain 3 9 % kohdun pahanlaatuisista kasvaimista on kohtusarkoomia. Taudin aiemmat pääluokat ovat olleet karsinosarkooma, leiomyosarkooma ja endometriaalinen stroomasarkooma. Nykykäsityksen mukaan karsinosarkooma on kohdun limakalvolta lähtöisin oleva syöpä. Uusittuun luokitukseen kuuluvat kohdun leiomyosarkooman sekä endometriaalisen stroomasarkooman lisäksi erilaistumaton endometriumin sarkooma ja adenosarkooma. Väitöstutkimuksessa selvitettiin kohdun karsinosarkooman, leiomyosarkooman ja endometriaalisen stroomasarkooman epidemiologisia piirteitä, kliinistä taudinkuvaa, ennustetta sekä siihen vaikuttavia tekijöitä. Pohjoismaisessa syöpärekisteritutkimuksessa (NORDCAN) tutkittiin kohdun leiomyosarkooman ja endometriaalisen stroomasarkooman ilmaantuvuutta väestössä ja eri ammattiryhmissä (Nordic Occupational Cancer Study, NOCCA). Helsingin yliopistollisen keskussairaalan (HYKS) Naistenklinikalla tehdyssä retrospektiivisessä tutkimuksessa analysoitiin vuosina 1990 2001 hoidettujen kohtusarkoomapotilaiden eloonjäämisennustetta ja ennusteellisia tekijöitä. Monikansallisessa syöpärekisteritutkimuksessa selvitettiin riskiä sairastua uuteen syöpään kohtusarkoomaan sairastumisen jälkeen vuosina 1943 2000. Sekä kohdun leiomyosarkooman ilmaantuvuuden (0.4 0.5/100 000) että endometriumin stroomasarkooman ilmaantuvuuden (0.2/100 000) todettiin säilyneen Pohjoismaissa lähes ennallaan vuosina 1987 2007. Kohdun leiomyosarkooman ilmaantuvuus oli suurinta 45 59-vuotiaiden naisten ikäryhmässä. Endometriumin stroomasarkooman ilmaantuvuus kasvoi aina 45 49-vuotiaiden ikäryhmään saakka ja pysyi ennallaan sitä vanhemmissa ikäryhmissä. NOCCA-kohortin analyysi osoitti, että nahkatyöntekijöillä, maanviljelijöillä sekä opettajilla oli kohonnut riski sairastua kohdun leiomyosarkoomaan. Vuosina 1990 2001 HYKS Naistenklinikalla hoidettiin 100 kohtusarkoomapotilasta: 40 karsinosarkoomaa, 39 leiomyosarkoomaa ja 21 endometriaalista stroomasarkoomaa. Kohtusarkoomapotilaista oli 2, 5 ja 10 vuoden kohdalla elossa 65 %, 56 % ja 38 %. Eri kohtusarkoomaluokissa 5 vuoden jälkeen oli elossa 49 % (karsinosarkooma), 57 % (leiomyosarkooma) ja 65 % potilaista (endometriaalinen stroomasarkooma). Kohtusarkoomien ennusteeseen liittyviä kliinisiä tekijöitä olivat taudin levinneisyys, kasvaimen koko, potilaan ikä sekä synnyttäneisyys. Immunohistokemiallisissa tutkimuksissa todettiin, että estrogeenireseptori-α- sekä progesteronireseptoripositiivisuus liittyivät tilastollisesti merkitsevästi kohdun leiomyosarkooma¬potilaiden parempaan ja proteiini p53 -positiivisuus huonompaan ennusteeseen. Monikansallisen syöpärekisteritutkimuksen kohortti koostui 8606 kohtusarkoomapotilaasta, joilla todettiin seuranta-aikana 499 uutta syöpää. Näillä potilailla oli 26 % suurempi riski sairastua uuteen syöpään elinaikanaan verrattuna muuhun väestöön. Lisääntynyt riski havaittiin koskien suu- ja nielu-, paksu- ja peräsuoli-, keuhko-, rinta-, virtsarakko-, munuais- ja kilpirauhassyöpää sekä pehmytkudossarkoomaa. Yhteenvetona voidaan todeta, että kohdun leiomyosarkooman ja endometriaalisen stroomasarkooman ilmaantuvuus Pohjoismaissa on ollut lähes muuttumaton 30 vuoden ajan. Kohdun leiomyosarkooman riski oli kohonnut nahkatyöntekijöiden ja eläinpölylle altistuneiden (maanviljelijät) ammattiryhmien keskuudessa. Taudin levinneisyys, potilaan ikä, kasvaimen koko sekä synnyttäneisyys olivat yhteydessä kohtusarkoomapotilaan ennusteeseen ja estrogeenireseptori-α, progesteronireseptori ja proteiini p53 olivat yhteydessä leiomyosarkoomapotilaiden ennusteeseen. Kohtusarkooman sairastaneiden naisten riski sairastua uuteen syöpään oli 26 % suurempi kuin verrokkiväestöllä. Suurentunut riski voi liittyä aiempiin syöpähoitoihin (säde- ja solunsalpaajahoidot), mutta taustalla saattaa olla myös syöpien yhteiset, yleiset riskitekijät

Clinical factors as prognostic variables among molecular subgroups of endometrial cancer

Background Clinical factors may influence endometrial cancer survival outcomes. We examined the prognostic significance of age, body mass index (BMI), and type 2 diabetes among molecular subgroups of endometrial cancer. Methods This was a single institution retrospective study of patients who underwent surgery for endometrial carcinoma between January 2007 and December 2012. Tumors were classified into four molecular subgroups by immunohistochemistry of mismatch repair (MMR) proteins and p53, and sequencing of polymerase-epsilon (POLE). Overall, cancer-related, and non-cancer-related mortality were estimated using univariable and multivariable survival analyses. Results Age >65 years was associated with increased mortality rates in the whole cohort (n = 515) and in the "no specific molecular profile" (NSMP) (n = 218) and MMR deficient (MMR-D) (n = 191) subgroups during a median follow-up time of 81 months (range 1-136). However, hazard ratios for cancer-related mortality were non-significant for NSMP and MMR-D. Diabetes was associated with increased overall and non-cancer-related mortality in the whole cohort and MMR-D subgroup. Overweight/obesity had no effect on outcomes in the whole cohort, but was associated with decreased overall and cancer-related mortality in the NSMP subgroup, and increased overall and non-cancer-related mortality in the MMR-D subgroup. Overweight/obesity effect on cancer-related mortality in the NSMP subgroup remained unchanged after controlling for confounders. High-risk uterine factors were more common, and estrogen and progesterone receptor expression less common in NSMP subtype cancers of normal-weight patients compared with overweight/obese patients. No clinical factors were associated with outcomes in p53 aberrant (n = 69) and POLE mutant (n = 37) subgroups. No cancer-related deaths occurred in the POLE mutant subgroup. Conclusions The prognostic effects of age, BMI, and type 2 diabetes do not appear to be uniform for the molecular subgroups of endometrial cancer. Our data support further evaluation of BMI combined with genomics-based risk-assessment.Peer reviewe

American Society of Anesthesiologists physical status score as a predictor of long-term outcome in women with endometrial cancer

Objective To study the association of the American Society of Anesthesiologists (ASA) physical status score with long-term outcome in endometrial cancer. Methods Overall, disease-specific and non-cancer-related survival were estimated using simple and multivariable Cox regression analyses and the Kaplan-Meier method. Results A total of 1166 patients were included in the study. Median follow-up time was 76 (range 1-136) months. All-cause and non-cancer-related mortality were increased in patients whose ASA physical status score was III (HRs 2.5 and 8.0, respectively) or IV (HRs 5.7 and 25, respectively), and cancer-related mortality was increased in patients whose score was IV (HR 2.7). Kaplan-Meier analyses demonstrated a worse overall, disease-specific and non-cancer-related survival for patients whose score was >= III (p= III in both subgroups of stages (p=0.003 and p=0.017 for stage I and stages II-IV, respectively). ASA physical status score remained an independent predictor of all-cause mortality (HR 2.2 for scores >= III), cancer-related mortality (HRs 1.7 and 2.2 for scores >= III and IV, respectively) and non-cancer related mortality (HR 3.1 for scores >= III) after adjustment for prognostically relevant clinicopathologic and blood-based covariates. ASA physical status score also remained an independent predictor of cancer-related mortality after exclusion of patients who were at risk for nodal involvement based on features of the primary tumor but who did not undergo lymphadenectomy, and patients with advanced disease who received suboptimal chemotherapy (HRs 1.6 and 2.5 for scores >= III and IV, respectively). Conclusions ASA physical status score independently predicts overall survival, disease-specific survival, and non-cancer-related survival in endometrial cancer.Peer reviewe

Molecular characterization in the prediction of disease extent in endometrial carcinoma

Objective: Patients with endometrial carcinoma are usually triaged to staging lymphadenectomy selectively based on estimated risk of lymphatic spread. The risk is generally assessed by the presence of uterine risk factors, but their preoperative and intraoperative identification remain a challenge. The objective of this study was to assess the capability of molecular classification, described by The Cancer Genome Atlas (TCGA), to predict the stage of endometrial carcinoma. Study design: Sequencing of polymerase-epsilon (POLE) and immunohistochemistry of mismatch repair (MMR) proteins and p53 were performed to stratify endometrial carcinomas into subgroups of POLE exonuclease domain mutation (EDM), MMR deficiency, abnormal p53 (p53 abn) and 'no specific molecular profile' (NSMP). NSMP was the reference subgroup for comparisons. Associations of molecular subgroups and uterine risk factors with stage were examined in univariable and multivariable analyses. Results: Six hundred and four patients were included in the study. None of the POLE EDM tumours extended beyond the uterine cervix. In an unadjusted analysis, p53 abn was associated with increased risk for stage IIIC-IV disease [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.3-9.2; p <0.0005]. When controlling for uterine risk factors (histotype and grade, depth of myometrial invasion, tumour size, lymphovascular space invasion), p53 was not an independent predictor of advanced disease. In contrast, POLE EDM independently predicted local disease (OR 0.12, 95% CI 0.015-0.99; p = 0.049 for stage II-IV cancer). Of the molecular subgroups, p53 abn was most strongly associated with the presence of high-risk uterine factors (ORs between 2.2 and 19; p Conclusion: Of the TCGA-based molecular subgroups, POLE EDM independently predicted early stage endometrial carcinoma. Although p53 abn was not an independent predictor of advanced disease, its association with uterine risk factors could allow utilization of molecular data in deciding the type of staging surgery if knowledge of uterine factors is deficient. (C) 2020 Elsevier B.V. All rights reserved.Peer reviewe

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.Facultad de Ciencias Naturales y Muse

Interleukin 8 activity influences the efficacy of adenoviral oncolytic immunotherapy in cancer patients

After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy. We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses. We found high baseline serum IL-8 concentration to be independently associated with poor prognosis (p <0.001). Further, normal baseline IL-8 was associated with improved prognostic potential of calculation of the neutrophil-to-lymphocyte ratio (p <0.001). Interestingly, a decrease in IL-8 concentration after treatment with oncolytic adenovirus predicted better overall survival (p <0.001) and higher response rate, although this difference was not significant (p=0.066). We studied the combination of adenovirus and IL-8 neutralizing antibody ex vivo in single cell suspensions and in co-cultures of tumor-associated CD15+ neutrophils and CD3+ tumor-infiltrating lymphocytes derived from fresh patient tumor samples. These results indicate a role for IL-8 as a biomarker in oncolytic virotherapy, but additionally provide a rationale for targeting IL-8 to improve treatment efficacy. In conclusion, curtailing the activity of IL-8 systemically or locally in the tumor microenvironment could improve anti-tumor immune responses resulting in enhanced efficacy of adenoviral immunotherapy of cancer. © Taipale et al.Peer reviewe

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.Facultad de Ciencias Naturales y Muse

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Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness

Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.Peer reviewe

Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.Peer reviewe