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Breast Myofibroblastoma
Introduction
Myofibroblastoma is a benign rare spindle-cell breast tumor, which is rare and reported to have a slight male predisposition.[1] It was first described in 1987, and since then, there have been various pathological, surgical, and radiographical publications in the literature. Given its rarity, myofibroblastoma poses a challenge to pathologists when differentiating between benign and malignant lesions on core biopsy, necessitating an excision.[2]
On palpation, myofibroblastoma appears as a solid, mobile mass. On histology, the lesion is well-circumscribed, consisting of randomly arranged fascicles of spindle-shaped cells missed together with adipocytes in an interrupted fashion within a collagenous and myxoid background. Ultrasonography and mammography imaging can be used for the diagnosis. The tumor can be confused with various lesions on imaging.
Myofibroblastoma is often confused with spindle cell lipoma, amongst other benign and malignant breast conditions. Its management involves surgical excision. Myofibroblastoma is not reported to have a malignant potential or recurrence risk.
Etiology
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Etiology
Myofibroblastoma of the breast is a rare benign spindle cell tumor first described in 1987 by Wargotz et al. after reviewing 16 cases, the first of which was noted in 1981.[3][4][5][6] Though this tumor has a male predisposition, it can also be seen in women.[7]
Myofibroblastoma of the breast presents most often between the ages of 40 and 87 years.[3] It is usually diagnosed in menopausal women and older males.[4] There is no evidence to indicate a relationship between myofibroblastoma and ethnicity, gender, medical comorbidities, medications, or hormonal supplements.[8]
Epidemiology
There is a lack of published data on the epidemiology of myofibroblastoma of the breast. Some published reports of myofibroblastoma diagnosis in patients with prior malignancies, including renal and prostate cancers.[9] In men, it has been reported to be associated with gynecomastia.[10]
Pathophysiology
Myofibroblastoma of the breast is a benign tumor of mesenchymal origin associated with the deletion of chromosome 13q14, similar to spindle cell lipoma and cellular angiofibroma.[11] To better elucidate the pathophysiology of myofibroblastoma, it is crucial to understand the molecular mechanisms controlling the growth and proliferation of myofibroblasts.
Myofibroblasts respond to tissue injury. The injured cells or cells with malignant potential produce cytokines, including transforming growth factor β1. This helps the fibroblasts to migrate into the injured tissue. This process is followed by the development of smooth muscle actin fibers, which eventually transform into myofibroblasts with contractility. The contraction in the injured tissue increases the speed of healing and repair.[12]
The size of myofibroblastomas usually ranges between 1 and 3 cm. However, larger masses measuring up to 13 cm have also been reported.[3][13]
Although extra-mammary location is uncommon, it can still occur mostly along the embryonic milk line, which extends from the axilla to the inguinal region.[14] Also, extra-mammary MFBs outside of this milk line have been reported.[15][16]
Histopathology
A myofibroblastoma is composed of oppositional spindle-shaped cells that are present in short traversing fascicles with a background of keloidal-like eosinophilic collagen bands. It is well-demarcated from normal breast parenchyma by a pseudo-capsule.[17]
The histological variants include epithelioid, deciduous, collagenous, fibrous, lipomatous, cellular, myxoid, or infiltrative types. Duct or lobule involvement is characteristically absent. Macroscopically, myofibroblastoma demonstrates a well-demarcated pale pink or tan round mass-like appearance.[3][18][19][20]
On immunohistochemistry, myofibroblastoma is positive for CD34, vimentin, CD10, CD99, estrogen receptors, progesterone receptors, BCL-2 protein, and variably positive for SMA, desmin, androgen receptors, and h-Caldesmon. It is negative for CD117 (C-kit), EMA, pan-cytokeratin, HMB-45, and S100. These results are aligned with the fibroblastic or myofibroblastic nature of the neoplastic cells.[3][11][21]
Immunohistochemically, myofibroblastoma is negative for nuclear staining of Rb in over 90% of the cases.[22] This is in contrast to solitary fibrous tumors, fibromatosis, and nodular fasciitis, which are intact for Rb staining.
When the diagnosis of myofibroblastoma is suspected with microscopic examination, an immunohistochemical investigation needs to be conducted with antibody panels to aid differentiation from other lesions.[3][4] Reported cases show a variant of mammary-type myofibroblastoma closely mimicking schwannoma.[23]
The importance lies in differentiating the myofibroblastoma from other benign or malignant soft tissue neoplasms of the breast. It is most often confused with spindle cell lipoma. These two benign entities are composed of spindle cells positive for CD34 staining on immunohistochemistry and are admixed with mature adipocytes. Both spindle cell lipoma and myofibroblastoma are associated with the loss of chromosome 13q14.[24]
However, one of the differentiating features between these two entities is the finding of a less prominent adipose tissue component in spindle cell lipoma. In myofibroblastoma, the stroma is very prominent and is also hyalinized. Additionally, spindle cell lipomas do not stain positive for desmin, whereas myofibroblastoma is always positive.[25]
History and Physical
Myofibroblastoma is a unilateral, solitary, painless, firm, and freely mobile mass on palpation that grows slowly for several months or years.[18] The diagnostic algorithm for myofibroblastoma typically includes a triple assessment approach consisting of clinical evaluation, appropriate imaging studies, and core needle biopsy.
Clinical evaluation should include detailed history taking, including assessment for cyclical pain, recent trauma, nipple or skin changes, or nipple discharge. Further emphasis must be laid on past medical and surgical history, previous cancers, family history of malignancies, social history, and medications.
It is always important to assess gynecologic and obstetric history in women, including age at menarche, menopause, and any prior oral contraceptive use or hormone replacement therapies. In men, it is important to assess the use of androgen deprivation therapies if treated for prostate cancer in the past.
Evaluation
Imaging
The appearance of myofibroblastoma on imaging is non-specific.[7] Most cases of breast myofibroblastoma were diagnosed either on mammograms in the female patients or chest CT of the male patients.[26] On mammography, it appears as a round or oval, well-circumscribed dense mass with rare coarse calcifications.[17][27][9]
Gynecomastia is an inconsistent finding.[26] In men, the benign appearance of myofibroblastoma needs to be contrasted with the appearance of breast cancer, which parallels that of breast cancer in women.[28] On ultrasonography, it presents as a homogeneous hypoechoic well-circumscribed solid mass that resembles fibroadenoma.[7]
However, some show a mass with a variable oval or irregular configuration and heterogeneous echo pattern, with more distal acoustic attenuation due to the incorporation of fat tissue and other types of tissue in the tumor. Applying the doppler modality may demonstrate peripheral hypervascularization of the tumor.[8][26][8]
Although not often done, MRI findings of myofibroblastoma show a homogeneously contrast-enhanced, circumscribed mass with internal septations and hyperintense signal in T2-weighted images with diffusion restriction surrounded by a hypointense capsule and plateau kinetics.[29][30]
Furthermore, some studies identified that the apparent diffusion coefficient (ADC) could be a useful MRI finding in distinguishing myofibroblastoma from other malignant lesions. Since low values of ADC are detected in malignant lesions, higher ADC values are likely representative of myofibroblastoma.[31]
Tissue Diagnosis
Fine-needle aspiration or an ultrasound-guided core needle biopsy may be performed for diagnosis. However, due to a lack of cellularity, fine needle aspiration shows non-specific whorls of spindle cells with benign ovoid nuclei or non-diagnostic results.[32][30] Most cases of breast MFBs have been diagnosed with the tissue specimen retrieved by core-needle biopsy.[26]
Treatment / Management
Myofibroblastoma can be treated with local excision mainly for symptomatic relief.[3][4][18] Since this is a benign lesion, surgery need not be compulsory. However, since all the previously reported cases underwent surgical excision, the long-term stability and implications of an unresected myofibroblastoma are not clearly understood.(B3)
Surgical excision is considered curative and local recurrence is not a recognized feature of myofibroblastoma. However, patients should be followed-up for a minimum of 24 months. There are no reports in the literature regarding the malignant transformation of these lesions.
Differential Diagnosis
Leiomyoma: Histologically, cells are arranged in intersecting fascicles with abundant eosinophilic cytoplasm and sparse intervening stroma. Immunohistochemistry is positive for h-Caldesmon, SMA, MSA, estrogen, and progesterone receptors, while CD34 is negative. The molecular analysis demonstrates HMGA2-RAD51B t(12;14) and FH mutation.
Solitary fibrous tumor: Morphologically uniform spindle to oval cells are seen around prominent staghorn vessels. There is perivascular hyalinization, and stroma can be variably fibrous. The lipomatous variant contains mature adipose tissue.[33][34][35] Immunohistochemistry is positive for CD34, STAT6, focal EMA, SMA, nuclear Rb, and negative for desmin. Molecular abnormality includes NAB2-STAT6 fusion.[36]
Spindle cell lipoma: Morphology demonstrates a mixture of mature adipose tissue, bland spindle cells, thin 'rope-like' collagen, and stromal mast cells. Myxoid stroma is not uncommon. 'Fat-poor' cases are also present. Immunohistochemistry demonstrates positive staining for CD34, while staining is negative for SMA, desmin, and Nuclear Rb.[19][37]
Fibromatosis: Microscopically noted to have an abundant collagenous matrix and is reportedly highly infiltrative. It is associated with familial adenomatous polyposis (FAP). Immunohistochemically, stains are positive for nuclear beta-catenin, Nuclear Rb, and stains are negative for hormonal receptors and CD34. It is associated with APC or CTNNB1 mutations.[38][39][40][41]
Pseudoangiomatous stromal hyperplasia (PASH): This is a common spindle cell lesion in premenopausal women or patients on hormone replacement therapy. Histologically PASH shows slit-like clefts resembling vascular spaces and is less cellular than myofibroblastoma. It is less likely to form a mass than myofibroblastoma and demonstrates entrapping ducts and lobules. Stains positive for desmin, SMA, vimentin, estrogen receptos, progesterone receptos, and nuclear Rb.[42][43][44][45]
Nodular fasciitis: It is associated with prior history of breast injury. Microscopy findings are notable for bland fibroblastic/myofibroblastic cells with variable cellularity in a tissue culture pattern. There is a myxoid stroma with extravasated red blood cells, stromal lymphocytes, and giant cells. Immunohistochemistry is negative for CD34 and positive for SMA, focal desmin, and nuclear Rb. Molecular analysis is positive for USP6 rearrangement, and MYH9 is the most common fusion partner.[46][47]
Metaplastic spindle cell carcinoma: On histology, epithelial components or epithelioid cells can be present, associated with high nuclear grade, and frequent mitosis in high-grade cases. This tumor is infiltrative and encases normal breast ducts, commonly with stromal lymphocytes. Immunohistochemistry is positive for cytokeratins, p63, and negative for estrogen receptors, progesterone receptors, and desmin. Genetic alterations involving PTEN, TP53, and EGFR have been reported.[48]
Invasive lobular carcinoma: This is notable for single files of low-grade dyscohesive cells, cytoplasmic vacuoles with absent spindle cells, and infiltrative borders. Atypical lobular hyperplasia and lobular carcinoma in situ can be present. Cells are positive for estrogen receptors, progesterone receptors, E-cadherin, cytokeratins, and GCDFP-15. Mutations are reported in CDH1.[49]
Other differential diagnoses include:
- Benign fibrous histiocytoma
- Hamartoma
- Fibroadenoma
- Low-grade sarcoma
- Lymphoma
- Malignant fibrous histiocytoma
- Phyllodes tumor
- Low-grade myofibroblastic sarcoma
- Angiomyolipoma
Radiation Oncology
Given the benign nature of this tumor, there is no indication for adjuvant radiation therapy after surgical resection of myofibroblastoma. There have been no reports of recurrence after surgical resection.
Medical Oncology
Given no evidence of local or distant recurrence or metastases with myofibroblastomas, there is no indication or role for adjuvant systemic therapies.
Prognosis
The prognosis for myofibroblastoma is excellent after surgical excision. Local recurrence or malignant transformation is not a recognized feature of myofibroblastoma.[3][4][18]
Complications
No long-term complications were identified in the literature, except those associated and expected from the type of surgical intervention, either breast-conserving surgery or mastectomy.
Deterrence and Patient Education
- Refer the patient to a breast specialist (breast radiologist and breast surgeon) to confirm the diagnosis and discuss treatment options if needed.
- A triple assessment of any breast mass, with clinical evaluation, imaging, and core needle biopsy for an accurate diagnosis is required.
Enhancing Healthcare Team Outcomes
Myofibroblastoma is a relatively newer diagnosis. There is a lack of information regarding the epidemiology of this entity. Myofibroblastoma is managed by an interprofessional team consisting of an internist/general practitioner, breast radiologist, anatomic pathologist, and breast surgeon. Nursing staff help to round out the interprofessional team, assisting at all phases of diagnosis and treatment.
Given that myofibroblastomas are benign lesions with no risk of local recurrence or transformation to malignant potential, surgical excision is curative but not compulsory.
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