Sequential treatment of recurrent mesenteric desmoid tumor

Sequential Treatment of Recurrent Mesenteric Desmoid Tumor Thomas Bauernhofer, M.D.' Herbert Sttiger, M.D.' Marianne Schmid, M.D.' Michael Smda, M.D? Barbara Gum-Lackner, M A 3 Gerald Hofler, M.D? Gerhard Ranner, M.D.' mil Reisinger, M.D.' Hellmut Samonigg, M.D.'

' Department of Internal Medicine, Division of Oncology, Karl Franzens University, Graz, Austria.

'

Department of Surgery, Karl Franzens University, Graz. Austria. Department of Pathology, Karl Franzens University, Graz, Austria.

'

Department of Radiology, Karl Franzens University, Graz. Austria.

BACKGROUND. The optimal management of inoperable desmoid tumors is still unclear. We report a 26 year-old female patient with familial adenomatous polyposis suffering from a recurrent inoperable intraabdominal desmoid tumor and its sequential treatment. METHODS. Treatment strategies included low-dose tamoxifen (30 mg orally per day), high-dose tamoxifen (90mg orally per day), and a subsequent combination of goserelin acetate (3.6mg subcutaneously once every four weeks) plus low-dose tamoxifen, medroxyprogesterone acetate (1000 mg orally per day) and interferon gamma (3 Mio IU subcutaneously 3 times a week). RESULTS. The combination of goserelin acetate and low-dose tamoxifen resulted in a decrease in tumor size and a complete relief of symptoms for 17 months. Thereafter the tumor progressed and again growth was stopped with interferon gamma therapy for another 6 months.All other treatment modalities had no effect. CONCUISIONS. This study demonstrates long-term regression of a desmoid tumor with combined endocrine therapy using goserelin acetate plus tarnoxifen. Tumor progression after 17 months was again stopped by a combination of interferongamma and goserelin acetate. Cancer 199s; 721061-5. 6 1996 American Cancer Sociery.

KEYWORDS: desmoids, famlllal adenomatom polyposis, goserelin acetate, tamoxifen, medroxyprogestemne acetate, interferon gamma, adenomatom polyposi coli gene.

D

Address for reprints: Thomas Bauernhofer, M.O., Department of Internal Medicine, Division of Oncology, Auenbruggerplatz 15, A-8036 Graz. Austria. Received July 19, 1995; revision received November 13,1995; accepted December 11,1995. 0 1996 American Cancer Society

esmoid tumors are rare neoplasms of mature fibroblasts within an extensive collagen matrix. These tumors are classified pathologically as aggressive fibromatosis with local invasiveness, showing recurrences after surgical treatment, and do not metastasize. The incidence of desmoid tumors has been shown to be between 2 and 4 cases per 1 million people per year in Finland.' They constitute about 3.5% of all fibrous tissue tumors and 0.03% of all neoplasms.2 Desmoids are common features of the familial adenomatous polyposis syndrome (FAP), an autosornal dominantly inherited disease, characterized by multiple adenomatous colorectal polyps. FAP is associated with a variety of benign soft tissue tumors. Approximately 45% of these soft tissue tumors are desm o i d ~ The . ~ clustering of FAP with fibromas, epidermal and sebaceus cysts, and osieomas was first described as Gardner's ~ y n d r o m eTrauma .~ and endocrine and genetic factors seem to be implicated in the pathogenesis of desmoid tumors; however, the exact pathogenesis is unclear.' Because 55-72% of aggressive fibromatoses are located within the mesent e ~ ytheir , ~ extensive proliferative nature may lead to intestinal or ureteric obstruction or small bowel infarction. These tumors often recur after resection. The mortality associated with desmoid tumors was reported to be approximately 11%of all deaths in patients with FAP and 31% of deaths

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TABLE 1 Use of Endocrine Therapy for Desmoid Tumors in the Literature Reference

No. of patients

Drug

Wacdell el al." Kinzbninner el al.' Lanari ci at." lonrs el all' Procter ei al." Klciii rt al.," lioh ei al." Ralducri er al.'" Shapira et al. " Easter er al:'!' Eage! pi al." McKinnon et al," htfi et al." Spnrtielln ct al." CVilken et al." Tsukada er al."' Brooks el al.'. van [)am er al.'" Total

2 II

Tamoxifer. Tamoxifrr. M PA Tamoxifen and MAID Tamoxifen Tamoxifen Tamoxifen Tamoxifen Tamoxifen Tamnxifrn Tamoxifen and MPA Tamoxifen Tamoxifen and MAID Tamoxifen Tamoxifen, MPA. and gncerelin Tarnowifen. MPA, and M A I D Tamoxifen, tomerifen Tamnxifen. p e r r l i n . SSAID, IFN-alpha

2 I 4

I I 1 3 1 1 3

I 2 6 20 5 fi6

Response 2 1 6

I I 0 0 I 0 0 0

1 2 I 2 3 13 0 34

SlP.4: medromrnetwernne awlale: NHI[): nnnrlcrnidal aniiinflammalntv h i e s : IFN aloha: inlerferon-aloha

after colectorny, making it the second most common cause of death once colorectal cancer is excluded." Therefore, alternative treatment strategies, including radiation therapy.'." nonsteroidal antiinflammatory agents,"'." antiestrogen compounds (Table I ) , " '"and cytotoxic chemotherapyJg have been employed. We report on a patient with a recurrent desmoid tumor in the mesentery of the small intestine and its partially successful sequential treatment using tamoxifen, goserelin acetate, medroxyprogesterone acetate, and interferon-gamma.

Case report A 26-year-old female presented with cachexia, severe pain in the lower abdomen, and syniptoms of small bowel obstruction due to a palpable tumor in the left lower quadrant of the abdomen. Six years prior to presentation, the patient had her first episode of hematochezia. Three years prior to presentation, barium enema examination of the colon and colorioscopy showed hundreds of polvps in the entire colon and rectum. The histologyof the biopsies revealed adenomas without signs of malignancy. A total proctocolectomy with ileostomy was performed. Due to a dense nodular tumor adherent to the left flexure of the colon and the spleen being suggestive for malignant infiltration, the spleen and the omentum were resected. Because the mobilized small bowel was too short for anastomosis with the anus, a restorative procedure was technically not possible. Histologic workup showed a desmoid tumor in the mesentery of the small bowel

without malignant infiltration. One year later, abdominal pain led to the diagnosis of a recurrent desmoid tumor in the mesentery of the small bowel. Two attempts to resect this tumor failed due to multiple adhesions and impaction of numerous jejunal and ileal loops. The patient was treated primarily with low dose tamoxifen (30 mg orally per day) but the tumor progressed continuously. An ureter stent was implanted due to a subtotal stenosis of the left ureter. Subsequently, high dose treatment with tamoxifen (90 mg orally per day) was started as suggested in the literature." Although no further tumor progression was observed after 8 weeks of treatment, severe pain, symptoms of small bowel obstruction, and intermittent urogenital tract infections due to the ureter stent continued. To block the endogenous estrogen and progesterone production, the luteinizing hormone-releasing hormone (LHRH) analogue goserelin acetate (3.6 mg subcutaneously every 4 weeks) was introduced. The tamoxifen dosage was reduced to 30 rng per day. This combination therapy led to a complete relief of pain within 2 weeks. A decrease in the size of the desmoid tumor to less than 50% of the initial volume was found by sequential compwed tomography scans within 3 months (Figs. 1 and 2). The ureter stent was removed. The patient gained 10 kg of bodyweight. The side effects were amenorrhea and intermittent hot flashes. Continuing this therapy, the patient had n o tumor related symptoms and tumor size remained stable for 17 months as assessed by computed tomography scans.

Treatment of Recurrent Dasmoid TumorlBauernhofer et al.

FIGURE 1. Computed tomography scan of the abdomen showing the desmoid tumor (arrow) before goserelin acetate treatment Thereafter, tunior progression was noted and symptoms of small bowel obstruction recurred (Fig. 3). Enterolysis and two enteroanastomoses bypassing the infiltrated and obstructed loops were made. Tanioxifen treatment was withdrawn and replaced by medroxyprogesterotie acetate (1000 mg orally per day) concomitantly to gosereliri acetate treatment. Tumor size increased twofold within a 3-month period. The reimplantation of a double-l stem was essential due to urinary obstruction. Treatment with medroxyprogesterone acetate was withdrawn while goserelin was continued and interferon-gamma l b (3 Mio 1U subcutaneously 3 times a week) was initiated. Tumor progression was stopped for another 6 months and a softening of the desmoid tumor was observed clinically. Fever was the primary side effect of interferon-ganima treatment; therefore, the intervals of treatment had to be extended to once a week. After several episodes of pulmonary embolism and the occurrence of multiple abscesses within the desmoid tumor, the patient died 7 years after diagnosis. The autopsy confirmed all clinical findings. Occlusion of pelvic veins due to compression of the inferior vena cava by the tumor had led to massive pulmonary embolism and death. Family history for polyposis coli or desmoid tumors was negative but a granduncle of the patient had died of colon cancer at the age of 43 years. It is remarkable that the patient’s father and his two sisters committed suicide due to severe endogenous depression, her brother is suffering from endogenous depression, and the patient herself once tried to commit suicide. We examined ten h i n g first-degree relatives (all on the patient’s mother’s side1 with respect to physical status, laboratory data, barium enema with double contrast, and X-ray of the skeleton. N o signs of FAP were found. Polymerase chain reaction analysis of the genoniic DNA isolated from lymphocytes from all the relatives investigated did not reveal mutations of the adenomatous pol-

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FIGURE 2. Computed tomography scan of the abdomen showing partial response of the desmoid tumor (arrow) 3 months after initiation of goserelin acetate treatment.

FIGURE 3. Computed tomography scan of the abdomen showing progression of the desmoid tumor (arrow) 22 months after initiation of goserelin acetate treatment,

yposis coli gene.”’ .” Sequence analysis of DNA isolated from tumor tissue of the index patient did not show deviations from the normal sequence in the mutation cluster region of the adenomatous polyposis coli gene.’.’ Due to these findings, no conclusion regarding hereditary or sporadic occurrence of the FAP syndrome in this family could be drawn.

DISCUSSION Formation of desmoid tumors in FAP often follows abdominal surgery but spontaneous occurrence discovered at initial surgery (as in this patient) has rarely been reported.‘ Surgical trauma seems to be a promoting factor in desmoid formation and a recurrence rate of u p to 50%, despite wide margin resection, has been described. ’”

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Therefore, surgical treatment strategies are controversial. recombinant interferon-gamma 1b, which led to a cessaMost authors consider surgery as the appropriate firsttion of tumor progression for another 6 months. line treatment a ppr~a c h,~.’.’~ but some authors recomThrombosis has been described as a complication of mend that resection of mesenteric desmoids should be tamoxifen treatn~ent.~’ However, in our patient, tamoxidelayed and reserved for the relief of symptomatic obfen treatment had been withdrawn 14 months before s t r u c t i o n ~However, . ~ ~ ~ ~ ~because of the high failure rate massive pulmonary embolism led to death. The autopsy of this procedure, other treatment modalities are being revealed compression of the inferior vena cava by the tumor and thrombotic occlusion of pelvic veins as a possought. sible cause for the embolism. Therefore, an association A hormonal dependance on the growth of desmoids between tamoxifen and pulmonary embolism does not is suggested because the highest growth rate is observed seem likely in our patient. in hormonally active women, during or shortly after pregRecent studies have demonstrated somatic and n a n c i e ~ , ~or, ~following ,~~ exposure to oral contracepgermline mutations on the long arm of chromosome 5, tives.’’ Abdominal fibromatosis could be induced by estrogens in animal experiments.36Estrogen receptors were including the adenomatous polyposis coli gene in desdemonstrated in the cytosol fraction in different percentmoid tumors of patients with FAP ~ y n d r o m e .Interest~~*~~ ages.’.”’ However, in another report, reactivity for estroingly, the long arm of chromosome 5 contains neurogen receptors was not f ~ u n d . In ~ ”our patient, estrogen transmitter receptor genes, which were associated with and progesterone receptors were negative. Reviewing the inheritance of manic depressive illness.44A defect in previously published reports, we found that an objective either of these genes may have contributed to the high response could be seen in 34 patients (52%) of 66 patients rate of suicide and depressive illness in this family. with desmoid tumors treated with endocrine therapy (TaThis report demonstrates the responsiveness of desble 1). moid tumors to endocrine treatment with goserelin aceInitially, neither a low dose nor a high dose tamoxifen tate plus tamoxifen. Recombinant interferon-gamma 1b treatment alone yielded tumor regression in our patient. might be beneficial if unresectable desmoids are no To block the endogenous estrogen and progesterone prolonger hormonally responsive. duction, the luteinizing hormone-releasing hormone analogue goserelin acetate was introduced in addition to low dose tamoxifen therapy. This combination led to a 1. Reitamo JJ, Scheinin TM, Hayry P. 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