Large desmoid tumors in familial adenomatous polyposis: a successful outcome

Vítor Devezas

Centro Hospitalar de São João, Portugal

University of Porto, Portugal

Laura Elisabete Barbosa

Centro Hospitalar de São João, Portugal

University of Porto, Portugal

Rosa Ramalho

Centro Hospitalar de São João, Portugal

Cristina Sarmento

Centro Hospitalar de São João, Portugal

José Costa Maia

Centro Hospitalar de São João, Portugal

Desmoid tumors (DT) develop from connective tissue, fasciae, and aponeuroses,1^,2 corresponding to a monoclonal proliferation of well-differentiated fibroblasts.3^-5 This can occur in the context of familial adenomatous polyposis (FAP), or may arise sporadically; also they may be extra-abdominal, intra-abdominal, or located in the abdominal wall.5 DT is considered a benign neoplasm due to the absence of metastasis, but has a great local aggressiveness, given the infiltrative growth and the invasion of adjacent structures,6 with a high local recurrence rate, ranging from 25% to 85%.2^,7

The familial form of this neoplasm may occur between 10% and 25% of FAP patients and is attributed to a germline mutation in the adenomatous polyposis coli (APC) gene.8^,9 The carriers of these mutations have “850 times greater risk than the general population.”2^,10 The sporadic forms of DT result from somatic mutations in the APC or the beta-catenin genes5^,11 and are relatively rare, affecting approximately two to five individuals per million per year in the general population.12^,13

FAP is an inherited condition “that results from the autosomal dominant transmission of a germline mutation in the APC tumor suppressor gene,” which is located on the long arm of chromosome 5.10 This pathology is characterized by the development of several (hundreds to thousands) of adenomatous polyps in the colon and rectum, with a subsequent risk of developing colorectal carcinoma.14 These patients have the risk of extra-colic manifestations like DT, upper gastrointestinal tract adenomas, osteomas, epidermoid cysts, as well as thyroid, adrenal gland, and central nervous system neoplasms.7 Of these, DT are the most frequent cause of death (after colorectal carcinoma) in patients with FAP, with mortality ranging from 18% to 31% (more than periampullary carcinomas at about 22%).15

We present the case of a 54-year-old woman with FAP in the context of germline APC mutation. She had undergone an open total colectomy 8 years before, after more than 10 years of endoscopic surveillance. Pathology revealed one site with an in situ adenocarcinoma (without positive nodes on the 68 isolated) and more than 100 adenomatous polyps with dysplasia. The patient preferred to preserve the rectum and maintain endoscopic surveillance.

During follow-up, an infiltrative solid intra-abdominal lesion in the root of the mesentery was identified in computed tomography and confirmed by magnetic resonance imaging. The hypothesis of peritoneal carcinomatosis was raised. A surgical biopsy was performed, revealing a fusiform cell tumor, which was consistent with reactive fibrosis.

At a multidisciplinary meeting, since the lesion was large, it was decided to initiate medical treatment with Cox-2 inhibitors, but no therapeutic response was observed. The disease progressed, and an intestinal obstruction developed due to a new lesion in the root of the mesentery, which measured 157 × 140 × 95 mm. Therefore, the patient underwent an en-bloc segmental enterectomy and R2 resection of the retroperitoneal tumor, with histological confirmation of a DT (Figure 1A-D). C-Kit mutations and the presence of estrogen-receptors were tested, but both markers were negative.

Figure 1
Photomicrograph of the retroperitoneal tumor. A - A sparse proliferation of elongated, slender, spindle-shaped cells of uniform appearance, set in a collagenous stroma (H&E); B - Cells with lack of hyperchromasia or atypia and with small, pale-staining nuclei. These cells are usually arranged in sweeping bundles (H&E); C - Lesion within the enteric wall (arrows) (H&E); D - Histochemistry showing strong expression of vimentin.

The patient was started on tamoxifen initially with 20 mg/day, increasing up to 40 mg/day, but because of a diagnosis of cholelithiasis it was decreased again to 20 mg/day. However, due to disease progression with the appearance of new lesions (Figure 2A), the chemotherapy regimen with dacarbazine (300 mg/m²) and doxorubicin (20 mg/m²)—administered at day 1, 2, and 3, and repeated every 21 days—was approved by the Institutional Ethics Committee. This regimen was further switched, after eight cycles, to vinorelbine (25 mg/m²) and methotrexate (30 mg/m²) because of the patient’s intolerance (with myelosuppression) and the progression of the pelvic lesion—albeit with the regression of all others. There was a significant response to this last protocol—administered at day 1, 8, and 15, and repeated every 28 days—with dimensional regression of all lesions (Figure 2B) and pain resolution after 14 cycles of chemotherapy.

Figure 2
A - Abdominal magnetic resonance imaging (MRI) T1-weighted image, acquired in the axial plane, showing two new lesions (arrows); B - Abdominal MRI T1-weighted image, acquired in the axial plane, after chemotherapy, showing the regression of previous lesions.

DT may arise sporadically or in the context of an extra-colic manifestation of FAP, and may be intra-abdominal, located in the abdominal wall, or extra-abdominal.5^,10^,11 They comprise only 0.03% of all neoplasms and 3% of all soft tissue tumors. The majority of cases occur between the ages of 15 and 60 years, with a peak incidence between 25 and 35 years.16

Despite being considered benign tumors, due to the lack of metastasizing capability DT has great local aggressiveness and the potential for local recurrence.6^,17 The most frequent locations are the small-bowel mesentery, followed by the abdominal wall, the extremities, and the trunk.12

The etiology of this condition is still not well understood. However, trauma or muscle strain (like surgical stress) induces a disproportionate inflammatory response, with an accumulation of fibroblasts. Another theory is that there is an endocrine factor related to neoplasm, since DT are more common in women—either when they’re pregnant or using hormonal contraceptives, and some women develop the tumor without previous trauma.17^,18

Therefore, surgical trauma may be implicated as one of the factors capable of leading to the development of DT, and appears unrelated to a specific type of surgery.8 Nevertheless, some authors observed a lower incidence of DT in laparoscopic versus open procedures, so minimally invasive approaches might presumably reduce the risk of the occurrence of DT after prophylactic colectomy in patients with FAP.10^,19

The mutation site on the APC gene may also interfere with the risk of development of DT and its severity. Mutations located distally to codon 1309 and especially at the 3′ end, are associated with a high risk of developing DT, and particularly in a severe form.12^,20^,21 Bertario et al.8 stated that, in patients with FAP, mutations located beyond codon 1309 and codon 1444 (“desmoid region”) increase 17-fold and 12-fold, respectively, the risk of DT development, compared with mutations located upstream.

In the case of intra-abdominal DT, the approach should be progressive,10 initially with observation,4 followed by medical treatment, as the first line, with non-steroidal anti-inflammatory drugs (NSAIDs; e.g. sulindac or celecoxib, with an efficacy rate close to 50%), or an anti-hormonal agent (tamoxifen or toremifene),14^,22^,23 even in estrogen receptor-free DT, because this therapy may still induce a response in that setting.24^,25 If tumor progression persists, chemotherapy should be started.10^,26 Surgery remains the final option10 in cases of resistance to medical treatment for symptomatic control, or resolution of tumor-related complications, such as intestinal obstruction, ischemia, enteric fistula, and hydronephrosis.1^,27^,28

However, in resectable extra-abdominal or abdominal wall DT, surgery may be an appropriate first-line treatment.29 Otherwise, a progressive approach similar to intra-abdominal DT is preferred.10

Although controversial, radiation therapy may be an alternative to surgery.30 Studies6^,31 confirm the important role of such therapeutic modality in cases of unresectable abdominal wall,32 extra-abdominal DT, or after R1 resections. Either pre- or post-operatively, radiotherapy can model fibrosis, with the consequent decrease in local recurrence.14^,33 In intra-abdominal DT, radiotherapy is rarely used, because of the low tumoral radiosensitivity10 and because of the risk of radiation enteritis.14

The role of chemotherapy in this setting was demonstrated by the efficacy of low doses of doxorubicin and dacarbazine, as well as the combination of methotrexate and vinblastine, in a progressive disease that did not respond to the medical therapy, which consisted in NSAIDs and anti-hormonal agents.26^,34^-36 Other combination therapy that demonstrated good response was cyclophosphamide plus doxorubicin,26 and doxorubicin plus tyrosine kinase inhibitors (TKI).37 For example, imatinib may have a role in the management of unresectable or difficult to resect DT.38 Sorafenib, another TKI, demonstrated a response in DT, especially in the extra-abdominal variety, and may be an option when chemotherapy fails.37

These patients should be managed by a multidisciplinary team, with individualized approaches and decisions. The strategy in intra-abdominal DT should be progressive, beginning with observation, followed by NSAIDs (e.g. sulindac), and/or an anti-hormonal agent (e.g. tamoxifen). If an unsatisfactory response persists and disease progression ensues, chemotherapy needs to be started. Surgery should be reserved for the final option, or for the resolution of tumor-related complications.

The authors declare that they have collected an informed consent from the patient to publish this article.