Aggressive Fibromatosis: Evidence for a Stable Phase

Purpose. Aggressive fibromatosis (AF) is an uncommon locally infiltrating benign disease of soft tissue for which treatment comprises complete surgical resection. Radiotherapy can be given postoperatively if the margin is incompletely resected. If the tumour is inoperable radiotherapy provides an alternative treatment. Hormone therapy and cytotoxic chemotherapy have also been used for unresectable or recurrent disease. All treatment modalities carry an associated morbidity. We believe that the natural history of aggressive fibromatosis may include a period of stable disease without progression, during which time, treatment is not always necessary. Patients and methods. We present a retrospective review of 42 patients referred to the Royal Marsden Hospital between 1988 and 1995 with aggressive fibromatosis. Evidence of periods of stable disease and the relationship to delivered treatment was obtained from the case notes, including the natural history prior to referral to our institution. Stable disease was defined as a period of no objective progression for 6 months or longer. Results. Seventeen patients could be assessed for stable disease and all (100%) experienced at least one episode of stable disease, eight of whom whilst receiving hormonal or cytotoxic therapy. Of the 23 patients who could not be assessed for stable disease, as they underwent surgery at presentation or recurrence of disease, only 2 had persisting disease at last follow-up. Both of these patients had had positive surgical resection margins. Discussion. This study demonstrates the variable natural history of AF, which can include a substantial period of stable disease in a significant number of patients. A less aggressive approach to the management of AF may therefore be appropriate, particularly if a subgroup of patients who are likely to experience a period of stable disease can be identified.


Introduction
Aggressive ® brom atosis is an uncom m on benign soft tissue neoplasm . Because of its tendency for recurrence, it is usually categorised together with m alignant soft tissue neoplasm s of which it constitutes less than 4%. 1 The reported annual incidence is 0.2± 0.5/100 000 population. 2 It occurs m ore comm only in wom en and in the younger population. Aetiology is unknown but there are associations with traum a (including surgery), pregnancy, and oestrogen exposure. There is a rare fam ilial type, which m ay be part of Gardner' s syndrom e.
Fibrom atosis w as ® rst described m ore than 150 years ago by M cFarlane. 2 Because of its rarity, m ost published series describe only sm all num bers of patients and there rem ains uncertainty as to the m ost approp riate m ethod of treatm ent. C urrent approaches include surgery, radiotherapy, chemotherapy, endocrine therapy and observation, either alone or in com bination.
Assessm ent of response to therapy has traditionally included only local control and recurrence rates.
H owever, there is the im pression in our institution that there m ay be a plateau phase in its natural history when there is no progression, i.e. a period of stable disease. If this exists then there are serious im plications for m anagement, particularly when treatments can involve either extensive surgery or potentially m utagenic treatments such as radiotherapy, chemotherapy and endocrine therapy. Furtherm ore, if there is a plateau phase then it m ust be taken into account when assessing response to treatm ent. G rowth arrest w ith any of these treatments m ay be unrelated to that treatment and failure to progress (stable state) cannot be considered an objective response.

M aterials and m ethods
A retrospective analysis was m ade of 42 evaluable patients referred to one surgeon at the Royal M arsden Hospital (RM H), with a diagnosis of aggressive ® brom atosis between 1988 and 1995. Tw enty-one patients were referred with recurrent disease after treatment elsewhere and 21 presented de novo. A T able 1. Tum our site in patients with or without stable disease (SD )   Site   Abdominal wall  Intra-abdominal  Pelvis  Others   Patients with SD  1  1  3  14  Patients without SD  3  3  1  16 range of treatm ents was offered from observation only, surgery alone, surgery and radiotherapy (30± 60 G y in 15± 30 fractions given over 3± 6 weeks), torem ifene 40 m g daily, or chemotherapy with m ethotrexate (50 mg weekly) plus vinblastine (10 m g w eekly). A wide excision was the aim of surgery, if practically possib le. W ide excision is the rem oval of all gross disease with a surrounding m argin of healthy tissue. Follow up ranged from 11 m onths to 8 years (m edian 3 years). Twelve patients were not followed up, but the natural history of their disease prior to referral is included in the analysis. F ollowup data are availab le on 30 patients. Stable disease was de® ned as a period of no objective progression for 6 m onths or longer. Evidence of stable disease was obtained from case notes, either reported by patients in their initial history or by docum ented reports during follow up at RM H. Progressive disease was de® ned as an increase in size or sym ptom s related to the tum our. C om plete response was resolution of all gross disease following therapy. Partial response was a reduction in size of the tum our by 50% or greater in all dim ensions m aintained for two consecutive assessm ents at least 3 m onths apart. Residual disease was de® ned as microscopic, if all gross disease w as rem oved but m argins w ere positive on m icroscopy, or macroscopic, if gross disease rem ained. The periods of progressive, stable or regressing disease were then correlated w ith the type of treatment adm inistered.

Results
T he case notes of 42 patients with aggressive ® bromatosis seen at RM H were retrospectively analysed. Tw enty nine patients were fem ale and 13 m ale. The age range at the time of referral was 16± 75 years (median 34 years). Of the patients who presented with recurrent disease, 2 were found to have scar tissue only, 8 patients had developed their ® rst recurrence and 11 had undergone m ultiple excisions with or without radiotherapy. Six patients had 2 or m ore sites of disease. The anatom ical sites of involvem ent are show n in T able l.

E pisodes of stable disease
Episodes of stable disease were seen in 17 patients (40% ). F ifteen patients had stable disease docu-m ented following referral to RM H , 4 of these also had stable disease prior to RM H referral. O nly two patients had stable disease that w as not observed at RM H but had been docum ented by the referring hospital. Spontaneous regression w as seen in 2 additional patients. O ne patient with stable disease also experienced spontaneous regression at one site and experienced stable disease at another, separate, site. T able 2 sum m arises these data. Twelve patients were fem ale and 7 m ale. T he period of stable disease ranged from 6 m onths to 12 years (m edian 3 years). N ine of these patients had periods of stable disease on no treatm ent. Eight patients had stable disease while on treatment. Seven were being treated w ith toremifene (20 m g daily). T hree patients were also treated with m ethotrexate plus vinblastine and one patient with chem otherapy alone.
Four of these patients continued to have stable disease after com pletion of therapy from 21 to 36 m onths and 4 have continued to have stable disease while continuing with therapy. T hree patients experienced a spontaneous regression.

N o episode of stable disease
T wenty-three patients could not be assesse d for stable disease as they w ere treated by surgery. All but two or these had recurrent disease at referral. T welve patients underwent surgery alone, 5 received surgery and radiotherapy, 3 comm enced torem ifene and one was started on chem otherapy. The latter 4 patients progressed on drug therapy and one of these had a further resection and rem ains disease free. Table 3 outlines outcom e after surgery in relation to the histological excision m argin in patients treated with surgery with or without radiotherapy. F ive patients had surgery follow ed by adjuvant radiotherapy for positive histological m argins. Follow-up data are availab le on only two of these: both rem ain free of disease 3 and 4 years postirradiation. T he ® nal three patients w ere not treated at RMH having been discharged after their initial consultation.
In sum m ary, of these 23 patients, only 2 still had persisting disease at their last follow-up, despite the presence of gross residual disease or positive resection m argins in 10 (13 if unknown excision m argins are included). Both patients with persisting disease had previously relapsed on m ore than one occasion   and had gross residual disease following their m ost recent resection.

D iscussion
T he ® brom atoses comprise a num ber of distinct clinicopathological types: palm ar and plantar ® bromatosis, penile ® brom atosis (Peyronie' s disease) and aggressive ® brom atosis (desm oid tum our). The latter are divided into abdominal or extra-abd om inal sites. The abdom inal tumours usually occur in the m uscular aponeurotic structures of the anterior abdom inal wall, particularly in postpartum w om en. Extra-ab dom inal tumours occur at any site but are m ore usual around the shoulder girdle, inguinal region and lower extremities.
Histologically the tum our consists of interlacing bundles of spindle cells (® broblasts) with variable am ounts of collagen, which in® ltrate the surrounding structures. T here can be vigorous cellularity at the edge of the lesion in com parison to a relatively poorly cellular core and this, together with the tendency to in® ltrate and a high tendency to recurrence post-excision, has led som e authors to describe the condition as low-grade ® brosarcom a. 3,4 M etastases do not occur.
The im portance of aggressive ® brom atosis is a tendency to in® ltrate widely w hich has led m ost practitioners to treat this tum our in a manner sim ilar to a low-grade sarcom a, by perform ing a wide excision. The risk of local recurrence after non-wide resection is 8± 70% . 1,5,6,7 Multiple previous recurrences and residual disease predict for further recurrence. H owever, there are also reports of lack of recurrence or progressive disease in cases that are known to have had either gross residual disease or m icroscopically positive m argins at surgery. 3,8,9,10 T his im plies that the persistence of tum our cells does not necessarily equate with progressive disease. T his has been con® rm ed in our series.
Other m odalities used in the m anagement of this disease include radiotherapy, horm one therapy and chem otherapy. Assessm ent of response includes recurrence rates or response rates (including partial and com plete response) and stable disease. In our series 40% of patients had stable disease either with or w ithout treatment. Therefore it is important to identify in reported series the type of response in order to assess the possible bene® t of treatment.
Radiotherapy is frequently recom mended in both the prim ary and adjuvant setting. Radiotherapy series have shown a local recurrence rate of 20± 46% . 4,5,7,9± 16 Som e series indicate the proportion of com plete, partial and stable disease response to treatment, which is sum m arised in Table 4, although the m ajority describes com plete response or persisting disease only.
The reported use of torem ifene and chem otherapy, in the m anagem ent of this disease is limited. 17± 21 Reports describe sm all num bers of patients and response rates are quoted as 65± 75%, but include stable disease, partial and com plete response. In our series, 8 patients (67% ) had stable disease while using toremifene or chem otherapy, but no patient had a partial or com plete response.
It can be seen that there is a w ide variation in the natural history of aggressive ® brom atosis, ranging from spontaneous rem ission to m ultiple recurrences post-treatment, regardless of the m odality of treatm ent used. F rom our results, 40% of patients have experienced a period of stable disease. T he variability of natural history has signi® cant im plications for m anagem ent in the individual patient. T he m ajority of patients will be successfully treated with It is our opinion that a signi® cant proportion of these patients m ay reach a stable phase of their disease and hence not require further treatm ent with agents that m ay have serious long-term toxicity. The dif® culty is to identify these patients. T his study has not revealed any particular features (other than m ultiple recurrences) w hich are less likely to have a stable phase.

C onclusion
T he natural history of aggressive ® bromatosis is variable and can include a substantial period of stable disease in a signi® cant proportion of patients. Aggressive ® brom atosis rarely causes life-threatening com plications, although it m ay be fatal. 22 H ence, w e have adopted a non-aggressive approach to m anagement following attempted wide excision. W e initially observe unresectable or recurrent disease on this`stable phase' principle. D ebulking surgery is frequently of value for palliation. W e now have a series of patients where the tum our has been debulked to achieve a good cosm etic and functional result. W e tend to avoid the use of radiotherapy even w hen resection is incom plete or if the m argins are positive, unless recurrence or further progression could have a potentially serious outcom e.