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Treatment of extra-abdominal aggressive fibromatosis with pegylated interferon
Treatment of extra-abdominal aggressive fibromatosis with pegylated interferon Gabriele Stengel, MD,a Dieter Metze, MD,a Bernd Do¨rflinger, MD,b Thomas A. Luger, MD,a and Markus Bo¨hm, MDa ¨ nster and Munich, Germany Mu Aggressive fibromatosis (desmoid tumor) is a very rare neoplasm arising from the musculoaponeurotic structures. It is characterized by locally aggressive growth, and a tendency to relapse but not to metastasize. We report on a young woman with a large desmoid tumor of the left foot. Multiple operations and radiotherapy had resulted in local recurrences. Long-term immunointervention with pegylated interferon alfa-2b, however, led to marked clinical improvement of the patient’s condition and a radiologically proven stabilization of the disease. ( J Am Acad Dermatol 2008;59:S7-9.)
CASE REPORT In April 2002, a 31-year-old woman presented to our department with a tumor of the left foot that had been present since early childhood. She had been diagnosed with aggressive fibromatosis (AF) and had undergone multiple surgeries (1978, 1989, and 1990) each followed by local relapses. She had subsequently received cobalt-60 radiotherapy (4 3 60 Gy) in 1990. However, since 2000 she had again experienced progressive swelling of the left foot and appearance of blackish nodules on the skin overlying the tumor. She was finally left with the option of foot amputation after consulting the department of surgery at her local university clinic. At the time of presentation the patient furthermore had severe daily pain in the left foot preventing her from any regular work. She was otherwise healthy and her family history was noncontributory. Physical examination revealed swelling of the back of the left foot and ankle with induration of the skin in these areas. There were numerous brownish to violaceous Kaposi sarcomaelike nodules on the middle and side aspects of the left ankle. The skin over the distal portion of the lower leg was scaly (Fig 1). A deep biopsy specimen from the ankle revealed nodular proliferation of myofibroblasts and
From the Department of Dermatology, University of Mu¨nster,a and Diagnoseklinik Mu¨nchen, Munich.b Funding sources: None. Conflicts of interest: None declared. Reprint requests: Markus Bo¨hm, MD, Department of Dermatology, University of Mu¨nster, Von Esmarch-Str. 58, D-48149 Mu¨nster, Germany. E-mail: [email protected]. 0190-9622/$34.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.07.019
fibroblasts within a collagenous stroma, focal inflammation, and an increased number of blood vessels consistent with the diagnosis of AF (desmoid tumor) (Fig 2). In addition, there was edema in the papillary dermis and pseudoepitheliomatous hyperplasia. Contrast-enhanced magnetic resonance imaging of the left ankle disclosed a soft-tissue tumor localized superficially to the muscular structures and tendon sheaths, and extended semicircularly around the ankle joint. The tumor reached dorsally to the tendon sheaths of the musculus tibialis posterior flexor digitorum longus and surrounded the Achilles tendon (Fig 3). Laterally from the outer ankle the tumor extended into the subcutaneous adipose tissue. There was no osseous involvement. Fluoro-2-deoxyd-glucose positron emission tomography confirmed massive radiotracer uptake in the soft tissue involving especially the middle, side, and back aspects of the left ankle and the distal portion of the lower leg but without any radiotracer uptake in other organs. Laboratory blood tests disclosed a slightly elevated C-reactive protein of 0.6 mg/dL (\0.5) whereas all other routine laboratory parameters were normal. Therapy with pegylated interferon alfa-2b (100 g/wk subcutaneously) was initiated. Already 2 months after therapy the patient experienced cessation of pain enabling her to work again. Regular follow-up visits twice a year revealed clinical improvement of her condition as evidenced by reduced swelling of the left foot with flattening and lightening of the tumor nodules. Magnetic resonance imaging performed twice a year showed an end of tumor progression already apparent 6 months after initiation of treatment. Interferon therapy was, therefore, continued for a total length of 51 months whereupon treatment was stopped. No worsening of her disease was subsequently noted and the most recent S7
S8 Stengel et al
J AM ACAD DERMATOL AUGUST 2008
Fig 1. Aggressive fibromatosis of left foot before therapy with pegylated interferon alfa-2b.
Fig 3. Magnetic resonance imaging of left foot taken before long-term therapy with pegylated interferon alfa2b. Note semicircular soft-tissue tumor extending around ankle (arrows).
Fig 2. Dermatohistopathology of soft-tissue tumor. Proliferation of spindle cells with dense collagenous stroma typical for desmoid tumor. (Hematoxylin-eosin stain; original magnifications: 325; insert: 3400.)
magnetic resonance imaging taken in December 2006 confirmed stabilization of the disease (Fig 4). In general, therapy with interferon alfa-2b was well tolerated except for some malaise during the first months of treatment.
DISCUSSION AF is an extremely rare tumor of intermediate malignancy with an annual incidence of approximately 2 to 4 per 1 million individuals.1 Its synonym desmoid tumor (derived from Greek de´so2 = tendonlike) denotes the origin of the neoplasm from fascial or deep musculoaponeurotic structures. The tumor displays local aggressiveness with a high
Fig 4. Magnetic resonance imaging of left foot after 56 months of treatment with pegylated interferon alfa-2b. Note same extent of tumor as in Fig 3.
propensity to relapse locally while there is no tendency to metastasize. AF has been categorized into two major forms: abdominal and extra-abdominal. Abdominal AF originates in the abdominal wall, intraperitoneally or within the mesentery. Extraabdominal AF occurs most often on the limb girdles, trunk, and extremities.2 As AF arises from aponeurotic structures. Skin changes, except the presence of a subcutaneous mass, are not a typical clinical finding. However, as in our patient and as described before,3 the tumor can be very painful as a result of direct pressure on contiguous nerves. In our patient, it is further possible that the skin changes represent a long-term consequence of the previous radiotherapy.
J AM ACAD DERMATOL
Stengel et al S9
VOLUME 59, NUMBER 2
Fig 5. Detection of interferon (IFN)-a/b receptor a in aggressive fibromatosis in situ. Paraffin-embedded tissue sections were deparaffinized, microwave-treated for epitope demasking, and incubated with anti-IFN-a/b receptor a antibody (Santa Cruz, 1:100). Bound antibodies were detected by immunoperoxidase technique. Note expression of IFN-a/b receptor a in many tumor cells. Endothelia of vessels are nonreactive. (Original magnification: 3400.)
The pathogenesis of AF is incompletely understood. Multiple factors appear to contribute to its development including genetic abnormalities, sex steroid hormones, trauma, deregulation of cytokine and growth factor expression, and deviations in cell signaling and cell cycle regulation.4 Although most cases of AF are sporadic there is an important association with familial adenomatosis polyposis (FAP) and Gardner’s syndrome suggesting a genetic link.5 In a study on 897 patients with FAP, AF developed in 12% of the patients before the diagnosis of FAP, in 20% simultaneously, and in 68% after the diagnosis of FAP.5 Mutations of the adenomatosis polyposis coli (APC) gene beyond codon 1444 were reported to markedly increase the risk of patients with FAP to develop AF.6 The tumor suppressor APC regulates expression of b-catenin, a mediator of Wingless. Mutational analysis of both the APC gene and the b-catenin gene disclosed a high percentage of somatic mutations even in sporadic AF.7 Surgery with marginal control is the principal therapy for AF.4 If the tumor infiltrates bone, neurovascular structures, or vital structures, complete excision can be difficult and may lead to high
morbidity. Noninvasive treatment options include radiotherapy, hormonal and anti-inflammatory agents, cytotoxic chemotherapy, and occasionally interferons.4,8 Because of the rarity of the disease there are no controlled randomized trials of patients with AF. Fernberg et al9 observed a complete response of a patient with AF of the knee after 55 months of interferon alfa-2b (3 3 106 U/d subcutaneously). We have treated our patient with pegylated interferon alfa-2b and achieved stable disease after 6 months of therapy. The precise mechanism of action of interferon alfa-2b in AF is unknown. However, immunohistochemistry of tumor tissue from our patient revealed in situ expression of the of interferon-a/b receptor a (Fig 5) in the majority of desmoid fibroblasts suggesting a direct growth inhibitory action of the cytokine. REFERENCES 1. Reitamo JJ, Hayry P, Nykyri E, Saxen E. The desmoid tumor, I: incidence, sex-, age- and anatomical distribution in the Finnish population. Am J Clin Pathol 1982;77:665-73. 2. Gronchi A, Casali PG, Mariani L, Lo Vullo S, Colecchia M, Lozza L, et al. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003;21:1390-7. 3. Simpson JL, Petropolis AA, Styles AR, Zabawski EJ, Cockerell CJ. Extra-abdominal desmoid tumor: an unusual subcutaneous lesion presenting as shoulder pain. Int J Dermatol 1998;37:780-4. 4. Mendenhall WM, Zlotecki RA, Morris CG, Hochwald SN, Scarborough MT. Aggressive fibromatosis. Am J Clin Oncol 2005;28:211-5. 5. Clark SK, Phillips RK. Desmoids in familial adenomatous polyposis. Br J Surg 1996;83:1494-504. 6. Bertario L, Russo A, Sala P, Eboli M, Giarola M, D’amico F, et al. Hereditary colorectal tumors registry: genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 2001;95: 102-7. 7. Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P, et al. Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene 1999;18:6615-20. 8. Janinis J, Patriki M, Vini L, Aravantinos G, Whelan JS. The pharmacological treatment of aggressive fibromatosis: a systematic review. Ann Oncol 2003;14:181-90. 9. Fernberg J-O, Brosjo¨ O, Larsson O, So¨derlund V, Strander H. Interferon-induced remission in aggressive fibromatosis of the lower extremity. Acta Oncol 1999;38:971-2.
CASE REPORT In April 2002, a 31-year-old woman presented to our department with a tumor of the left foot that had been present since early childhood. She had been diagnosed with aggressive fibromatosis (AF) and had undergone multiple surgeries (1978, 1989, and 1990) each followed by local relapses. She had subsequently received cobalt-60 radiotherapy (4 3 60 Gy) in 1990. However, since 2000 she had again experienced progressive swelling of the left foot and appearance of blackish nodules on the skin overlying the tumor. She was finally left with the option of foot amputation after consulting the department of surgery at her local university clinic. At the time of presentation the patient furthermore had severe daily pain in the left foot preventing her from any regular work. She was otherwise healthy and her family history was noncontributory. Physical examination revealed swelling of the back of the left foot and ankle with induration of the skin in these areas. There were numerous brownish to violaceous Kaposi sarcomaelike nodules on the middle and side aspects of the left ankle. The skin over the distal portion of the lower leg was scaly (Fig 1). A deep biopsy specimen from the ankle revealed nodular proliferation of myofibroblasts and
From the Department of Dermatology, University of Mu¨nster,a and Diagnoseklinik Mu¨nchen, Munich.b Funding sources: None. Conflicts of interest: None declared. Reprint requests: Markus Bo¨hm, MD, Department of Dermatology, University of Mu¨nster, Von Esmarch-Str. 58, D-48149 Mu¨nster, Germany. E-mail: [email protected]. 0190-9622/$34.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.07.019
fibroblasts within a collagenous stroma, focal inflammation, and an increased number of blood vessels consistent with the diagnosis of AF (desmoid tumor) (Fig 2). In addition, there was edema in the papillary dermis and pseudoepitheliomatous hyperplasia. Contrast-enhanced magnetic resonance imaging of the left ankle disclosed a soft-tissue tumor localized superficially to the muscular structures and tendon sheaths, and extended semicircularly around the ankle joint. The tumor reached dorsally to the tendon sheaths of the musculus tibialis posterior flexor digitorum longus and surrounded the Achilles tendon (Fig 3). Laterally from the outer ankle the tumor extended into the subcutaneous adipose tissue. There was no osseous involvement. Fluoro-2-deoxyd-glucose positron emission tomography confirmed massive radiotracer uptake in the soft tissue involving especially the middle, side, and back aspects of the left ankle and the distal portion of the lower leg but without any radiotracer uptake in other organs. Laboratory blood tests disclosed a slightly elevated C-reactive protein of 0.6 mg/dL (\0.5) whereas all other routine laboratory parameters were normal. Therapy with pegylated interferon alfa-2b (100 g/wk subcutaneously) was initiated. Already 2 months after therapy the patient experienced cessation of pain enabling her to work again. Regular follow-up visits twice a year revealed clinical improvement of her condition as evidenced by reduced swelling of the left foot with flattening and lightening of the tumor nodules. Magnetic resonance imaging performed twice a year showed an end of tumor progression already apparent 6 months after initiation of treatment. Interferon therapy was, therefore, continued for a total length of 51 months whereupon treatment was stopped. No worsening of her disease was subsequently noted and the most recent S7
S8 Stengel et al
J AM ACAD DERMATOL AUGUST 2008
Fig 1. Aggressive fibromatosis of left foot before therapy with pegylated interferon alfa-2b.
Fig 3. Magnetic resonance imaging of left foot taken before long-term therapy with pegylated interferon alfa2b. Note semicircular soft-tissue tumor extending around ankle (arrows).
Fig 2. Dermatohistopathology of soft-tissue tumor. Proliferation of spindle cells with dense collagenous stroma typical for desmoid tumor. (Hematoxylin-eosin stain; original magnifications: 325; insert: 3400.)
magnetic resonance imaging taken in December 2006 confirmed stabilization of the disease (Fig 4). In general, therapy with interferon alfa-2b was well tolerated except for some malaise during the first months of treatment.
DISCUSSION AF is an extremely rare tumor of intermediate malignancy with an annual incidence of approximately 2 to 4 per 1 million individuals.1 Its synonym desmoid tumor (derived from Greek de´so2 = tendonlike) denotes the origin of the neoplasm from fascial or deep musculoaponeurotic structures. The tumor displays local aggressiveness with a high
Fig 4. Magnetic resonance imaging of left foot after 56 months of treatment with pegylated interferon alfa-2b. Note same extent of tumor as in Fig 3.
propensity to relapse locally while there is no tendency to metastasize. AF has been categorized into two major forms: abdominal and extra-abdominal. Abdominal AF originates in the abdominal wall, intraperitoneally or within the mesentery. Extraabdominal AF occurs most often on the limb girdles, trunk, and extremities.2 As AF arises from aponeurotic structures. Skin changes, except the presence of a subcutaneous mass, are not a typical clinical finding. However, as in our patient and as described before,3 the tumor can be very painful as a result of direct pressure on contiguous nerves. In our patient, it is further possible that the skin changes represent a long-term consequence of the previous radiotherapy.
J AM ACAD DERMATOL
Stengel et al S9
VOLUME 59, NUMBER 2
Fig 5. Detection of interferon (IFN)-a/b receptor a in aggressive fibromatosis in situ. Paraffin-embedded tissue sections were deparaffinized, microwave-treated for epitope demasking, and incubated with anti-IFN-a/b receptor a antibody (Santa Cruz, 1:100). Bound antibodies were detected by immunoperoxidase technique. Note expression of IFN-a/b receptor a in many tumor cells. Endothelia of vessels are nonreactive. (Original magnification: 3400.)
The pathogenesis of AF is incompletely understood. Multiple factors appear to contribute to its development including genetic abnormalities, sex steroid hormones, trauma, deregulation of cytokine and growth factor expression, and deviations in cell signaling and cell cycle regulation.4 Although most cases of AF are sporadic there is an important association with familial adenomatosis polyposis (FAP) and Gardner’s syndrome suggesting a genetic link.5 In a study on 897 patients with FAP, AF developed in 12% of the patients before the diagnosis of FAP, in 20% simultaneously, and in 68% after the diagnosis of FAP.5 Mutations of the adenomatosis polyposis coli (APC) gene beyond codon 1444 were reported to markedly increase the risk of patients with FAP to develop AF.6 The tumor suppressor APC regulates expression of b-catenin, a mediator of Wingless. Mutational analysis of both the APC gene and the b-catenin gene disclosed a high percentage of somatic mutations even in sporadic AF.7 Surgery with marginal control is the principal therapy for AF.4 If the tumor infiltrates bone, neurovascular structures, or vital structures, complete excision can be difficult and may lead to high
morbidity. Noninvasive treatment options include radiotherapy, hormonal and anti-inflammatory agents, cytotoxic chemotherapy, and occasionally interferons.4,8 Because of the rarity of the disease there are no controlled randomized trials of patients with AF. Fernberg et al9 observed a complete response of a patient with AF of the knee after 55 months of interferon alfa-2b (3 3 106 U/d subcutaneously). We have treated our patient with pegylated interferon alfa-2b and achieved stable disease after 6 months of therapy. The precise mechanism of action of interferon alfa-2b in AF is unknown. However, immunohistochemistry of tumor tissue from our patient revealed in situ expression of the of interferon-a/b receptor a (Fig 5) in the majority of desmoid fibroblasts suggesting a direct growth inhibitory action of the cytokine. REFERENCES 1. Reitamo JJ, Hayry P, Nykyri E, Saxen E. The desmoid tumor, I: incidence, sex-, age- and anatomical distribution in the Finnish population. Am J Clin Pathol 1982;77:665-73. 2. Gronchi A, Casali PG, Mariani L, Lo Vullo S, Colecchia M, Lozza L, et al. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003;21:1390-7. 3. Simpson JL, Petropolis AA, Styles AR, Zabawski EJ, Cockerell CJ. Extra-abdominal desmoid tumor: an unusual subcutaneous lesion presenting as shoulder pain. Int J Dermatol 1998;37:780-4. 4. Mendenhall WM, Zlotecki RA, Morris CG, Hochwald SN, Scarborough MT. Aggressive fibromatosis. Am J Clin Oncol 2005;28:211-5. 5. Clark SK, Phillips RK. Desmoids in familial adenomatous polyposis. Br J Surg 1996;83:1494-504. 6. Bertario L, Russo A, Sala P, Eboli M, Giarola M, D’amico F, et al. Hereditary colorectal tumors registry: genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 2001;95: 102-7. 7. Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P, et al. Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene 1999;18:6615-20. 8. Janinis J, Patriki M, Vini L, Aravantinos G, Whelan JS. The pharmacological treatment of aggressive fibromatosis: a systematic review. Ann Oncol 2003;14:181-90. 9. Fernberg J-O, Brosjo¨ O, Larsson O, So¨derlund V, Strander H. Interferon-induced remission in aggressive fibromatosis of the lower extremity. Acta Oncol 1999;38:971-2.