Fibromatosis

Objective.-To predict if antiestrogenic agents are useful in the treatment of breast fibromatoses, we undertook an immunohistochemical study of sex steroid hormone receptors (estrogen receptor, progesterone receptor, and androgen receptor) and protein pS2 in 33 cases.

Methods.-The morphologic and immunohistochemical findings were correlated to patient menstrual status, which was categorized as childbearing age (n 15), perimenopausal (n = 8), and postmenopausal (n 10).

Results.-Fibromatoses in women of childbearing age were more cellular, more mitotically active, and displayed a larger proportion of cells with mild atypia than those in perimenopausal and postmenopausal women. The hormonal status of these 3 groups does not explain the morpho

logic variations observed in these groups, inasmuch as no immunostaining for any of the hormone receptors was detected in the tumors.

Conclusions.-The absence of estrogen receptor and pS2 in breast fibromatoses suggests that antiestrogenic agents are unlikely to be beneficial in the management of these tumors. Assessment of the hormone receptor profile is a useful adjunct in the diagnosis of spindle cell lesions of the breast. Although most spindle cell carcinomas as well as fibromatoses of the breast do not express estrogen or progesterone receptors, the absence of androgen receptor reactivity would favor a diagnosis of fibromatosis over that of myofibroblastoma.

(Arch Pathol Lab Med. 2000;124:276-280)

Fibromatosis is an infiltrative fibroblastic and myofibroblastic proliferation with significant risk for local recurrence, but no metastatic potential.1 It originates principally from the fascia or aponeuroses of the abdominal wall muscles or the muscles of the shoulders and pelvic girdles.1 Fibromatosis is uncommon in the mammary gland and accounts for less than 0.2% of all primary breast lesions.2 Indeed, mammary involvement usually occurs by extension of a lesion arising from the pectoral fascia.

Although the morphologic features of fibromatosis are well described, its pathogenesis remains poorly understood. Sex steroid hormones may play a role in its development, in view of several reported cases of estrogen receptor (ER)-positive extramammary fibromatosis.3-6 Furthermore, regression of extramammary desmoid tumors has been documented after administration of antiestrogens, such as tamoxifen.7

Although fibromatosis of the breast arises in a hormoneresponsive organ, we found no reports of antihormonal treatment in this setting. Steroid hormone receptor status in mammary fibromatosis has seldom been studied, and the results of the few reported cases are conflicting.8-11 Neither the presence of such receptors nor the histopathologic features of breast fibromatosis have been correlated with patient age or menstrual status.

To investigate the hormone receptor profile and correlate the findings with patient menstrual status, we undertook an immunohistochemical study of ER, progesterone receptor (PR), and androgen receptor (AR) reactivity in 33 examples of mammary fibromatosis. The 33 patients were divided into 3 age groups: childbearing age, perimenopausal, and postmenopausal. Immunohistochemical detection of pS2, a protein associated with an enhanced response to tamoxifen in ER-positive or -negative breast carcinomas, 12 was also evaluated.

MATERIALS AND METHODS

Thirty-three cases of fibromatosis of the breast with available paraffin blocks were retrieved from the files of the Armed Forces Institute of Pathology (Washington, DC) for the period 1970 to 1997. All cases were reviewed by the authors. Two of these cases have been reported previously." Cases with muscular or skin extension were excluded in order to study only primary intramammary lesions with normal breast parenchyma present. One to 14 (median, 4) hematoxylin-eosin-stained slides were available for each case, and 1 representative tissue section was chosen for immunohistochemical study using avidin-biotin-peroxidase complex technique as described previously.14 The following primary antibodies were used: ER (monoclonal, 1:40 dilution; Dako Corporation, Carpinteria, Calif), PR (monoclonal, 1:80 dilution; Novocastra, Burlingame, Calif), AR (monoclonal, 1:40 dilution; BioGenex, San Ramon, Calif), pS2 (monoclonal, prediluted; BioGenex), and MIB-1 (Ki-67, 1:40 dilution; Immunotech, Opa Locka, Fla). A case of well-differentiated infiltrative ductal carcinoma of the breast was used as a positive control.

The clinical and macroscopic findings were obtained from patient charts. Microscopic features evaluated included the number of mitotic figures per 10 high-power fields (HPF) and the presence of cellular atypia (mild, moderate, or severe). Cellularity was graded as mild, moderate, or high and was recorded as previously described"; neoplasms composed of at least 75% cells and less than 25% stromal collagen were considered cellular, and those with 25% or fewer cells and 75% or more collagen were considered fibrous. The presence of inflammatory cells within the tumors was graded as mild or prominent.

Any nuclear staining with antibodies against ER, PR, AR, or MIB-1 and any cytoplasmic staining with pS2 were noted; the percentage of positive cells was recorded for each case. For steroid hormone receptor, we used a cutoff of 10% nuclear staining for a positive result.15

RESULTS

Clinical Findings

All patients were female and 3 age groups were defined, as listed in the Table, Ages of the 15 women in the childbearing age group ranged from 14 to 32 years (median, 21 years). The perimenopausal age group included 8 patients, aged 43 to 51 years (median, 47 years), and the postmenopausal age group was composed of 10 women, aged 60 to 80 years (median, 76 years).

Two patients, aged 24 and 22 years, were pregnant at the time of presentation, and a 47-year-old patient reported a history of trauma to the same breast 17 years prior to the diagnosis. Another 47-year-old woman had undergone an excisional biopsy for fibroadenoma at the same site 2 years previously. Thirty of the 33 patients presented with a palpable mass. In 3 cases, an abnormal mammogram (suspicious for carcinoma in 2 patients) led to the breast biopsy.

The lesion involved the right breast in 15 (46.8%) patients and the left breast in 16 (50%) patients. One lesion in a 19-year-old patient was bilateral (3.2%). In one case, the laterality was unknown.

Gross Findings

The lesions ranged from 0.5 to 6 cm and had a mean diameter of 2.5 cm. The majority were irregular, poorly demarcated, firm, and white-gray on cut surface, and they showed no cysts, hemorrhage, or calcifications.

Histopathology

All the lesions were composed of a spindle cell proliferation forming sweeping or interlacing fascicles. The cellularity varied from mild to moderate. A variable amount of collagen was present and was predominantly located in the center of the lesions. The cellularity varied according to the patient's age. The majority (60%) of the lesions in the childbearing age group were more cellular than fibrous (Figure 1), while only 25% of the lesions in the perimenopausal women and 20% of the lesions in the postmenopausal women displayed increased cellularity. Using the Fisher exact test, the difference in cellularity of the lesions in the childbearing age group versus perimenopausal and postmenopausal women was statistically significant (P = .038). The lesions in the postmenopausal group disclosed more prominent, keloidlike collagen bands (Figure 2), whereas those of the childbearing age group were most often edematous. This difference was also statistically significant (P = .014).

Mild cellular atypia was noted in 9 cases. Large atypical fibroblasts were absent. Lesions in patients of childbearing age presented with more atypical cells than did those in perimenopausal and postmenopausal women; however, the difference was not significant (P = .239). Mitotic figures were absent in 20 cases and varied from 1 to 5 per 10 HPF in the remaining 13 cases. Lesions of the childbearing age group showed more mitoses than those in perimenopausal and postmenopausal women, but the difference did not reach statistical significance (P = .17).

At the periphery of the lesions, there were at least focally irregular and infiltrating fingerlike projections extending into the adjacent breast tissue in all cases. However, a nodular growth pattern was observed focally in 5 cases.

A lymphoplasmacytic inflammatory infiltration was present at the periphery of the lesions in all but 5 cases and was prominent in 8 cases, with follicle development in 3 cases. The inflammation was more prominent in the lesions from perimenopausal and postmenopausal women than in those of the childbearing age group. This finding was statistically significant (P = .014).

Dilated vessels and extravasated red cells were noted throughout most lesions. None of the cases contained the digital fibroma-like inclusion bodies previously described in 2 mammary fibromatoses. 16 Entrapped mammary lobules were present mostly at the periphery of the lesions and displayed atrophic changes. Within the entrapped ducts, we noted intraductal hyperplasia of usual type in 9 cases and atypical intraductal hyperplasia in 2 cases.

Immunohistochemical Findings

Estrogen, Progesterone, and Androgen Receptors.-In 31 tumors, there was absolutely no positive immunoreaction with ER, PR, or AR. Two tumors did contain sporadic positive cells comprising less than 10% of the tumor; these tumors also qualified as negative. One of these tumors was a lesion from a 22-year-old patient that showed staining for AR in 1% of the cells. The other was a lesion from a 49-year-old patient that displayed weak positive nuclear staining for ER in 10% of the cells.

pS2 Protein.-All cases were absolutely negative for pS2 reactivity, whereas a case of infiltrative ductal carcinoma used as a positive control exhibited cytoplasmic staining in 80% of the cells. Thirteen cases with positive internal control displayed focal and patchy cytoplasmic staining of normal epithelial cells in the surrounding mammary ducts and lobules. In secretory lobules, the staining was stronger and more diffuse. In addition, weak nuclear staining of the normal epithelial cells was observed in 5 cases.

MIB-1 (Ki-67).-The majority of the lesions (65.6%) demonstrated less than 1% cycling cells with Ki-67 immunostaining (64.3% in childbearing age group, 100% in perimenopausal women, and 40% in postmenopausal women). The only lesion with more than 10% positive cells was that of a 16-year-old girl. The remaining cases (28.5% in childbearing age group and 60% in postmenopausal women) demonstrated positive staining in 5% of cells. The staining was predominantly located in endothelial and perivascular cells within the tumors. Given the high number of cases with less than 1% stained nuclei, no correlation between Ki-67 index and patient age could be drawn.

COMMENT

The morphologic features of mammary fibromatosis are well documented.10,13,17 To our knowledge, a correlation between morphofunctional findings and patient age has never been attempted. In this study, we compared the morphologic features and hormone receptor profiles of 33 cases of mammary fibromatosis separated into 3 groups based on age-approximated menstrual status (childbearing age [14-32 years; median, 21 years], perimenopausal [43-51 years; median, 47 years], and postmenopausal [6080 years; median, 76 years]). No difference was noted in either the site of occurrence (left vs right breast) or the tumor size among these groups. The lesions in the younger patients (childbearing age) were significantly (P = .034) more cellular than those of the perimenopausal and postmenopausal groups (60% vs 25% and 20%, respectively), displayed a larger proportion of cells with mild atypia (40% vs 12.5% and 20%, respectively), and were mitotically more active (1.4 vs 0.1 and 0.3, respectively). Compared to the lesions in the childbearing age group, the tumors in perimenopausal and postmenopausal patients were significantly (P = .014) more fibrous (40% vs 75% and 80%, respectively) and presented with prominent inflammatory cells (6.6% vs 50% and 30%, respectively; P = .046).

Recently, superficial fibromatoses have been divided into 3 phases, namely, proliferative, involutional, and residual, based on histologic appearances."' The first 2 phases express a higher level of transforming growth factor a and its receptor's (epidermal growth factor receptor) messengers and proteins, reflecting the active and early phases of the disease, than is found in the residual phase.19

The 15 fibromatoses in our patients of childbearing age are comparable to the proliferative phase used in a study by Margo et al,18 with a greater cellularity, whereas those of our perimenopausal and postmenopausal patients displayed the characteristics of a regressing phase with a more fibrous pattern and greater amount of keloidlike collagen bands.

Only one lesion, arising in a 49-year-old patient, demonstrated weak immunostaining of 10% of the cells with ER. However, staining of less than 10% of tumor cells in breast carcinoma has been interpreted as a negative result in other studies,15 and we also have considered this weak and focal immunostaining as negative. The remaining 32 cases were totally negative for the antibodies we tested. Given the absence of ER and PR reactivity in all age groups in this study, the morphologic differences of fibromatosis in the different age groups (menstrual states) cannot be attributed to different hormonal levels.

The presence of inflammatory cells was noted by Margo et all" in any of the phases of fibromatosis. The more abundant cellular infiltrate in the tumors from the 2 older groups might reflect an involutional process comparable to the involutional changes of the breast parenchyma in postpartum and menopausal women.20

Despite the abundance of reported cases and series of extramammary fibromatoses in the literature, the etiology of this lesion is still the subject of debate. Trauma, particularly surgical trauma, has been emphasized as an etiologic factor.1 The occurrence of extramammary fibromatoses in younger women, often during pregnancy,' the rapid tumor growth in women of childbearing age compared to juvenile and postmenopausal women and men 3 and spontaneous regression at menopause 21 have suggested the influence of sex steroid hormones in the growth of this tumor.

in mammary fibromatoses, however, these etiologic factors have not been observed. Although only a few cases have been reported after surgical breast implants22 and trauma,10 physical factors alone seem insufficient to initiate fibromatosis in the breast.10 In our series of 33 cases, only 2 patients described a physical or surgical trauma occurring 2 to 17 years prior to the development of a palpable breast lesion.

In our study, fibromatosis was more common in the childbearing age group than in the perimenopausal and postmenopausal groups; no association with menstrual status was noted in previously reported series. Two of our patients and 1 patient each described by Rosen et al,111 Gump et al, 17 and Wargotz et a113 were pregnant at the time of diagnosis. However, the coexistence of the 2 conditions has been described as coincidental.10

In fact, fibromatosis arising within the breast parenchyma appears to represent a separate entity from extramammary fibromatosis, although both lesions may display a similar morphology. Whereas abdominal and extra-abdominal fibromatoses arise from the muscular fascia or aponeurosis,' mammary fibromatoses appear to originate from fibroblasts and myofibroblasts within the breast parenchyma. The extramammary lesions display a higher propensity for local recurrence (57%23) compared to mammary fibromatoses (21%,17 23%, 13 and 27%10).

Fibromatosis in the breast also differs from fibromatosis arising in other parts of the body in its hormone receptor profile. Although 30% of reported extramammary fibromatoses tested for ER were positive, 3--6,24 and 51% of the lesions treated by antiestrogen agents regressed,24 none of our cases, regardless of patient age, demonstrated positivity for ER or PR.

Nine previously reported cases of mammary fibromatosis were analyzed for ER and PR either by immunohistochemistry9,11 or by enzyme immunoassay.11,10 With the exception of one case," the results were similar to ours, confirming the absence of ER and PR. The only case of mammary fibromatosis with significant cytosol assay positivity for ER and PR was reported in a 44-year-old woman.8 This tumor was described as "partially fixed to the chest wall." This case may well have arisen from chest wall musculoaponeurosis rather than from the mammary stroma.

Because of the consistent absence of immunoreactivity for ER and PR in mammary fibromatosis, a positive reaction for either receptor in a spindle cell neoplasm of the breast would help exclude fibromatosis from differential diagnostic consideration for practical purposes. A positive epithelial marker in such cases would support the diagnosis of metaplastic carcinoma 25 of epithelial origin, since myoepithelial cells or tumors are also generally negative for ER and PR.

It is somewhat surprising that lesions derived from muscle fascia and aponeuroses without any hormone receptivity may express ER and PR, while lesions originating from breast stroma, an organ known to be hormonally responsive with cyclic stromal changes during the menstrual cycle,26 do not demonstrate ER or PR expression. Positive immunoreactivity for PR has, however, been reported in some mammary stromal proliferations, such as pseudoangiomatous hyperplasia.27

Myofibroblastoma of the breast has been found to express AR .211 The negativity of AR in our cases argues against any influence of male sex steroid hormone in the proliferation of mammary stromal cells, although fibromatosis is also considered to be of myofibroblastic origin. For practical purposes, AR positivity in a well-delineated myofibroblastic proliferation of the breast would favor the diagnosis of myofibroblastoma over that of fibromatosis.

The expression of the cytoplasmic protein pS2 is induced by estrogen and has been found to be a marker of hormone responsiveness in ER-positive and -negative breast cancer. 12 Its constantly negative immunoreactivity in our 33 cases, as well as in 6 previously reported cases,9 indicates the absence of any functional ER in the cases of mammary fibromatosis evaluated to date.

These results suggest that unlike some cases of abdominal and extra-abdominal desmoid tumor, no benefit from antiestrogen therapies would be expected in mammary fibromatosis. One caveat to this would be that tamoxifen has been shown to induce synthesis of transforming growth factor P1 by ER-negative fibroblasts,29 which in turn could inhibit aberrant proliferative fibroblasts.-IO The effectiveness of tamoxifen on ER-negative fibromatoses might be explained through this mechanism .31, The hormonal milieu in young patients may indirectly facilitate or promote fibromatosis through influences exerted on presently unknown factors responsible for the initiation of the process.

References

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17. Gump FE, Sternschein MJ, Wolff M. Fibromatosis of the breast. Surg Gynecol Obstet. 1981;153:57-60.

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19. Margo G, Lanteri E, Micali G, Paravizzint G. Travali S, Lanzfame S. Myofibroblasts of palmar fibromatosis co-express transforming growth factor-alpha and epidermal growth factor receptor. I Pathol. 1997;181 :213-217.

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22. Jewett ST. Mead JH. Extra-abdominal desmoid arising from a capsule around a silicone breast implant. Plast Reconstr Surg. 1979;63:577-579.

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24. Serpell JW, Paddle-Ledinek JE, Johnson WR. Modification of growth of desmoid turnouts in tissue culture by anti -oestrogen ic substances: a preliminary report. Aust N Z I Surg. 1996;66:45 7-463.

25. Gobbi H, Simpson IF, Borowsky A, Jesen RA, Page DL. Fibromatosis as the major mesenchymal element in metaplastic breast tumors: risk of local recurrence. Mod Pathol. 1999; 12-2 ]A.

26. Longacre TA, Bartow SA. A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol. 1986;10:382-393.

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Mojgan Devouassoux-Shisheboran, MD; Maj David P Schammel, USAF, MC; Yan-Gao Man, MD, PhD; Fattaneh A. Tavassoli, MD

Accepted for publication July 21, 1999.

From the Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC.

The opinions and assertions expressed herein are the private views of the authors and are not to be construed as official or as representing the views of the Departments of the Air Force, Army, or Defense.

Reprints: Maj David P. Schammel, USAF, MC, Department of Gynecology and Breast Pathology, Armed Forces Institute of Pathology, 6825 16th St, Bldg 54, Washington, DC 20306-6000.

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