Desmoid tumor : Oncological management and prognostic biomarkers

Desmoid-type fibromatosis, also known as aggressive fibromatosis or desmoid tumors, are very rare neoplasms, accounting for 0.03% of all newly diagnosed neoplasms and less than 3% of all soft tissue tumors. Desmoid tumors occur in different anatomic locations in musculoaponeurotic tissues and may be painful, although they are seldom fatal. Approximately 10% of desmoid tumors are associated with an inherited condition called familial adenomatous polyposis (FAP) while the majority of desmoid tumor patients harbor a somatic mutation in the CTNNB1 gene. Indolent tumors are surveilled; however, progressing and symptomatic desmoid tumors are managed with surgery, radiotherapy, or systemic therapy. Different systemic approaches include non-steroidal anti-inflammatory agents, endocrine therapy, tyrosine kinase inhibitors, and chemotherapy. This thesis evaluated the outcome of oncological treatments at Helsinki University Hospital. We tried to seek novel molecular markers to identify different risk groups. We also aimed to illuminate the underlying pathobiological mechanisms in desmoid tumors. The patients were treated at Helsinki University Hospital between 1987 and 2010 in study I (49 radiotherapies) and until 2011 in studies III (n = 76) and IV (n = 83). The patterns of recurrences after radiotherapy were analyzed using image co-registration. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. were utilized for response evaluation in studies I and II; additionally, World Health Organization (WHO) criteria were used in study II. Study II examined the effect of cyclin-dependent kinase inhibitor ribociclib together with endocrine treatment in a patient with multifocal desmoid tumors and FAP. A tissue microarray was built of the formalin-fixed paraffin-embedded desmoid tumor specimen. The slides were immunohistochemically stained with Ki67, cyclin D1, cyclin A, and estrogen receptor β antibodies. Digitally assisted evaluation of the slides was carried out using Pannoramic Viewer software (3DHistech, Budapest, Hungary). Radiation dose was independently associated with time to progression in patients treated with surgery combined with radiotherapy or radiotherapy alone (hazard ratio 0.71, p = 0.02). Local control rate was 75% at five years. The majority of recurrences after radiotherapy occurred at the margin of radiotherapy target (82%, 9/11), two were in-target (18%, 2/11), but none was out-of-target. Ribociclin, goserelin, and letrozole reduced symptoms and stabilized multiple desmoid tumors in a patient with treatment-resistant multiple desmoid tumors for ten months. High expression of cyclin A predicted poor outcome after surgery (hazard ratio 1.9, p = 0.02) whereas Ki67 or cyclin D1 expression rate did not reach statistical significance. Estrogen receptor β expression level had a positive association with proliferation. This thesis is a comprehensive investigation of a rare disease entity. The results demonstrate that radiotherapy is an effective treatment in desmoid tumors. High cyclin A expression is a novel risk factor for recurrence after surgery.Desmoidit ovat erittäin harvinaisia kasvaimia, jotka kasvavat eri ruumiinosissa lihaksissa ja kalvojänteissä. Ne voivat aiheuttaa kipua, mutta johtavat vain harvoin kuolemaan. Noin 10%:lla desmoidipotilaista on familiaalinen adenomatoottinen polypoosi (FAP), kun suurimmalla osalla potilaista on somaattinen geenimutaatio. Rauhallisesti käyttäytyviä kasvaimia seurataan, mutta kasvavia ja oireisia desmoideja voidaan hoitaa leikkaamalla, sädehoidolla tai lääkehoidoilla. Käytettyihin lääkehoitoihin kuuluvat tulehduskipulääkkeet, hormonaalinen hoito, tyrosiinikinaasin estäjät ja solunsalpaajat. Tämän väitöskirjan tavoitteena oli arvioida onkologisten hoitojen tuloksia Helsingin yliopistollisessa keskussairaalassa. Pyrimme etsimään uusia biomerkkiaineita, joiden avulla voisimme erotella ennusteellisia ryhmiä. Lisäksi tarkoituksemme oli valaista desmoidien kehittymisen ja kasvun taustalla vaikuttavia patologisia ja biologisia tapahtumia. Potilaat hoidettiin Helsingin yliopistollisessa sairaalassa vuosien 1987 ja 2011 välillä. Sädehoitovasteet arvioitiin ja sädehoidon jälkeiset uusiutumat analysoitiin yhdistämällä kuvantamistutkimukset uusiutumista sädehoitosuunnitelmiin. Solusyklin estäjä ribosiklibin vaikutusta yhdessä hormonaalisen hoidon kanssa tutkittiin potilaalla, jolla oli FAP:iin liittyen useita desmoideja. Kudossirukokoelman desmoidikudosnäytteet värjättiin immunohistokemiallisesti Ki67-, sykliini D1-, sykliini A- ja estrogeenireseptori β -vasta-aineilla. Näytteet arvioitiin tietokoneavusteisesti. Korkeampi sädehoitoannos oli itsenäisesti yhteydessä pidentyneeseen etenemättömyysaikaan leikkauksen ja sädehoidon jälkeen tai yksin sädehoidon jälkeen. Paikalliskontrolli oli 75% viiden vuoden kohdalla. Sädehoidon jälkeen suurin osa uusiutumista ilmaantui hoitokohteen reunalle, kaksi oli sädehoitokohteessa, mutta yksikään ei kasvanut täysin kohdealueen ulkopuolella. Ribosiklibi, gosereliini ja letrotsoli vähensivät oireita ja vakauttivat monipesäkkeiset desmoidit kymmeneksi kuukaudeksi. Korkea sykliini A:n immunopositiivisuus ennusti nopeampaa uusiutumista leikkauksen jälkeen, kun taas Ki67:n tai sykliini D1:n ilmentymisellä ei havaittu merkittävää vaikutusta desmoidien uusiutumiseen. Estrogeenireseptori β:n korkeampi immunopositiivisuus oli yhteydessä solujen jakautumisnopeuteen. Tämä väitöskirja sisältää perusteellisen selvityksen harvinaisesta kasvaintyypistä. Tuloksemme selvästi osoittavat, että sädehoito on desmoidien tehokas hoitomuoto. Korkea sykliini A:n immunopositiivisuus on uusi lisääntynyttä uusiutumisriskiä ennustava tekijä leikkauksen jälkeen

Estrogen receptor beta expression correlates with proliferation in desmoid tumors

Background and objectivesEstrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ER beta) and cyclin D1 in desmoid tumors. MethodsThis study consists of 83 patients with a surgically treated desmoid tumor. ER beta and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work. ResultsMedian ER beta expression was 10.8%. ER beta expression correlated with expression of the proliferation antigens Ki67 (r(p)=0.35, P=0.003), cyclin D1 (r(p)=0.34, P=0.004), and cyclin A (r(p)=0.34, P=0.004). ER beta immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ER beta expression was related to high risk of relapse (hazard ratio [HR] 2.6; P=0.02).Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence. ConclusionsER beta and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ER beta expression might be predictive for postoperative recurrence.Peer reviewe

High cyclin A expression, but not Ki67, is associated with early recurrence in desmoid tumors

Background and Objectives: Desmoid tumors are soft-tissue tumors originating from myofibroblasts with a tendency to recur after surgery. High expression of proliferation markers is associated with shortened progression-free and/or overall survival in many neoplasms, including soft-tissue sarcomas. We investigated the prognostic role of cyclin A and Ki67 in desmoid tumors by immunohistochemistry. Methods: The study included 76 patients with desmoid tumor operated at Helsinki University Hospital between 1987 and 2011. A tissue micro array (TMA) was constructed and the TMA sections were immunostained with cyclin A and Ki67 antibodies. A computer-assisted image analysis was performed. Results: Cyclin A expression was evaluable in 74 and Ki67 in 70 patients. Cyclin A immunopositivity varied from 0% to 9.9%, with a mean of 1.9%. Cyclin A expression correlated significantly with Ki67. Cyclin A expression was associated with recurrence-free survival (HR 1.9, 95% CI = 1.1-3.2, P = .02), as were positive margin (HR 6.0, 95% CI = 1.6-22.5, P = .008) and extremity location (HR 5.3, 95% CI = 1.7-16.8, P = 0.005). Ki67 immunopositivity varied from 0.33% to 13.8%, with a mean of 4.6%, but had no significant prognostic impact (HR 1.1, P = .2). Conclusions: Our study indicates that cyclin A may be a new prognostic biomarker in surgically treated desmoid tumors.Peer reviewe

Local relapse of soft tissue sarcoma of the extremities or trunk wall operated on with wide margins without radiation therapy

Background: The quality of surgical margins is the most important factor affecting local control in soft tissue sarcoma (STS). Despite this, there is no universally accepted consensus on the definition of an adequate surgical margin or on which patients should be offered radiation therapy. This study focuses on local control and its prognostic factors in patients with trunk wall and extremity STS. Methods: Adult patients with a final diagnosis of trunk wall or extremity STS referred to a single tertiary referral centre between August 1987 and December 2016 were identified from a prospective institutional database. Patients were treated according to a protocol instituted in 1987. The classification of surgical margins and indications for radiation therapy were based on anatomy and strict definition of surgical margins as metric distance to the resection border. Local treatment was defined as adequate if patients received either surgery with wide margins alone or marginal surgery combined with radiation therapy. Margins were considered wide if the tumour was excised with pathological margins greater than 2.5 cm or with an uninvolved natural anatomical barrier. After treatment, patients were followed up with local imaging and chest X-ray: 5 years for high-grade STS, 10 years for low-grade STS. Results: A total of 812 patients were included with a median follow-up of 5.8 (range 0.5-19.5) years. Forty-four patients had a grade 1 tumour: there were no instances of recurrence in this group thus they were excluded from further analysis. Five-year local control in the 768 patients with grade 2-3 STS was 90.1 per cent in patients receiving adequate local treatment according to the protocol. Altogether, 333 patients (43.4 per cent) were treated with wide surgery alone and their 5-year local control rate was 91.1 per cent. Among patients treated with wide surgery alone, deep location was the only factor adversely associated with local relapse risk in multivariable analysis; 5-year local control was 95.3 per cent in superficial and 88.3 per cent in deep-sited sarcomas (hazards ratio 3.154 (95% c.i. 1.265 to 7.860), P = 0.014). Conclusion: A high local control rate is achievable with surgery alone for a substantial proportion of patients with STS of the extremities or superficial trunk wall.Peer reviewe

Radiotherapy in desmoid tumors Treatment response, local control, and analysis of local failures

Background Desmoid tumors (aggressive fibromatosis) are rare soft tissue tumors which frequently recur after surgery. Desmoid tumors arise from musculoaponeurotic tissue in the extremities, head and neck, abdominal wall, or intraabdominally. Our aim was to examine the outcome of radiotherapy of desmoid tumors in a single institution series. Patients and methods We evaluated 41 patients with desmoid tumors treated with 49 radiotherapies between 1987 and 2012. Radiologic images for response evaluation were reassessed and responses to treatment registered according to RECIST criteria 1.1. For patients with local failures radiation dose distribution was determined in each local failure volume using image co-registration. Recurrences were classified as in-target, marginal, or out-oftarget. Prognostic factors for radiotherapy treatment failure were evaluated. Results Radiotherapy doses varied from 20-63Gy (median 50 Gy) with a median fraction size of 2 Gy. The objective response rate to definitive radiotherapy was 55% (12/22 patients). Median time to response was 14 months. A statistically significant dose-response relation for definitive and postoperative radiotherapy was observed both in univariate (p-value 0.002) and in multivariate analysis (p-value 0.02) adjusted for potential confounding factors. Surgery before radiotherapy or surgical margin had no significant effect on time to progression. Nine of 11 (82%) local failures were classified as marginal and two of 11 (18%) in-target. None of the recurrences occurred totally out-of-target. Conclusions Radiotherapy is a valuable option for treating desmoid tumors. Radiotherapy dose appears to be significantly associated to local control.Peer reviewe