1 DIAGNOSIS AND MULTIDISCIPLINARY TREATMENT OF SPORADICAL DESMOID TUMORS Ph.D. Thesis Zoltán Tamás Mátrai, M.D. Promoter: Prof. dr. Miklós Kásler Ph.D., D.Sc., Dr.h.c. National Institute of Oncology Budapest

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1 DIAGNOSIS AND MULTIDISCIPLINARY TREATMENT OF SPORADICAL DESMOID TUMORS Ph.D. Thesis Zoltán Tamás Mátrai, M.D. Promoter: Prof. dr. Miklós Kásler Ph.D., D.Sc., Dr.h.c. National Institute of Oncology Budapest Szeged 2012 2 I. PUBLICATIONS II. III. IV. TABLE OF CONTENTS 1. Publications related to the thesis... ABBREVIATIONS... INTRODUCTION 1. Definition Epidemiology Clinical presentation Symptomatology Clinical behaviour Etiology The neoplastic nature of desmoids Desmoid tumor and β-catenin/apc Wnt signaling pathway β-catenin and desmoid tumors APC and desmoid tumors The endocrine etiology of desmoids Desmoid etiology and wound healing Histology Differential diagnosis Clinical diagnostic of desmoid tumors The value of the different biopsy methods in the diagnosis of desmoid Tumors Imaging features Evaluation of FAP associated desmoid tumors Treatment of desmoid tumors Observation Surgical treatment of desmoid tumors Special surgical considerations by intra-abdominal desmoid tumors Special surgical considerations by thoracic desmoid tumors Special surgical considerations by abdominal desmoids Special surgical considerations by extra-abdominal desmoids Non-surgical treatments of desmoid tumors Non-surgical locoregional therapy of desmoid tumors Radiation therapy Locoregional chemotherapy Non-surgical systemic therapy of desmoid tumors Antihormonal therapy Non-steroidal anti-inflammatory drugs Interferon Cytotoxic chemotherapy Targeted therapies: Imatinib mesylate and sorafenib Posttreatment surveillance... AIMS OF THE THESIS... V. MATERIALS AND METHODS The creation of a cohort of sporadic desmoid cases and a data base Confirmation of the sporadical origin of desmoid tumors by ruling out the 3 germ line mutation of APC gene Detection of the β-catenin mutation status with locked nucleic acid (LNA) probe-based real-time polymerase chain reaction (PCR) followed by melting curve analysis Three groups were formed following the analysis and comparison of clinical and pathological data: sporadical desmoid tumors of the chest, abdominal wall tumors and fibromatoses originating in the extremities Assessment of the expression of ERs and PRs in sporadical desmoid tumors by immunohistochemical assays Statistical methods... VI. RESULTS The successful gathering of a cohort of sporadic desmoid cases and creation of a database Confirmation of the sporadical origin by ruling out germ line mutations of the APC gene by genetic investigations The detection of the β-catenin mutation status CTNNB1 mutations are highly prevalent in sporadic desmoid tumors CTNNB1 45F mutations significantly correlate with increased desmoid recurrence The analysis and comparison of the clinical and pathological data of the sporadical desmoids in the three subgroups Sporadical desmoid tumors of the chest Sporadical desmoid tumors of the abdominal wall Sporadical desmoid tumors of the extremities Comparisons of the clinical results among the three cohorts of different tumor locations Assessment of the expression of ERs and PRs in sporadical desmoid tumors by immunohistochemical assays. VII. DISCUSSION Successful creation of a cohort of sporadic desmoid cases and a database 2. Confirmation of the sporadical origin of the desmoid tumors The detection of the β-catenin mutation status Three subgroups formed as a consequence of the analysis and comparison of the clinical and pathological data of sporadical desmoid tumors Sporadical desmoid tumors of the chest Sporadical desmoid tumors of the abdominal wall Sporadical desmoid tumors originating in the extremities Comparisons of the clinical results among the three cohorts of different tumor locations Assessment of the expression of ERs and PRs in sporadical desmoid tumors. VIII. NEW STATEMENTS... IX. MAGYAR ÖSSZEFOGLALÓ. X. REFERENCES XI. APPENDIX 1. LIST OF FIGURES 2. LIST OF TABLES 4 XII. ACKNOWLEDGEMENT XIII. PUBLICATIONS 5 I. PUBLICATIONS 1. Publications related to the thesis 1. Mátrai Z, Tóth L, Szentirmay Z, Papp J, Langmár Z, Kásler M. Multidisciplinary treatment of intra-thoracic desmoid tumours: case series and narrative review. Med Sci Monit. 2012, 18: IF: 1.699* 2. Mátrai Z, Tóth L, Szentirmay Z, Papp J, Antal I, Vadász P, Bartal A, Kásler M. Surgical challenges of chest wall and intra-thoracic desmoid tumors. Orvosi Hetilap. 2011, 152: Mátrai Z, Tóth L, Gulyás G, Szabó E, Szentirmay Z, Kásler M. A desmoid tumor associated with a ruptured silicone breast implant. Plast Reconstr Surg. 2011, 127: 1-4. IF: 2.635* 4. Mátrai Z, Tóth L, Szentirmay Z, Vámos FR, Klepetko W, Vadász P, Kenessey I, Kásler M. Sporadic desmoid tumors of the chest: long-term follow-up of 28 multimodally treated patients. Eur J Cardiothorac Surg. 2011, 40: IF: 2.293* 5. Mátrai Z, Tóth L, Rényi Vámos F, Papp J, Gıdény M, Bartal A, Szentirmay Z, Kásler M. Giant intra-thoracic desmoid tumour. Case report. Med. Thor. 2010, 63: Mátrai Z, Papp J, Polgár C, Hitre E, Köves I, Oláh E, Andi J, Kiss A, Vámosi Nagy I, Tóth L, Orosz Z. Long-term experience with therapy of a Gardner's syndrome female, first presenting with extra-abdominal desmoid tumor, and review of the literature. Magy Seb. 2009, 62: ΣIF = * * Source: Magyar Tudományos Mővek Tárháza 6 ABBREVIATIONS AFAP Attenuated Familial Adenomatous Polyposis APC gene adenomatous polyposis coli gene Bcl-2 B-cell lymphoma 2 CI confidence interval CNB core needle biopsy c-erbb2 human epidermal growth factor receptor 2 CT computed tomography COX-2 cyclooxygenase-2 Dsh dishevelled EGFR epidermal growth factor receptor EORTC European Organization for Research and Treatment of Cancer ER-α estrogen receptor-alpha ER-β estrogn receptor beta EREs estrogen response elements FAP familial adenomatous polyposis 18F-FDG-PET/ CT 2-(fluorine 18) fluoro-2- deoxy-d-glucose-positron emission tomography FNA fine needle aspiartion GSK-3β glycogen synthase kinase-3β HA heteroduplex analysis HSC hematopoietic stem cell IMT inflammatory myofibroblastic tumor IHC immunohistochemistry Lef lymphoid enhancer-binding factor LRP LDL-receptor-related protein MLPA Multiplex Ligation-dependent Probe Amplification MRI magneting resonance imaging MSC mesencyhmal stromal cells NIO National Institute of Oncology NSAIDs non-steroidal anti-inflammatory drugs p53 protein 53 or tumor protein 53, a tumor suppressor protein that in humans is encoded by the TP53 gene PCR polymerase chain reaction PDGFR plateled-derived growth factor receptor PR progesteron receptor PTT protein truncation test RECIST Response Evaluation Criteria in Solid Tumors RPC/IPAA restorative proctocolectomy with ileal pouch anal anastomosis RR response rate RT radiotherapy SERM selective estrogen receptor modulator SMA smooth muscle actin SUV standardized uptake value SSCP single-strand conformation polymorphism Tcf T-cell factor TPC total proctocolectomy US ultrasonograpy WHO World Health Organization Wnt a hybrid of Int (integration 1) and Wg (wingless) in Drosophila, characterized by Wnt gene 7 III. INTRODUCTION 1. Definition The World Health Organization (WHO) defines desmoid tumors or agressive fibromatoses, as clonal fibroblastic proliferations that arise in the deep soft tissues and are characterized by infiltrative growth and a tendency toward local recurrence but an inability to metastasize (1). Regarding the biological background of the tumor, it is classified between benign fibrous tissue proliferation and fibrosarcoma (1, 2). The entity was first described by John MacFarlane in 1832, and was named desmoid (from the Greek word desmos meaning band or tendon-like) by Johannes Müller in 1838 (3, 4). 2. Epidemiology Desmoid tumors are rarely occurring tumors which account for 0.03% of all neoplasms and 3% of all soft tissue tumors (2, 5, 6, 7, 8). The estimated annual incidence in the general population is 2 4 per million (5, 8, 9). Desmoids may be diagnosed at any age, but the peak incidence is between 25 and 40 years of age (2, 5, 9). Two different types have been described: most of them belong to the sporadically occuring type (95%) and the rest are associated with hereditary cancer syndromes (5%). The autosomal dominant familial adenomatous polyposis (FAP, Gardner syndrome), hereditary desmoid disease (HDD) and familial infiltrative fibromatosis (FIF) belong to the latter group with an incidence of 3.5% 32% in these patients (2, 8-13). The incidence of desmoids in FAP patients is approximately 850 to 1000 times that of the general population and was 29% in the original Gardner kindred (11, 14, 15). The sporadic types are more common in women than in men with a ratio between 1.8 : 1 and 5 : 1 (5, 9, 16, 17). 3. Clinical presentation Desmoids develop from musculoaponeurotic structures throughout the body and are classified as extra-abdominal (~ 60% of the cases), abdominal (~ 25% of the cases) and intra-abdominal (~ 15% of the cases) (2, 5, 7, 8, 15, 18, 19). Many studies have confirmed that 37 to 50% of desmoids arise in the abdominal region, and approximately 10% of all cases are multicentric (7, 19, 20). Significant differences were detected in the originating between sporadical and hereditary forms. While just 5% of sporadic tumors are intra-abdominal, 80% of patients with FAP-associated disease present with desmoids localised intra-abdominally (2). The anatomical distribution of extra-abdominal fibromatoses varies greatly. The principal sites 8 identified are the regions of the shoulder, chest wall, back, thigh and head and neck (1, 8). Abdominal desmoids arise from musculoaponeurotic structures of the abdominal wall, especially the rectus and internal oblique muscles and their fascial coverings. Intra-abdominal tumors develop in the pelvis, mesentery or retroperitoneum and are frequently found in patients with FAP, in whom it commonly originates in the retroperitoneal space following prophylactic proctocolectomy (5, 8, 13, 20). 3.1 Symptomatology The clinical manifestation of desmoid tumors is non-specific (21, 22). Symptoms are usually present for an average of months before diagnosis and the tumor is typically discovered as palpable mass by the patient or physician or accidentally by chest-abdominal imagines (Xray, CT, ultrasonograpy (US)) (5, 8, 15, 22, 23). Little or no pain accompanies extraabdominal fibromatoses, which typically arise as firm, poorly circumscribed, deep-seated, furtively grown masses (2, 5, 7, 24). Tumors are fixed to the musculoaponeurotic plane and are usually free in relation to the bone, and joint capsule, only rarely adhering to these. Muscular retractions, deformity, limited or lost joint functions or even the lifethreatening compression of vital organs may be caused if the tumor reaches a large size, and irradiated pain and paralysis may occur if the tumor compresses a nerve trunk (2, 5, 8, 11, 25). The skin and subcutis may only be involved after repeated surgery for recurrence or after radiation therapy (16, 25). Desmoids account for 0.2% of primary breast tumors, occassionally mimicing breast cancer (2, 8). Abdominal wall lesions are typically associated with young age, female gender, present or previous pregnancy often arising in the scar of a previous Cesarean section (5, 11, 25). Intra-abdominal desmoids remain asymptomatic until their growth and infiltration cause compression of visceral organs or serious morbidity (5, 8). Although asymptomatic abdominal mass is the only complaint of most patients with mesenteric lesions and only some have mild abdominal pain. Patients with diffuse mesenteric lesions may less commonly present with initial symptoms of intestinal, vascular, ureteric, or neural involvement, gastrointestinal bleeding, bowel perforation, obstruction or ischemia (5, 8, 25). Pelvic fibromatoses arise as slowly growing palpable masses, are initially asymptomatic, often mimicing ovarian neoplasms (5, 8, 25, 26). When a desmoid is diagnosed, a thorough family history is necessary to be taken, examination, genetic counseling and colonoscopy should be performed in order to diagnose or outrule Gardner s syndrome (25, 27). 3.2 Clinical behaviour 9 The clinical behavior and natural history of desmoids is typically heterogeneous and unpredictable due to the progressive fibroblastic and fibrous proliferation that lays in the background of its development. It is characterised not only by tumor growth, proliferation, and disease progression but also by stabilization and spontaneous remission (2, 7, 8, 11, 25, 28, 29). Church et al. (2008) found that 10% of agressive fibromatoses resolved spontaneously, 30% were unpredictably interchanging between progression and resolution, 50% remained stable following diagnosis, and 10% were characterised by rapid progression (30). Variant desmoid growth patterns have been identified: some progress rapidly and aggressively whereas others are more indolent and may remain stable (2, 8, 11, 15). Most desmoids are however slowly growing neoplasms typically measuring between 5 and 10 cm, they aggressively invade surrounding tissues and organs, do not metastasize but bear a high propensity for local recurrence (5, 11, 25). Despite their benign nature and their negligible metastatic potential, the tendency to recur and the infiltrative growth remain significant problems in terms of morbidity and mortality (5, 8). Overall recurrence rates range from 20% to 85% in 10 years following primary treatment, and recurrence is more frequent with extraabdominal than intra-abdominal desmoids (2, 5, 8, 11, 15, 25, 30-32). About 80% of recurrences are observed within 3 years postoperatively, even after radical excision (32-34). A close surveillance of patients is essential, as disease progression may occur even years after primary treatment (11). 4. Etiology The morphology of desmoid tumors has been well characterized, but their nature and pathogenetic background remained indistinctive. Stout (1954), who first introduced the term fibromatosis, defined desmoids as the most incomprehensible group (35). Some authors considered them as non-neoplastic processes and others described desmoids as welldifferentiated low grade sarcomas (2, 7, 9). In fact, the etiology is likely multifactorial and includes genetic, endocrine and physical factors as well (2, 5, 7, 8, 15, 25). The association of desmoids with FAP syndrome, first described by Nichols in 1923 is well known, and served as an evidence to the underlying genetic bacground (36). E. J. Gardner reported the familial occurrence of intestinal polyposis, osteomas and epidermal cysts in 1951, and although the current view is that Gardner syndrome is a variant of the phenotypic expression of FAP, the two terms are sometimes used as synonyms (37, 38). The role of endocrine factors in the pathogenesis are supported by clinical observations such as the female predominance, regular occurrence in the childbearing age, progression via the use of oral contraceptives, and 10 regression in post-menopausal or post-oophorectomy patients or those undergoing antiestrogen therapy (8, 11, 15, 25). An antecedent history of trauma to the site of the tumors, often surgical in nature (prophylactic proctocolectomy, Cesarean section), has been identified in about 25% of cases (5, 27, 30, 33) The neoplastic nature of desmoids Since desmoid tumors are characterised by infiltrative gorwth, low mitotic activity, and the absence of metastases, they are most frequently classified as benign neoplasms or deep fibromatoses (10). Multiple studies described the clonal nature of desmoids pointing at malignant capacities that place these tumors into the category of fibroblastic malignancies (8, 39-43). The presence of trisomy 8 and/or 20 (which are non-random clonal aberrations acquired during neoplastic progression) and the proportion of cells with these trisomies vary greatly between desmoid tumor specimens (range 0 to 25%) (8, 42-44). It can be therefore concluded that trisomies 8 and 20 contribute to neoplastic aberrations in a wide spectrum of pathologic fibrous proliferations, without any distinction between benign or malignant (8, 42, 43). The non-random inactivation of the female X-chromosome is a sign of monoclonal neoplastic proliferation (not a sign of malignancy), and its occurrence was also subject to investigation during the demonstration of the clonal nature of aggressive fibromatoses (8, 40, 45). A nonrandom X inactivation pattern was found in 72% of patients with sporadic desmoids, with a lesion clonality ratio ranging between 1.3 and 18.7 (40, 45). Evidence of malignancy has also been sought by assessing expression of tumor markers in desmoid tissue. In comparison to other malignancies, desmoids were found with a relatively low expression of metastasis promoting extracellular matrix proteins such as osteopontin and osteonectin, suggested to be the reason for the inability to disseminate (39, 45). Other common malignant tumor markers as Ki-67, prb or Bcl-2 have not been observed to be upregulated in desmoid tissue (39, 43, 46-48). Appropriate tumor markers may explain the clinical behavior of desmoids, and still need to be identified (10). Although the properties of desmoids and the lack of malignant tumor markers simply do not conform to the definition of malignant tumors, and the term benign is biologically valid, it does not properly reflect the clinical picture. To resolve this conflict the understanding of the molecular etiology of desmoids, identified by previous studies, is mandatory (8, 41, 49-51). A common feature detected is deregulated Wnt signaling via β-catenin dependent activation of latent T-cell factor/lymhpoid enhancer factor (Tcf/Lef), a pathway with a critical role for instance in embryogenesis, cell adhesion, 11 carcinogenesis, adult stem cell survival and self-renewal during wound healing (8, 41, 49). Desmoids arising in patients with FAP show loss of adenomatous polyposis coli (APC) tumor suppressor function, which leads to high intracellular β-catenin levels and is correlated with the constitutive activation of Wnt signaling (50, 51). In sporadic desmoids most tumors contain specific point mutations in the catenin (cadherin-associated protein) beta 1 (CTNNB1) gene, that stabilizes β-catenin and achieves a similar result described above (8, 52) Desmoid tumor and β-catenin/apc A germline mutation of the APC tumor suppressor gene predisposes patients with FAP to develop large numbers of colonic polyps and several extra-intestinal neoplasms including desmoid tumors (8, 10, 53). The germline mutation results in a null-allele of the APC gene while a somatic mutation in the other allele results in functionally homozygous knockout of the APC gene and the subsequent malignant transformation of the colonic polyps (47, 53). The precise location of the germline mutation within the gene or the associated genetic background of the affected individual determines the likelihood and form of occurrence of the somatic mutation, and the penetrance of the disease (28, 47, 54) Wnt signaling pathway Upon activation, APC forms a cytoplasmic multiprotein complex that includes glycogen synthase kinase (GSK)-3β and axin (8, 10, 55). APC and axin phosphorylate β-catenin on its APC binding sites, causing the degradation and inactivation of the protein. The binding of β- catenin to APC requires phosphorylation by GSK-3β. Axin promotes GSK-3β-dependent phosphorylation of β-catenin (56). Figure 1. The two major functions of β-catenin are forming a complex with E-cadherin and α-catenin functioning within the adherens junctions between neighboring cells, and, upon activation, translocating to the nucleus and binding to transcription factors of the Tcf-LEF family (8, 10, 57). In its unphosphorylated, active form, β-catenin stimulates DNA transcription through Tcf4 and consequent cell proliferation. A well-known nuclear protein involved in carcinogenesis, c-myc is one of the possible target genes of activated β-catenin (58). T
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