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Fibromatosis of the head and neck: A challenging lesion
REVIEW ARTICLE Fibromatosis of the head and neck: A challenging lesion NOAH S. SIEGEL, MD, and CAROL R. BRADFORD, MD, Boston, Massachusetts, and Ann Arbor, Michigan
Fibromatosis is a histologically benign fibrous neoplasm that arises from the musculoaponeurotic tissues of the body. It can have significant morbidity when it occurs in the head and neck region because of the proximity of vital structures. This review article considers the etiology, demographics, pathology, natural history, and various treatment modalities for this lesion. Therapeutic guidelines are provided. (Otolaryngol Head Neck Surg 2000;123:269-75.)
Fibromatosis is a fibroblastic proliferation of cells that arises from the musculoaponeurotic tissues of the body. It is microscopically benign but can be locally invasive with a tendency to recur locally after resection. Fibromatosis has no malignant or metastatic potential. When this lesion occurs in the head and neck, the proximity of vital structures and the complexity of fascial planes often preclude complete resection. Therefore recurrence rates are high. This review draws on the surgical, medical, radiotherapy, and basic science literature to describe this entity and to propose a therapeutic protocol for fibromatosis of the head and neck. BACKGROUND
The elusiveness of this tumor is reflected in the variety of terminologies used, including desmoplastic fibroma, desmoma, aggressive fibromatosis, and fibrosarcoma grade I.1 The lesion is most commonly referred to as a desmoid tumor, reflecting its gross tendon-like appearance and suggesting the fibroblast as the cell of origin. Aggressive fibromatosis is also a commonly used term, but in actuality there is no way to predict the tumor’s aggressiveness. It has been recommended that From the Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School (Dr Siegel); and the Department of Otolaryngology–Head and Neck Surgery, University of Michigan Medical School (Dr Bradford). Reprint requests: Noah S. Siegel, MD, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114. Correspondence: Noah S. Siegel, MD, 825 Washington St, Suite 310, Norwood, MA 02062. 0194-5998/2000/$12.00 + 0 23/10/107456 doi:10.1067/mhn.2000.107456
the term fibrosarcoma be abandoned because malignant potential and a tendency to metastasize are not features of fibromatosis.2,3 Use of the term fibrosarcoma might thereby unnecessarily prompt radical surgical procedures. These authors favor the classification scheme described by Enzinger and Weiss,3 whereby fibromatoses are divided into 2 types: superficial and deep. Superficial fibromatoses include palmar, plantar, penile, and knuckle pad lesions. Deep fibromatoses include the extra-abdominal, abdominal, and intra-abdominal subtypes. Head and neck lesions are considered deep fibromatoses of the extra-abdominal subtype. Fibromatosis is a rare entity. The incidence of fibromatosis is 2.4 to 4.3 cases per million inhabitants per year in the Finnish population; approximately one third are extra-abdominal in location.4 In a review of all neoplasms at one hospital between 1917 and 1943, Pack and Ehrlich5 reported a 0.03% incidence of desmoid tumors. From 9.5% to 33% of extra-abdominal fibromatoses have been reported to occur in the head and neck.6,7 In a series by Mason and Soule,8 12% of fibromatoses in all locations occurred in the head and neck. The supraclavicular region was most commonly involved (9/34), followed by the lateral cervical region (7/34) and the posterior cervical region (6/34). Overall, the neck was the location of 85% of fibromatoses found in the head and neck in that series. This is in contrast to a study by Conley et al,9 who reported that 40% of head and neck fibromatoses occur in the neck. The next most common locations are the face, oral cavity, scalp, paranasal sinuses, and orbital region.10 Review of the literature indicates that when fibromatosis does occur in the head and neck, it is frequently located in the neck (Table 1). Infantile fibromatosis is the pediatric counterpart to fibromatosis.3 This lesion presents between birth and 8 years of age, most commonly in the first 2 years of life. Infantile fibromatosis often involves the muscles of the head and neck, shoulder, and upper arm. The most frequent sites in the head and neck are the tongue, mandible, maxilla, and mastoid. Although there have been reports of spontaneous regression, the natural history is similar to its adult counterpart.14 A number of fibrous tumors of childhood may occur in the head and neck and should be distinguished from 269
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Table 1. Frequency of extra-abdominal fibromatosis in the head and neck.
Study
Extra abdominal tumors
Hunt et al11 Conley et al9 Reitamo et al4 Siemssen and Anagnostaki12 Fasching et al13* Das Gupta et al7 Enzinger and Weiss3
29 NR 38 NR NR 72 367
TOTAL
Fig 1. Photomicrograph showing a typical case of fibromatosis. (Hematoxylin-eosin stain; original magnification ×400.)
infantile fibromatosis.3 First, myofibromas are neoplastic growths that occur in the dermis or subcutis of infants. These lesions may be multifocal and are frequently found in the head and neck but may involve visceral organs. Solitary or multiple lesions of the soft tissue or bone often regress spontaneously. Second, juvenile hyaline fibromatosis is an autosomal recessive condition characterized by multiple cutaneous papules of the head, back, and extremities. They often present from the ages of 2 to 5 years and persist unless surgically excised. Third, gingival fibromatosis is slowgrowing ill-defined gingival hyperplasia in children that may be related to the eruption of teeth. Excision or tooth extraction is considered if it interferes with speech or feeding. Finally, fibromatosis colli is a fibrous growth of the sternocleidomastoid muscle that generally occurs from the second to fourth weeks of life. These growths resolve spontaneously in approximately two thirds of cases but may require further physical or surgical therapy if persistent. PATHOLOGY
The natural history of fibromatosis is slow, progressive growth with invasion of adjacent tissues. Fibromatosis has no malignant or metastatic potential. However, these lesions may be unpredictable. The literature contains occasional reports of spontaneous regression and descriptions of arrested growth after incomplete resection without subsequent therapy.15 There are, although scattered, reports of metastatic lesions and malignant degeneration.15,16 These findings may be a reflection of an error in diagnosis. The gross appearance of deep fibromatosis is that of a poorly circumscribed firm, gray-white, rubbery mass adherent to musculoaponeurotic tissue. It may extend along fascial planes and infiltrate adjacent tissues. In
No. in the head and neck
No. (%) in the neck
5 40 6 5 48 8 35 149
3 (60) 16 (40) 6 (75) 4 (80) 34 (71) 5 (63) 28 (80) 96 (64)
NR, Not reported. *Patients in this series include patients reported by Masson and Soule.8
addition, it has the capacity to encapsulate neurovascular structures. Fibromatosis should be characterized as an intermediate-grade lesion between the benign, bland fibroma and the malignant, atypical fibrosarcoma. The histologic appearance of fibromatosis is one in which collections of uniform-appearing, spindle-shaped cells are grouped in poorly defined fascicles and separated by collagen strands (Fig 1). Remnants of striated muscle are often found interlaced within bundles of fibroblasts near the periphery of the tumor, indicative of its propensity for local invasion. The tumor does not form a pseudocapsule or infiltrate the skin. Characteristically, there is no nuclear hyperchromasia or cellular atypia, but the degree of cellularity may vary from region to region. Mitotic figures are rare. Of paramount importance is the pathologic distinction between fibromatosis and fibrosarcoma. In addition, fibromatosis may be confused with entities such as reactive fibrosis, myxoma, nodular fasciitis, keloid, fibrous hamartomas, neurofibroma, neuroma, and rhabdomyosarcoma. Infantile fibromatosis is classified into 3 distinct histologic types—diffuse, fibroblastic, and desmoid— which reflect the stages of fibroblast proliferation.3 ETIOLOGY
The etiology of these tumors is unclear. Traumatic, endocrine, and genetic factors have all been implicated in the pathogenesis. Because few publications are specific to the head and neck, literature related to all deep fibromatoses have been considered. Many researchers have proposed a history of trauma preceding the development of fibromatosis. Early reports indicate a high rate of fibromatosis at the site of a previous surgical scar.17 This finding was also observed by Hayry et al,18 who reported that 13 of 40
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patients with abdominal fibromatosis had undergone surgery in the region of the tumor. Enzinger and Shiraki6 also reported a correlation with trauma and the development of fibromatosis. In that series, 0 of 33 patients with extra-abdominal fibromatosis had a history of surgery in the region of the tumor. These findings are in contrast to those of a study in which only 9 of 29 patients with extra-abdominal fibromatosis had histories of local trauma.11 A mechanism for the development of fibromatosis was proposed by Goellner and Soule,19 who suggested that immature fibroblasts in the region of the trauma display an uncontrolled attempt at healing and lead to tumor formation. Although a history of trauma may give clues to the etiology of fibromatosis, it is likely of little clinical significance. Hayry et al18 reported that women with abdominal fibromatosis had a statistically significant higher rate of pregnancy than patients with extra-abdominal tumors. Pack and Ehrlich5 reported that 14 of 15 patients with abdominal fibromatosis had a recent pregnancy. This finding may be related to the trauma of pregnancy and the force of uterine contractions, but it is difficult to exclude a hormonal component. An endocrinologic etiology for fibromatosis has been considered over the years. Findings that lend support to such a theory are observations of tumor regression just before menstruation, after menopause, or after irradiation to the ovaries. Accelerated growth has also been associated with high estrogen levels.18,20-22 Growth rates have been reported to be slowest in premenarchal girls, faster in the fertile age group, maximum at menopause, and then declining thereafter.18 Lipschultz and Vargas23 showed that high levels of estrogen given to guinea pigs induced formation of fibromatosis. Further evidence for a role of estrogen in the pathogenesis of fibromatosis can be inferred from the finding that some tumors regressed when patients were treated with the antiestrogen agent tamoxifen.24,25 In 1979 McDougall and McGarrity26 identified the existence of estrogen receptors in a fibromatosis specimen. This finding may lend credence to the theory of an estrogen-responsive tumor, but according to Easter and Halasz,27 “Estrogen receptor assays can be difficult to interpret because most tissues and tumors nonspecifically bind estrogen.” Nevertheless, estrogen binding levels in fibromatosis have been reported to be similar to those found in known estrogen-responsive organs. In 1986 Lim et al28 performed a quantitative evaluation of cytosol estrogen receptors and antiestrogen binding sites in 15 samples of fibromatosis. They identified presence of receptors and binding sites in 33% and 79%, respectively. The therapeutic implications of this finding are unclear. Maddalozzo et al29 suggested a sub-
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classification of juvenile fibromatosis based on the existence of estrogen and progesterone receptors. They concluded that receptor-positive tumors may be treated with tamoxifen. Genetic factors seem to play a role in the etiology of fibromatosis. Gardner’s syndrome, an inherited condition characterized by osteomas, cutaneous cysts, and intestinal polyps, conveys an added risk of fibromatosis development. One report in the literature described a Jordanian family with fibromatosis in a mother and 2 children, suggesting an autosomal dominant or recessive inheritance pattern.30 Another report described a family in which 5 members had fibromatosis, suggesting an autosomal dominant pattern.31 Much evidence for an inherited predisposition to forming fibromatosis comes from work by Reitamo et al.32 They found a statistically significant (P < 0.001) incidence of radiographic abnormalities in the bones of 53 patients with histories of fibromatosis. These abnormalities included cortical thickening, cystic regions, exostosis, osteomas of the mandible, and sacralization of the fifth lumbar vertebra. They also found bone abnormalities in the families of patients with fibromatosis at a significantly higher rate than in a control group. These findings are consistent with an autosomal dominant pattern of inheritance with variable penetrance. Reitamo et al postulated that an inherited factor that causes abnormal bone growth also predisposes patients to the development of fibromatosis. They defined desmoid syndrome as a desmoid tumor in conjunction with an inherited familial tendency to form abnormal bone. More recent studies of the pathogenesis of fibromatosis have taken place at the molecular level. With Northern blot analysis, immunofluorescence, and in situ hybridization, inappropriate expression of c-sis and consequent production of prostaglandin 2 in 10 of 10 samples were described in various anatomic locations.33 It was postulated that the trigger for increased expression of c-sis might be related to sex hormones or sex hormone receptors. Another genetic study identified a higher incidence of trisomy 8 in samples taken from recurrent tumors than in samples taken from nonrecurrent tumors.34 These researchers concluded that trisomy 8 might be a marker of higher recurrence rate. Although none of these studies provided sufficient evidence for a true etiology of fibromatosis, they did provide evidence that cytogenetic abnormalities are associated with tumor growth. Most recently, laboratory studies have clearly shown that fibromatosis is a monoclonal proliferation of cells. Bridge et al35 conducted a cytogenetic study of 22 cases of abdominal and extra-abdominal fibromatosis. Clonal
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Table 2. Recurrence rates of fibromatosis of the head and neck Study
Hunt et al11 Conley et al9 Fasching et al13*
Therapy
Cases with Recurrences follow-up (%)
Excision 5 Excision 40 Complete excision 32 ± XRT Incomplete excision 14 ± XRT Reitamo et al4 Excision 7 TOTAL — 98
2 (40) 19 (47) 8 (25) 12 (86) 3 (43) 44 (45)
XRT, Radiation therapy. *Patients in this series include patients reported by Masson and Soule.8
abnormalities in 7 patients with defects involving chromosomes Y and 5q were found. The preservation of these cytogenetic abnormalities in the tumor cells suggested a true neoplastic etiology. Two other recent molecular studies of fibromatosis clearly indicated that fibromatosis is a monoclonal proliferation of cells.36,37 Both groups used polymerase chain reaction amplification of archival specimens to study patterns of X chromosome inactivation. Findings indicated that tumor cells arose from a single progenitor cell. A single case report in the literature suggested an autoimmune etiology in a case of neck fibromatosis.38 A histologic diagnosis of fibromatosis, an elevated erythrocyte sedimentation rate, and high titers of antithyroid and smooth muscle antibodies suggested an autoimmune etiology. In addition, the patient responded well to corticosteroid therapy. TREATMENT Surgery
The mainstay of treatment of fibromatosis of the head and neck is complete surgical excision. In patients with tumors in the head and neck region, it is often difficult to achieve negative margins because of the complex anatomy, close proximity of vital structures, and complicated exposure. Difficulty with complete excision is reflected in the relatively high recurrence rates of fibromatoses excised from the head and neck region. Some surgeons have advocated aggressive surgical resection for tumors of the extremities and reported low recurrence rates: According to Das Gupta et al,7 “To avoid recurrence adequate excision of the lesion is mandatory; this means major amputation when indicated.” For obvious reasons these reports are not easily applied to the head and neck. Table 2 details the recurrence rates after primary resection of fibromatosis of the head and neck in larger series.
Fasching et al13 showed that fibromatosis recurred at a very high rate when margins were positive but also frequently when margins were considered negative. At initial resection, when the pathologist reported negative margins, 8 of 32 tumors (25%) recurred. Without complete excision, 12 of 14 tumors (86%) recurred. Miralbell et al39 reported recurrence in 5 of 5 patients with positive surgical margins. Similar recurrence patterns have been reported in pediatric patients. In a series of 63 children with fibromatosis, histologically negative margins recurred at a rate of 28%, whereas positive margins recurred in 82%.40 In a multivariant analysis of 128 patients undergoing attempted surgical resection, less than adequate margins of resection were correlated with a higher recurrence rate.15 However, Catton et al41 found that tumor margin status had no impact on recurrence in 36 patients treated with surgery alone. In a review of fibromatosis in the Finnish population, a higher incidence of tumor recurrence was reported when the tumor was initially resected from an anatomically complex region (10% vs 48%).32 In that series, 3 of 7 head and neck fibromatoses recurred. A review of 25 cases of fibromatosis of the sinonasal tract and nasopharynx from the Armed Forces Institute of Pathology reported a 21% incidence of recurrence with a mean follow-up of 8 years 2 months.10 The authors suggested that the bony confines of this anatomic region limited extension. Conley et al9 and Fasching et al13 both found that when fibromatosis occurs in the base of the neck, recurrence rates may be higher than if it occurs in other regions of the neck. The above findings have therapeutic implications. First, meticulous surgical excision is essential. Wide local excision with frozen-section control may be necessary. Second, if tumor margins are known to be positive, postoperative adjunctive therapy should be considered. Finally, close follow-up is essential. With a greater than 40% recurrence rate of all fibromatoses of the head and neck and a greater than 25% recurrence rate with negative margins, it is clear that these patients need to be followed up very closely. We recommend frequent physical examination and interval CT scan examination. In addition, new patient symptoms need to be aggressively evaluated. Re-excision of recurrences should be considered if clinically feasible. Radiation Therapy
Because of the rarity of fibromatosis of the head and neck, most of the studies of chemotherapy and radiation therapy include treatment of tumors in all anatomic locations. These authors assume that deep fibromatosis is the same entity regardless of its location. A common conception is that fibromatosis of the head and neck is
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a more aggressive entity than other deep fibromatoses. This conception is likely a reflection of the difficulty with complete resection from an anatomically complex region. After extensive review of the literature, no reports indicate any differences in the intrinsic nature or tumor cell biology among deep fibromatoses. Information obtained from the study of deep fibromatosis in all locations is extrapolated to the head and neck with special considerations because of the complex and vital anatomy of this region. A role for radiation therapy has been clearly established.39,42-48 Radiation therapy is useful if there is gross residual tumor after resection, if a tumor recurs, or if a tumor is considered inoperable. Schmitt et al46 reviewed the outcomes of 164 patients treated with radiation therapy (with or without surgery) from several series and reported the overall recurrence rate to be 22%. In addition, there was virtually no difference in recurrence rates with respect to microscopic or macroscopic tumor at the outset of radiation therapy (21% and 23%, respectively). Although the radiation oncology literature is consistent in its success at treating these patients, Fasching et al13 found little value in the use of radiation therapy as either adjunctive or primary therapy. They did, however, report a transient decrease in tumor size in several patients. The most common protocols for treating fibromatosis involve fractionalization to a total dose of 50 to 60 Gy. Schmitt et al46 described a dose-response relationship between 30 and 60 Gy. In addition, if radiation is to be used, a wide field should be implemented to treat all microscopic disease. This is particularly important in the head and neck, where recurrences can involve vital structures. In a recent series 53 patients were treated with radiation therapy for both microscopic and gross disease.48 Local control was achieved in 83% of treated patients. Of the 9 recurrences in this series, 3 were in the radiated field, 4 were at the field margin, and 2 were outside the field. In another series, only 1 of 6 recurrences were within the radiated field.43 The radiation oncology literature calls for meticulous treatment planning to help avoid recurrences.41 Radiation therapy should be strongly considered in the following situations: (1) if primary excision is not possible because of the tumor location, patient desires, or the medical condition of the patient; (2) if there is gross residual disease after surgery; and (3) if there is microscopic disease after resection. In the third scenario, close observation may also be considered an appropriate treatment, and therapeutic plans should be individualized. The possible benefits of radiation therapy need to be weighed against its potential for long- and short-term complications. Radiation-induced tissue
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changes can make future surgical resection more difficult. In addition, maximal tumor regression may take many months to years.41 Radiation therapy should be used with caution in the pediatric population because of the well-known effects of radiation on bone growth and the potential for the delayed development of a cancerous lesion. One author obtained excellent results with tamoxifen as adjuvant therapy in a child with positive margins after the resection of a sinonasal lesion.49 Pharmacologic Therapy
Several pharmacologic approaches have been made to the treatment of fibromatosis. These approaches have had variable success, and results are somewhat anecdotal. Nevertheless, there may be a role for pharmacologic treatment of fibromatosis in certain situations, and they are therefore worth review. Clinicians have attempted cyclic adenosine monophosphate (cAMP) modulators, estrogen blockers, progesterone, prostaglandin manipulation, and classic chemotherapy during the past few decades. The earliest reports on the pharmacologic treatment of fibromatosis used progesterone to inhibit tumor growth. In 1944, Lipschultz and Maas50 reported the use of progesterone to inhibit the formation of fibromatosis in guinea pigs when exposed to high doses of estrogen. Although this finding was not reproducible in other animals, it prompted others to use intramuscular progesterone to treat patients with fibromatosis with favorable results.51,52 Waddell et al25,53-55 used other pharmacologic interventions such as antiestrogens, nonsteroidal antiinflammatory drugs, warfarin, vitamin K, and ascorbate in various combinations. Waddell55 stated that the goal of these agents is “to minimize the effects of estrogens and to inhibit the prostaglandin and cAMP synthesis, both of which influence growth and proliferation of fibroblasts.” The use of tamoxifen or testolactone is based on the theory that fibromatosis may be responsive to estrogen. Tamoxifen would theoretically limit the tumor response to estrogen by competitive inhibition at either estrogen binding sites or an allosteric site on or within tumor cells.56 Testolactone is a steroid derivative that blocks cAMP and may inhibit aromatase thereby, leading to decreased levels of estrogen.56 In one series of patients treated with various pharmacologic interventions, patients who received either tamoxifen or testolactone and nonsteroidal anti-inflammatory agents had the greatest tumor response. Five of 7 patients had major tumor regression.55 Several other reports described favorable responses when fibromatosis was treated with
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tamoxifen.24,25,57 Others reported positive results when patients with fibromatosis were treated with testolactone.25,55,58,59 Most reports do not designate the existence of estrogen receptors, thereby making it difficult to draw conclusions regarding the relative responsiveness of estrogen receptor–positive tumors when treated with tamoxifen or testolactone. We and others advocate the determination of estrogen and progesterone receptors in fibromatosis samples.29 This information may help guide pharmacologic therapy, provide insight into tumor biology, or act as a prognostic indicator for patients with fibromatosis. The use of traditional antineoplastic agents has been reported in small numbers.25,60-63 Goepfert et al60 preoperatively treated 6 children with desmoid fibromatosis using various combinations of low-dose adriamycin, dacarbazine, vincristine, dactinomycin, and cyclophosphamide. He found that 4 of 5 were free from disease at the time of manuscript submission (3 months to 6 years). One patient had a recurrence at 21 months. Complications were common. Three of 5 patients had wound infections, and 2 patients had cardiotoxic effects of adriamycin. Weiss and Lackman61 published the largest series of patients treated with traditional chemotherapy for fibromatosis. They recommended the use of methotrexate and Vinca alkaloids because of their relatively favorable toxicity profiles. In the treatment of 12 patients judged to be unsuitable for surgical intervention, there was complete tumor regression in 3 patients, partial remission in 7 patients, and minimal benefit in 2 patients. Another report applied the same combination therapy of methotrexate and vinblastine to 10 children with fibromatosis.62 Three patients had complete resolution, and 2 had partial resolution. In a fourth series studying fibromatosis, Waddell et al25 treated patients with adriamycin and cyclophosphamide with little to no benefit. Summary
The mainstay of therapy for fibromatosis of the head and neck is complete surgical resection. If gross tumor remains after resection or the patient is unfit for surgical intervention, radiation therapy is indicated. In addition, radiation therapy is indicated for recurrent tumors if repeat resection is not feasible. If microscopic margins are positive, there is a higher incidence of recurrence; therefore radiation therapy should be considered, and the patient should be followed up closely. In addition, pharmacologic therapy may be considered if the more proven methods of surgical excision and radiation therapy have failed. These therapeutic recommendations should be considered guidelines only, and treat-
ment should be individualized based on the specific lesion, patient’s condition and desires, as well as the resources available. CONCLUSION
Although fibromatosis is considered a benign tumor, it can have significant morbidity, particularly when it occurs in the head and neck. Their propensity for infiltrative local growth with encroachment on vital structures and their tendency to recur make fibromatoses of the head and neck extremely challenging lesions. We thank Alison Begleiter, MD, for outstanding editorial assistance, and Suzanne Keel, MD, for the photomicrograph. REFERENCES 1. Batsakis JG, Raslan W. Pathology consultation—extra-abdominal desmoid fibromatosis. Ann Otol Rhinol Laryngol 1994;103: 331-4. 2. El-Sayed Y. Fibromatosis of the head and neck. J Laryngol Otol 1992;106:459-62. 3. Enzinger FM, Weiss SW. Soft tissue tumors. 3rd ed. St Louis: Mosby; 1995. 4. Reitamo JJ, Hayry P, Nykri E, et al. The desmoid tumor. I. Incidence, sex-, age- and anatomical distribution in the Finnish population. Am J Clin Pathol 1983;77:665-73. 5. Pack GI, Ehrlich HE. Neoplasms of the anterior abdominal wall with special consideration of desmoid tumors: experience with 391 cases and collective review of the literature. Int Abs Surg 1944;79:177-98. 6. Enzinger FM, Shiraki M. Musculo-aponeurotic fibromatosis of the shoulder girdle (extra-abdominal desmoid). Analysis of ten cases followed up for ten or more years. Cancer 1967;20:1131-40. 7. Das Gupta TK, Brasfield RD, O’Hara J. Extra-abdominal desmoids: a clinicopathologic study. Ann Surg 1969;170:109-21. 8. Masson JK, Soule EH. Desmoid tumors of the head and neck. Am J Surg 1966;112:615-22. 9. Conley J, Healey WV, Stout AP. Fibromatosis of the head and neck. Am J Surg 1966;112:609-14. 10. Gnepp DR, Henley J, Weiss S, et al. Desmoid fibromatosis of the sinonasal tract and nasopharynx—a clinicopathologic study of 25 cases. Cancer 1996;78:2572-9. 11. Hunt R, Morgan HC, Acherman LV. Principles in the management of extra-abdominal desmoids. Cancer 1960;July-August: 825-36. 12. Siemssen SJ, Anagnostaki T. Aggressive fibromatosis (extraabdominal desmoids) of the head and neck. Br J Plast Surg 1984;37:453-7. 13. Fasching MC, Saleh J, Woods JE. Desmoid tumors of the head and neck. Am J Surg 1988;156:327-31. 14. Human A, Chou S, Carpenter B. Fibromatosis in infancy and childhood: the spectrum. J Pediatr Surg 1993;28:1446-50. 15. Posner MC, Shiu MH, Newsome JL, et al. The desmoid tumor not a benign disease. Arch Surg 1989;124:191-6. 16. Soule EH, Scanlon PW. Fibrosarcoma arising in an extra-abdominal desmoid tumor: report of a case. Proc Staff Meetings Mayo Clin 1962;37:443-51. 17. Penick RM. Desmoid tumors developing in operative scars. Int Surg Digest 1937;23:323-9. 18. Hayry P, Reitamo JJ, Totterman S, et al. The desmoid tumor. II. Analysis of factors possibly contributing to the etiology and growth behavior. Am J Clin Pathol 1982;77:681-5. 19. Goellner JR, Soule EH. Desmoid tumors: an ultrastructural study of eight cases. Hum Pathol 1980;11:43-50. 20. Booher RJ, Pack GT. Desmoids of the abdominal wall in children. Cancer 1951;4:1052-65.
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21. Strode JE. Desmoid tumors particularly related to their surgical removal. Ann Surg 1954;139:335-40. 22. Dahn I, Jonsson N, Lundh G. Desmoid tumors. A series of 33 cases. Acta Chir Scand 1963;126:305-14. 23. Lipschultz A, Vargas L. Experimental tumorigenesis with subcutaneous tablets of oestradiol. Lancet 1939;1:1313-8. 24. Kinzbrunner B, Ritter S, Domingo J, et al. Remission of rapidly growing desmoid tumors after tamoxifen therapy. Cancer 1983; 52:2201-4. 25. Waddell WR, Gerner RE, Reich MP. Nonsteroidal antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach. J Surg Oncol 1983;22:197-211. 26. McDougall A, McGarrity G. Extra-abdominal desmoid tumors. J Bone Joint Surg Br 1979;61-B:373-7. 27. Easter DW, Halasz NA. Recent trends in the management of desmoid tumors. Ann Surg 1989;210:765-9. 28. Lim CL, Walker MJ, Mehta RR, et al. Estrogen and antiestrogen binding sites in desmoid tumors. Eur J Clin Oncol 1986;22:583-7. 29. Maddalozzo J, Tenta LT, Hutchingson LR, et al. Juvenile fibromatosis: hormonal receptors. Int J Pediatr Otorhinolaryngol 1993;25:191-9. 30. Zayid I, Dihmis C. Familial multicentric fibromatosis—desmoids. A report of three cases in a Jordanian family. Cancer 1969;24: 786-95. 31. Young ID, Fortt RW. Familial fibromatosis. Clinical Genet 1981;20:211-6. 32. Reitamo JJ, Scheinen TM, Hayry P. The desmoid syndrome. Am J Surg 1986;151:230-7. 33. Alman BA, Goldberg MJ, Naber SP, et al. Aggressive fibromatosis. J Pediatr Orthop 1992;12:1-10. 34. Naeem R, Fletcher JA. Trisomy 8 is a potential genetic marker of high risk in desmoid tumors [abstract]. Am J Hum Genet 1992; 51A:279. 35. Bridge JA, Sreekantaiah C, Mouron B, et al. Clonal abnormalities in desmoid tumors. Cancer 1992;69:430-6. 36. Alman BA, Pajerski ME, Diaz-Cano S, et al. Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder. Diagn Mol Pathol 1997;6:98-101. 37. Lucas DR, Shroyer KR, McCarthy PJ, et al. Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation. Am J Surg Pathol 1997;21:306-11. 38. Feinmesser K, Berger S, Gapany-Gapanavicius B, et al. Autoimmune fibromatosis of the neck—a new entity? J Laryngol Otol 1987;101:527-8. 39. Miralbell R, Suit HD, Mankin HJ, et al. Fibromatoses: from postsurgical surveillance to combined surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1990;18:535-40. 40. Faulkner LB, Hajdu SI, Kher U, et al. Pediatric desmoid tumor: retrospective analysis of 63 cases. J Clin Oncol 1995;13:2813-8. 41. Catton CN, O’Sullivan BO, Bell R, et al. Aggressive fibromatosis: optimisation of local management with a retrospective failure analysis. Radiother Oncol 1995;34:17-22. 42. Greenberg HM, Goebel R, Weichselbaum RR, et al. Radiation therapy in the treatment of aggressive fibromatosis. Int J Radiat Oncol Biol Phys 1981;7:305-10.
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43. Leibel SA, Wara WM, Hill DR, et al. Desmoid tumors: local control and patterns of relapse following radiation therapy. Int J Radiat Oncol Biol Phys 1983;9:1167-71. 44. Kiel KD, Suit HD. Radiation therapy in the treatment of aggressive fibromatosis (desmoid tumors). Cancer 1984;54:2051-5. 45. Sherman NE, Romsdahl M, Evans H, et al. Desmoid tumors: a 20 year radiotherapy experience. Int J Radiat Oncol Biol Phys 1990; 19:37-40. 46. Schmitt G, Mills EED, Levin V, et al. Radiotherapy of aggressive fibromatosis. Eur J Cancer 1992;28A:832-5. 47. Spear MA, Jennings LC, Efird JT, et al. Indications for radiation therapy and surgery in the treatment of fibromatosis [abstract]. Int J Radiat Oncol Biol Phys 1995;32:288. 48. Kamath SS, Parsons JT, Marcus RB, et al. Radiotherapy for local control of aggressive fibromatosis. Int J Radiat Oncol Biol Phys 1996;36:325-8. 49. Maillard AJA, Kountakis SE. Pediatric sino-orbital desmoid fibromatosis. Ann Otol Rhinol Laryngol 1996;105:463-6. 50. Lipschultz A, Maas M. Progesterone treatment of uterine and other abdominal fibroids induced in guinea pigs by alpha estradiol. Cancer Res 1944;4:18-23. 51. Lanari A. Effect of progesterone on desmoid tumors. N Engl J Med 1983;309:1523. 52. Lanari A, Molinas FC, Castro Rios M, et al. Eficaz tratamiento de diversas fibromatosis con progesterona: mediatinits fibrosa, tumores desmoides, fibrosis paraneoplastica. Medicina (B Aires) 1978;38:123-32. 53. Waddell WR. Treatment of intra-abdominal and abdominal wall desmoid tumor with drugs that affect the metabolism of cyclic 3´,5´-adenosine monophosphate. Ann Surg 1975;181:299-302. 54. Waddell WR, Gerner RE. Indomethacin and ascorbate inhibit desmoid tumors. J Surg Oncol 1980;15:85-90. 55. Waddell WR, Kirsch WM. Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors. Am J Surg 1991;161:416-21. 56. Sciarra F. Anti-estrogens and aromatase inhibitors: tamoxifen and testolactone. J Endocrinol Invest 1988;11:755-62. 57. Procter H, Singh L, Baum M, et al. Response of multicentric desmoid tumours to tamoxifen. Br J Surg 1987;74:401. 58. Sauven P. Musculo-aponeurotic fibromatosis treated by surgery and testolactone. J R Soc Med 1982;75:281-3. 59. Fujimoto Y, Hidai K. Aggressive fibromatosis in the neck. A case treated effectively by testolactone with a long follow-up study. Surg Today 1990;20:453-7. 60. Goepfert H, Cangir A, Ayala AG, et al. Chemotherapy of locally aggressive head and neck tumors in the pediatric age group. Am J Surg 1982;144:437-44. 61. Weiss AJ, Lackman RD. Low-dose chemotherapy of desmoid tumors. Cancer 1989;64:1192-4. 62. Skapek SX, Hawk BJ, Hoffer FA, et al. Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children. J Clin Oncol 1998;16:30217. 63. West CB, Shaget FW, Manfield MJ. Nonsurgical treatment of aggressive fibromatosis in the head and neck. Otolaryngol Head Neck Surg 1989;101:338-43.
Fibromatosis is a histologically benign fibrous neoplasm that arises from the musculoaponeurotic tissues of the body. It can have significant morbidity when it occurs in the head and neck region because of the proximity of vital structures. This review article considers the etiology, demographics, pathology, natural history, and various treatment modalities for this lesion. Therapeutic guidelines are provided. (Otolaryngol Head Neck Surg 2000;123:269-75.)
Fibromatosis is a fibroblastic proliferation of cells that arises from the musculoaponeurotic tissues of the body. It is microscopically benign but can be locally invasive with a tendency to recur locally after resection. Fibromatosis has no malignant or metastatic potential. When this lesion occurs in the head and neck, the proximity of vital structures and the complexity of fascial planes often preclude complete resection. Therefore recurrence rates are high. This review draws on the surgical, medical, radiotherapy, and basic science literature to describe this entity and to propose a therapeutic protocol for fibromatosis of the head and neck. BACKGROUND
The elusiveness of this tumor is reflected in the variety of terminologies used, including desmoplastic fibroma, desmoma, aggressive fibromatosis, and fibrosarcoma grade I.1 The lesion is most commonly referred to as a desmoid tumor, reflecting its gross tendon-like appearance and suggesting the fibroblast as the cell of origin. Aggressive fibromatosis is also a commonly used term, but in actuality there is no way to predict the tumor’s aggressiveness. It has been recommended that From the Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School (Dr Siegel); and the Department of Otolaryngology–Head and Neck Surgery, University of Michigan Medical School (Dr Bradford). Reprint requests: Noah S. Siegel, MD, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114. Correspondence: Noah S. Siegel, MD, 825 Washington St, Suite 310, Norwood, MA 02062. 0194-5998/2000/$12.00 + 0 23/10/107456 doi:10.1067/mhn.2000.107456
the term fibrosarcoma be abandoned because malignant potential and a tendency to metastasize are not features of fibromatosis.2,3 Use of the term fibrosarcoma might thereby unnecessarily prompt radical surgical procedures. These authors favor the classification scheme described by Enzinger and Weiss,3 whereby fibromatoses are divided into 2 types: superficial and deep. Superficial fibromatoses include palmar, plantar, penile, and knuckle pad lesions. Deep fibromatoses include the extra-abdominal, abdominal, and intra-abdominal subtypes. Head and neck lesions are considered deep fibromatoses of the extra-abdominal subtype. Fibromatosis is a rare entity. The incidence of fibromatosis is 2.4 to 4.3 cases per million inhabitants per year in the Finnish population; approximately one third are extra-abdominal in location.4 In a review of all neoplasms at one hospital between 1917 and 1943, Pack and Ehrlich5 reported a 0.03% incidence of desmoid tumors. From 9.5% to 33% of extra-abdominal fibromatoses have been reported to occur in the head and neck.6,7 In a series by Mason and Soule,8 12% of fibromatoses in all locations occurred in the head and neck. The supraclavicular region was most commonly involved (9/34), followed by the lateral cervical region (7/34) and the posterior cervical region (6/34). Overall, the neck was the location of 85% of fibromatoses found in the head and neck in that series. This is in contrast to a study by Conley et al,9 who reported that 40% of head and neck fibromatoses occur in the neck. The next most common locations are the face, oral cavity, scalp, paranasal sinuses, and orbital region.10 Review of the literature indicates that when fibromatosis does occur in the head and neck, it is frequently located in the neck (Table 1). Infantile fibromatosis is the pediatric counterpart to fibromatosis.3 This lesion presents between birth and 8 years of age, most commonly in the first 2 years of life. Infantile fibromatosis often involves the muscles of the head and neck, shoulder, and upper arm. The most frequent sites in the head and neck are the tongue, mandible, maxilla, and mastoid. Although there have been reports of spontaneous regression, the natural history is similar to its adult counterpart.14 A number of fibrous tumors of childhood may occur in the head and neck and should be distinguished from 269
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Table 1. Frequency of extra-abdominal fibromatosis in the head and neck.
Study
Extra abdominal tumors
Hunt et al11 Conley et al9 Reitamo et al4 Siemssen and Anagnostaki12 Fasching et al13* Das Gupta et al7 Enzinger and Weiss3
29 NR 38 NR NR 72 367
TOTAL
Fig 1. Photomicrograph showing a typical case of fibromatosis. (Hematoxylin-eosin stain; original magnification ×400.)
infantile fibromatosis.3 First, myofibromas are neoplastic growths that occur in the dermis or subcutis of infants. These lesions may be multifocal and are frequently found in the head and neck but may involve visceral organs. Solitary or multiple lesions of the soft tissue or bone often regress spontaneously. Second, juvenile hyaline fibromatosis is an autosomal recessive condition characterized by multiple cutaneous papules of the head, back, and extremities. They often present from the ages of 2 to 5 years and persist unless surgically excised. Third, gingival fibromatosis is slowgrowing ill-defined gingival hyperplasia in children that may be related to the eruption of teeth. Excision or tooth extraction is considered if it interferes with speech or feeding. Finally, fibromatosis colli is a fibrous growth of the sternocleidomastoid muscle that generally occurs from the second to fourth weeks of life. These growths resolve spontaneously in approximately two thirds of cases but may require further physical or surgical therapy if persistent. PATHOLOGY
The natural history of fibromatosis is slow, progressive growth with invasion of adjacent tissues. Fibromatosis has no malignant or metastatic potential. However, these lesions may be unpredictable. The literature contains occasional reports of spontaneous regression and descriptions of arrested growth after incomplete resection without subsequent therapy.15 There are, although scattered, reports of metastatic lesions and malignant degeneration.15,16 These findings may be a reflection of an error in diagnosis. The gross appearance of deep fibromatosis is that of a poorly circumscribed firm, gray-white, rubbery mass adherent to musculoaponeurotic tissue. It may extend along fascial planes and infiltrate adjacent tissues. In
No. in the head and neck
No. (%) in the neck
5 40 6 5 48 8 35 149
3 (60) 16 (40) 6 (75) 4 (80) 34 (71) 5 (63) 28 (80) 96 (64)
NR, Not reported. *Patients in this series include patients reported by Masson and Soule.8
addition, it has the capacity to encapsulate neurovascular structures. Fibromatosis should be characterized as an intermediate-grade lesion between the benign, bland fibroma and the malignant, atypical fibrosarcoma. The histologic appearance of fibromatosis is one in which collections of uniform-appearing, spindle-shaped cells are grouped in poorly defined fascicles and separated by collagen strands (Fig 1). Remnants of striated muscle are often found interlaced within bundles of fibroblasts near the periphery of the tumor, indicative of its propensity for local invasion. The tumor does not form a pseudocapsule or infiltrate the skin. Characteristically, there is no nuclear hyperchromasia or cellular atypia, but the degree of cellularity may vary from region to region. Mitotic figures are rare. Of paramount importance is the pathologic distinction between fibromatosis and fibrosarcoma. In addition, fibromatosis may be confused with entities such as reactive fibrosis, myxoma, nodular fasciitis, keloid, fibrous hamartomas, neurofibroma, neuroma, and rhabdomyosarcoma. Infantile fibromatosis is classified into 3 distinct histologic types—diffuse, fibroblastic, and desmoid— which reflect the stages of fibroblast proliferation.3 ETIOLOGY
The etiology of these tumors is unclear. Traumatic, endocrine, and genetic factors have all been implicated in the pathogenesis. Because few publications are specific to the head and neck, literature related to all deep fibromatoses have been considered. Many researchers have proposed a history of trauma preceding the development of fibromatosis. Early reports indicate a high rate of fibromatosis at the site of a previous surgical scar.17 This finding was also observed by Hayry et al,18 who reported that 13 of 40
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patients with abdominal fibromatosis had undergone surgery in the region of the tumor. Enzinger and Shiraki6 also reported a correlation with trauma and the development of fibromatosis. In that series, 0 of 33 patients with extra-abdominal fibromatosis had a history of surgery in the region of the tumor. These findings are in contrast to those of a study in which only 9 of 29 patients with extra-abdominal fibromatosis had histories of local trauma.11 A mechanism for the development of fibromatosis was proposed by Goellner and Soule,19 who suggested that immature fibroblasts in the region of the trauma display an uncontrolled attempt at healing and lead to tumor formation. Although a history of trauma may give clues to the etiology of fibromatosis, it is likely of little clinical significance. Hayry et al18 reported that women with abdominal fibromatosis had a statistically significant higher rate of pregnancy than patients with extra-abdominal tumors. Pack and Ehrlich5 reported that 14 of 15 patients with abdominal fibromatosis had a recent pregnancy. This finding may be related to the trauma of pregnancy and the force of uterine contractions, but it is difficult to exclude a hormonal component. An endocrinologic etiology for fibromatosis has been considered over the years. Findings that lend support to such a theory are observations of tumor regression just before menstruation, after menopause, or after irradiation to the ovaries. Accelerated growth has also been associated with high estrogen levels.18,20-22 Growth rates have been reported to be slowest in premenarchal girls, faster in the fertile age group, maximum at menopause, and then declining thereafter.18 Lipschultz and Vargas23 showed that high levels of estrogen given to guinea pigs induced formation of fibromatosis. Further evidence for a role of estrogen in the pathogenesis of fibromatosis can be inferred from the finding that some tumors regressed when patients were treated with the antiestrogen agent tamoxifen.24,25 In 1979 McDougall and McGarrity26 identified the existence of estrogen receptors in a fibromatosis specimen. This finding may lend credence to the theory of an estrogen-responsive tumor, but according to Easter and Halasz,27 “Estrogen receptor assays can be difficult to interpret because most tissues and tumors nonspecifically bind estrogen.” Nevertheless, estrogen binding levels in fibromatosis have been reported to be similar to those found in known estrogen-responsive organs. In 1986 Lim et al28 performed a quantitative evaluation of cytosol estrogen receptors and antiestrogen binding sites in 15 samples of fibromatosis. They identified presence of receptors and binding sites in 33% and 79%, respectively. The therapeutic implications of this finding are unclear. Maddalozzo et al29 suggested a sub-
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classification of juvenile fibromatosis based on the existence of estrogen and progesterone receptors. They concluded that receptor-positive tumors may be treated with tamoxifen. Genetic factors seem to play a role in the etiology of fibromatosis. Gardner’s syndrome, an inherited condition characterized by osteomas, cutaneous cysts, and intestinal polyps, conveys an added risk of fibromatosis development. One report in the literature described a Jordanian family with fibromatosis in a mother and 2 children, suggesting an autosomal dominant or recessive inheritance pattern.30 Another report described a family in which 5 members had fibromatosis, suggesting an autosomal dominant pattern.31 Much evidence for an inherited predisposition to forming fibromatosis comes from work by Reitamo et al.32 They found a statistically significant (P < 0.001) incidence of radiographic abnormalities in the bones of 53 patients with histories of fibromatosis. These abnormalities included cortical thickening, cystic regions, exostosis, osteomas of the mandible, and sacralization of the fifth lumbar vertebra. They also found bone abnormalities in the families of patients with fibromatosis at a significantly higher rate than in a control group. These findings are consistent with an autosomal dominant pattern of inheritance with variable penetrance. Reitamo et al postulated that an inherited factor that causes abnormal bone growth also predisposes patients to the development of fibromatosis. They defined desmoid syndrome as a desmoid tumor in conjunction with an inherited familial tendency to form abnormal bone. More recent studies of the pathogenesis of fibromatosis have taken place at the molecular level. With Northern blot analysis, immunofluorescence, and in situ hybridization, inappropriate expression of c-sis and consequent production of prostaglandin 2 in 10 of 10 samples were described in various anatomic locations.33 It was postulated that the trigger for increased expression of c-sis might be related to sex hormones or sex hormone receptors. Another genetic study identified a higher incidence of trisomy 8 in samples taken from recurrent tumors than in samples taken from nonrecurrent tumors.34 These researchers concluded that trisomy 8 might be a marker of higher recurrence rate. Although none of these studies provided sufficient evidence for a true etiology of fibromatosis, they did provide evidence that cytogenetic abnormalities are associated with tumor growth. Most recently, laboratory studies have clearly shown that fibromatosis is a monoclonal proliferation of cells. Bridge et al35 conducted a cytogenetic study of 22 cases of abdominal and extra-abdominal fibromatosis. Clonal
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Table 2. Recurrence rates of fibromatosis of the head and neck Study
Hunt et al11 Conley et al9 Fasching et al13*
Therapy
Cases with Recurrences follow-up (%)
Excision 5 Excision 40 Complete excision 32 ± XRT Incomplete excision 14 ± XRT Reitamo et al4 Excision 7 TOTAL — 98
2 (40) 19 (47) 8 (25) 12 (86) 3 (43) 44 (45)
XRT, Radiation therapy. *Patients in this series include patients reported by Masson and Soule.8
abnormalities in 7 patients with defects involving chromosomes Y and 5q were found. The preservation of these cytogenetic abnormalities in the tumor cells suggested a true neoplastic etiology. Two other recent molecular studies of fibromatosis clearly indicated that fibromatosis is a monoclonal proliferation of cells.36,37 Both groups used polymerase chain reaction amplification of archival specimens to study patterns of X chromosome inactivation. Findings indicated that tumor cells arose from a single progenitor cell. A single case report in the literature suggested an autoimmune etiology in a case of neck fibromatosis.38 A histologic diagnosis of fibromatosis, an elevated erythrocyte sedimentation rate, and high titers of antithyroid and smooth muscle antibodies suggested an autoimmune etiology. In addition, the patient responded well to corticosteroid therapy. TREATMENT Surgery
The mainstay of treatment of fibromatosis of the head and neck is complete surgical excision. In patients with tumors in the head and neck region, it is often difficult to achieve negative margins because of the complex anatomy, close proximity of vital structures, and complicated exposure. Difficulty with complete excision is reflected in the relatively high recurrence rates of fibromatoses excised from the head and neck region. Some surgeons have advocated aggressive surgical resection for tumors of the extremities and reported low recurrence rates: According to Das Gupta et al,7 “To avoid recurrence adequate excision of the lesion is mandatory; this means major amputation when indicated.” For obvious reasons these reports are not easily applied to the head and neck. Table 2 details the recurrence rates after primary resection of fibromatosis of the head and neck in larger series.
Fasching et al13 showed that fibromatosis recurred at a very high rate when margins were positive but also frequently when margins were considered negative. At initial resection, when the pathologist reported negative margins, 8 of 32 tumors (25%) recurred. Without complete excision, 12 of 14 tumors (86%) recurred. Miralbell et al39 reported recurrence in 5 of 5 patients with positive surgical margins. Similar recurrence patterns have been reported in pediatric patients. In a series of 63 children with fibromatosis, histologically negative margins recurred at a rate of 28%, whereas positive margins recurred in 82%.40 In a multivariant analysis of 128 patients undergoing attempted surgical resection, less than adequate margins of resection were correlated with a higher recurrence rate.15 However, Catton et al41 found that tumor margin status had no impact on recurrence in 36 patients treated with surgery alone. In a review of fibromatosis in the Finnish population, a higher incidence of tumor recurrence was reported when the tumor was initially resected from an anatomically complex region (10% vs 48%).32 In that series, 3 of 7 head and neck fibromatoses recurred. A review of 25 cases of fibromatosis of the sinonasal tract and nasopharynx from the Armed Forces Institute of Pathology reported a 21% incidence of recurrence with a mean follow-up of 8 years 2 months.10 The authors suggested that the bony confines of this anatomic region limited extension. Conley et al9 and Fasching et al13 both found that when fibromatosis occurs in the base of the neck, recurrence rates may be higher than if it occurs in other regions of the neck. The above findings have therapeutic implications. First, meticulous surgical excision is essential. Wide local excision with frozen-section control may be necessary. Second, if tumor margins are known to be positive, postoperative adjunctive therapy should be considered. Finally, close follow-up is essential. With a greater than 40% recurrence rate of all fibromatoses of the head and neck and a greater than 25% recurrence rate with negative margins, it is clear that these patients need to be followed up very closely. We recommend frequent physical examination and interval CT scan examination. In addition, new patient symptoms need to be aggressively evaluated. Re-excision of recurrences should be considered if clinically feasible. Radiation Therapy
Because of the rarity of fibromatosis of the head and neck, most of the studies of chemotherapy and radiation therapy include treatment of tumors in all anatomic locations. These authors assume that deep fibromatosis is the same entity regardless of its location. A common conception is that fibromatosis of the head and neck is
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a more aggressive entity than other deep fibromatoses. This conception is likely a reflection of the difficulty with complete resection from an anatomically complex region. After extensive review of the literature, no reports indicate any differences in the intrinsic nature or tumor cell biology among deep fibromatoses. Information obtained from the study of deep fibromatosis in all locations is extrapolated to the head and neck with special considerations because of the complex and vital anatomy of this region. A role for radiation therapy has been clearly established.39,42-48 Radiation therapy is useful if there is gross residual tumor after resection, if a tumor recurs, or if a tumor is considered inoperable. Schmitt et al46 reviewed the outcomes of 164 patients treated with radiation therapy (with or without surgery) from several series and reported the overall recurrence rate to be 22%. In addition, there was virtually no difference in recurrence rates with respect to microscopic or macroscopic tumor at the outset of radiation therapy (21% and 23%, respectively). Although the radiation oncology literature is consistent in its success at treating these patients, Fasching et al13 found little value in the use of radiation therapy as either adjunctive or primary therapy. They did, however, report a transient decrease in tumor size in several patients. The most common protocols for treating fibromatosis involve fractionalization to a total dose of 50 to 60 Gy. Schmitt et al46 described a dose-response relationship between 30 and 60 Gy. In addition, if radiation is to be used, a wide field should be implemented to treat all microscopic disease. This is particularly important in the head and neck, where recurrences can involve vital structures. In a recent series 53 patients were treated with radiation therapy for both microscopic and gross disease.48 Local control was achieved in 83% of treated patients. Of the 9 recurrences in this series, 3 were in the radiated field, 4 were at the field margin, and 2 were outside the field. In another series, only 1 of 6 recurrences were within the radiated field.43 The radiation oncology literature calls for meticulous treatment planning to help avoid recurrences.41 Radiation therapy should be strongly considered in the following situations: (1) if primary excision is not possible because of the tumor location, patient desires, or the medical condition of the patient; (2) if there is gross residual disease after surgery; and (3) if there is microscopic disease after resection. In the third scenario, close observation may also be considered an appropriate treatment, and therapeutic plans should be individualized. The possible benefits of radiation therapy need to be weighed against its potential for long- and short-term complications. Radiation-induced tissue
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changes can make future surgical resection more difficult. In addition, maximal tumor regression may take many months to years.41 Radiation therapy should be used with caution in the pediatric population because of the well-known effects of radiation on bone growth and the potential for the delayed development of a cancerous lesion. One author obtained excellent results with tamoxifen as adjuvant therapy in a child with positive margins after the resection of a sinonasal lesion.49 Pharmacologic Therapy
Several pharmacologic approaches have been made to the treatment of fibromatosis. These approaches have had variable success, and results are somewhat anecdotal. Nevertheless, there may be a role for pharmacologic treatment of fibromatosis in certain situations, and they are therefore worth review. Clinicians have attempted cyclic adenosine monophosphate (cAMP) modulators, estrogen blockers, progesterone, prostaglandin manipulation, and classic chemotherapy during the past few decades. The earliest reports on the pharmacologic treatment of fibromatosis used progesterone to inhibit tumor growth. In 1944, Lipschultz and Maas50 reported the use of progesterone to inhibit the formation of fibromatosis in guinea pigs when exposed to high doses of estrogen. Although this finding was not reproducible in other animals, it prompted others to use intramuscular progesterone to treat patients with fibromatosis with favorable results.51,52 Waddell et al25,53-55 used other pharmacologic interventions such as antiestrogens, nonsteroidal antiinflammatory drugs, warfarin, vitamin K, and ascorbate in various combinations. Waddell55 stated that the goal of these agents is “to minimize the effects of estrogens and to inhibit the prostaglandin and cAMP synthesis, both of which influence growth and proliferation of fibroblasts.” The use of tamoxifen or testolactone is based on the theory that fibromatosis may be responsive to estrogen. Tamoxifen would theoretically limit the tumor response to estrogen by competitive inhibition at either estrogen binding sites or an allosteric site on or within tumor cells.56 Testolactone is a steroid derivative that blocks cAMP and may inhibit aromatase thereby, leading to decreased levels of estrogen.56 In one series of patients treated with various pharmacologic interventions, patients who received either tamoxifen or testolactone and nonsteroidal anti-inflammatory agents had the greatest tumor response. Five of 7 patients had major tumor regression.55 Several other reports described favorable responses when fibromatosis was treated with
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tamoxifen.24,25,57 Others reported positive results when patients with fibromatosis were treated with testolactone.25,55,58,59 Most reports do not designate the existence of estrogen receptors, thereby making it difficult to draw conclusions regarding the relative responsiveness of estrogen receptor–positive tumors when treated with tamoxifen or testolactone. We and others advocate the determination of estrogen and progesterone receptors in fibromatosis samples.29 This information may help guide pharmacologic therapy, provide insight into tumor biology, or act as a prognostic indicator for patients with fibromatosis. The use of traditional antineoplastic agents has been reported in small numbers.25,60-63 Goepfert et al60 preoperatively treated 6 children with desmoid fibromatosis using various combinations of low-dose adriamycin, dacarbazine, vincristine, dactinomycin, and cyclophosphamide. He found that 4 of 5 were free from disease at the time of manuscript submission (3 months to 6 years). One patient had a recurrence at 21 months. Complications were common. Three of 5 patients had wound infections, and 2 patients had cardiotoxic effects of adriamycin. Weiss and Lackman61 published the largest series of patients treated with traditional chemotherapy for fibromatosis. They recommended the use of methotrexate and Vinca alkaloids because of their relatively favorable toxicity profiles. In the treatment of 12 patients judged to be unsuitable for surgical intervention, there was complete tumor regression in 3 patients, partial remission in 7 patients, and minimal benefit in 2 patients. Another report applied the same combination therapy of methotrexate and vinblastine to 10 children with fibromatosis.62 Three patients had complete resolution, and 2 had partial resolution. In a fourth series studying fibromatosis, Waddell et al25 treated patients with adriamycin and cyclophosphamide with little to no benefit. Summary
The mainstay of therapy for fibromatosis of the head and neck is complete surgical resection. If gross tumor remains after resection or the patient is unfit for surgical intervention, radiation therapy is indicated. In addition, radiation therapy is indicated for recurrent tumors if repeat resection is not feasible. If microscopic margins are positive, there is a higher incidence of recurrence; therefore radiation therapy should be considered, and the patient should be followed up closely. In addition, pharmacologic therapy may be considered if the more proven methods of surgical excision and radiation therapy have failed. These therapeutic recommendations should be considered guidelines only, and treat-
ment should be individualized based on the specific lesion, patient’s condition and desires, as well as the resources available. CONCLUSION
Although fibromatosis is considered a benign tumor, it can have significant morbidity, particularly when it occurs in the head and neck. Their propensity for infiltrative local growth with encroachment on vital structures and their tendency to recur make fibromatoses of the head and neck extremely challenging lesions. We thank Alison Begleiter, MD, for outstanding editorial assistance, and Suzanne Keel, MD, for the photomicrograph. REFERENCES 1. Batsakis JG, Raslan W. Pathology consultation—extra-abdominal desmoid fibromatosis. Ann Otol Rhinol Laryngol 1994;103: 331-4. 2. El-Sayed Y. Fibromatosis of the head and neck. J Laryngol Otol 1992;106:459-62. 3. Enzinger FM, Weiss SW. Soft tissue tumors. 3rd ed. St Louis: Mosby; 1995. 4. Reitamo JJ, Hayry P, Nykri E, et al. The desmoid tumor. I. Incidence, sex-, age- and anatomical distribution in the Finnish population. Am J Clin Pathol 1983;77:665-73. 5. Pack GI, Ehrlich HE. Neoplasms of the anterior abdominal wall with special consideration of desmoid tumors: experience with 391 cases and collective review of the literature. Int Abs Surg 1944;79:177-98. 6. Enzinger FM, Shiraki M. Musculo-aponeurotic fibromatosis of the shoulder girdle (extra-abdominal desmoid). Analysis of ten cases followed up for ten or more years. Cancer 1967;20:1131-40. 7. Das Gupta TK, Brasfield RD, O’Hara J. Extra-abdominal desmoids: a clinicopathologic study. Ann Surg 1969;170:109-21. 8. Masson JK, Soule EH. Desmoid tumors of the head and neck. Am J Surg 1966;112:615-22. 9. Conley J, Healey WV, Stout AP. Fibromatosis of the head and neck. Am J Surg 1966;112:609-14. 10. Gnepp DR, Henley J, Weiss S, et al. Desmoid fibromatosis of the sinonasal tract and nasopharynx—a clinicopathologic study of 25 cases. Cancer 1996;78:2572-9. 11. Hunt R, Morgan HC, Acherman LV. Principles in the management of extra-abdominal desmoids. Cancer 1960;July-August: 825-36. 12. Siemssen SJ, Anagnostaki T. Aggressive fibromatosis (extraabdominal desmoids) of the head and neck. Br J Plast Surg 1984;37:453-7. 13. Fasching MC, Saleh J, Woods JE. Desmoid tumors of the head and neck. Am J Surg 1988;156:327-31. 14. Human A, Chou S, Carpenter B. Fibromatosis in infancy and childhood: the spectrum. J Pediatr Surg 1993;28:1446-50. 15. Posner MC, Shiu MH, Newsome JL, et al. The desmoid tumor not a benign disease. Arch Surg 1989;124:191-6. 16. Soule EH, Scanlon PW. Fibrosarcoma arising in an extra-abdominal desmoid tumor: report of a case. Proc Staff Meetings Mayo Clin 1962;37:443-51. 17. Penick RM. Desmoid tumors developing in operative scars. Int Surg Digest 1937;23:323-9. 18. Hayry P, Reitamo JJ, Totterman S, et al. The desmoid tumor. II. Analysis of factors possibly contributing to the etiology and growth behavior. Am J Clin Pathol 1982;77:681-5. 19. Goellner JR, Soule EH. Desmoid tumors: an ultrastructural study of eight cases. Hum Pathol 1980;11:43-50. 20. Booher RJ, Pack GT. Desmoids of the abdominal wall in children. Cancer 1951;4:1052-65.
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