32. Fibroadenoma of the Breast.pdf

FIBROADENOMA OF THE BREAST. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1061-1063. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pa...

FIBROADENOMA OF THE BREAST. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1061-1063. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pages 655-656. CASE PRESENTATION: EDWINA PARKER. A 34-year-old woman presented for assessment of a palpable right breast lump. She detected the breast lump six weeks previously during routine self-examination and did not complain of any pain, nipple discharge, or skin changes. She had no personal or family history of breast cancer and had never used the oral contraceptives or hormone replacement therapy. On physical examination, a non-tender, freely mobile 2 cm solid mass, firm in consistency, was noted in the upper outer quadrant of the right breast with no adherence to the skin or fixity to the posterior wall. Ultrasound examination showed a hypoechoic mass compared to the breast parenchyma, with a homogenous echotexture. Mammography showed a 2-cm diameter oval mass with equal density and circumscribed margin. Axillary lymph nodes were not palpable. Left breast examination was normal. The patient opted for surgical excision of the lesion. Gross examination of the surgically excised specimen revealed a well-circumscribed firm nodule measuring 1.9 × 2.0 cm (0.74 x 0,78 inches). The cut surface was firm and tan-gray in color, with a whorled appearance. Microscopically the tumor had a benign epithelial component with elongated, branching ducts and a fibroblastic stroma proliferating around ducts. Pathological diagnosis was fibroadenoma of the breast. INTRODUCTION. There are two types of stroma in the breast: intralobular stroma and interlobular stroma. Each one gives rise to distinct types of neoplasms. 1. Neoplasms arising from intralobular stroma. Intralobular stroma is a specialized stroma, which may elaborate growth factors for epithelial cells, resulting in the proliferation of the non-neoplastic epithelial component of these tumors. The breast specific biphasic tumors arise from intralobular stroma. Biphasic tumors of the breast are composed of various combinations of proliferating epithelial and stromal elements. There are two major types of biphasic tumors: fibroadenoma and phyllodes tumor. 2. Neoplasms arising from interlobular stroma. Interlobular stroma is the source of the same types of tumors found in connective tissue in other sites of the body. FIBROADENOMA. 1. Definition. Fibroadenoma of the breast is a common, benign tumor composed of both epithelial and stromal components. Proliferation of stromal cells is commonly considered the primary event, followed by secondary proliferation of epithelial cells. 1 2. Epidemiology. Fibroadenoma occurs in a wide age range from adolescent females to octogenarians. This tumor is most common in women in their 20s and 30s. After the age of 30 years, the risk decreases and drops sharply at the time of menopause. It is estimated that 10% of women in the United States have breast fibroadenomas. Fibroadenomas are more frequent among African American women. 3. Pathogenesis. (A) Estrogen dependency. Patients with fibroadenoma have higher than normal levels of plasma estradiol. An estrogen dependency has been suggested for the growth of fibroadenomas. In addition, tamoxifen treatment significantly reduces the proliferation activity in the stroma of fibroadenomas. (B) Polyclonality. Analyses of the cellular components of fibroadenomas by means of polymerase chain reaction have demonstrated that both the stromal and the epithelial cells are polyclonal, supporting the theory that fibroadenomas are hyperplastic lesions associated with aberration of the normal maturation of the breast, rather than true neoplasms. (C) MED12 gene mutations. The pathogenesis of fibroadenomas overall remains poorly understood. Very recently, mutations of the MED12 gene have been identified fibroadenomas. They have been found in up to 65% of cases. These mutations involve only the stromal component of the tumor. MED12 gene is mapped to chromosome Xq13.1.8. It encodes for a protein called mediator complex subunit 12, which is involved in transcriptional regulation of the RNA polymerase II complex. MED12 gene mutations also occur in another highly frequent tumor, uterine leiomyomas. In both these benign stromal tumors, they apparently act as driver mutations. The identification of stromal MED12 mutations is indicative of monoclonality and supports the classification of at least some fibroadenomas as neoplastic rather than hyperplastic lesions. 4. Clinical presentation. Fibroadenomas generally present as a solitary neoplasm, but in 15% of cases fibroadenomas are multiple, in one or both breasts. Presenting as a painless small nodule, fibroadenomas grow slowly up to 2-3 cm, after which further growth is arrested in most cases. Sometimes these tumors assume massive proportions. Fibroadenomas larger than 5 cm (about 4% of the total) are commonly defined as being giant fibroadenoma. • Fibroadenomas may involute in postmenopausal women, and coarse calcifications may develop. • Conversely, fibroadenomas may grow rapidly during pregnancy, during hormone replacement therapy, or during immunosuppression. • On clinical examination, fibroadenomas are oval, freely mobile, rubbery masses. Their size varies from smaller than 1 cm in diameter to as large as 15 cm in diameter in the giant forms. In young women, the tumors are usually palpable. In older women, the tumors typically appear as a mass on mammograms and may be palpable or nonpalpable. 5. Pathology. (A) Gross appearance. Grossly, fibroadenomas presents as a spherical nodule sharply demarcated, that bulges above the surrounding tissue. The tumor is often encapsulated, has firm consistency, and is grayish white in color. The cut section shows a whorled-like pattern. (B) Microscopic appearance. There is combined proliferation of mesenchymal and epithelial elements. The stromal component is made up of loose connective tissue and resembles intralobular stroma. The fibroblast is the predominant proliferating stromal cell. The epithelial component arises from the terminal duct lobular unit. Depending on the proportion and the relationship between these two components, there are two main histological features: intracanalicular and pericanalicular. Often, both types are found in the same tumor. Intracanalicular fibroadenoma is characterized by predominant stromal proliferation which compresses the ducts, which are irregular, reduced to slits. In pericanalicular fibroadenoma, stroma proliferates around the ductal spaces, so that they remain round or oval, on cross section. The tubules and glands in a fibroadenoma are lined by cuboidal or low columnar epithelium with uniform nuclei and no atypia, surrounded by a myoepithelial layer. The basement membrane is intact. 2 7. Risk of subsequent breast cancer. Fibroadenoma is a marker for increased risk of breast cancer. Studies have demonstrated a 1.3 to 2.1 increased risk of breast cancer in women with fibroadenomas compared with the general population. • There are two types of fibroadenomas: simple and complex. • Simple fibroadenomas are benign fibroepithelial neoplasms. • A “complex fibroadenoma” is a subtype of fibroadenoma that harbors one of the following four pathologic features: sclerosing adenosis, papillary apocrine hyperplasia, cystic change, or epithelial calcification. These four features are basically those of benign fibrocystic change, which is also exceedingly common in the breast. The size of the lesion does not determine if it is or is not complex. • Simple fibroadenomas are not correlated with an increased risk of breast cancer. • A complex fibroadenoma is associated with a modest, 1.3 to 2.1 increased risk of breast cancer compared with the general population. However, the changes of complex fibroadenoma are also associated with a higher likelihood of finding other lesions in the surrounding breast tissue (e.g., atypical hyperplasia), and these may be the true drivers of the increased risk. • Malignant transformations in the epithelial components of fibroadenomas are generally considered very rare. The incidence of a carcinoma in situ or invasive breast carcinoma evolving within a fibroadenoma was reported to be 0.002% to 0.0125%. 8. Imaging studies. On mammograms, a fibroadenoma appears as a smooth-margined oval or round mass. On ultrasound they appear solid, well-circumscribed and hypoechoic. 3 9. Natural history. It is believed that most fibroadenomas grow over a 12-month period to gain a size of 2 to 3 cm, after which they remain unchanged for several years. After this period, regression, or complete resolution of the fibroadenomas is noted in 50% of all cases. The mechanisms offered to explain the regression of fibroadenomas are infarction, calcification, and hyalinization. 10. Fibroadenoma in male breast. Fibroadenomas are very uncommon in the male breast. Presenting clinical features are enlarged breast with painful nodule. These lesions are usually diagnosed clinically as gynecomastia. The mechanism of fibroadenoma is believed to be hormonal imbalance, some due to medication use. 11. Principles of treatment. In many cases, fibroadenomas require no treatment. However, some women choose surgical removal for their peace of mind. PHYLLODES TUMOR. 1. Definition. Phyllodes tumor is an uncommon biphasic tumor composed of benign epithelial elements and a cellular spindle-cell stroma. Phyllodes tumor, like fibroadenoma, arises from intralobular stroma. 2. Epidemiology. Phylodes tumors are rarer than fibroadenomas, accounting for 2.5% of all fibroepithelial tumors of the breast. Phyllodes tumors account for less than 0.5% of all breast malignancies. Although they can occur at any age, the median age at presentation is 42-45 years, 10 to 20 years later than the peak age for fibroadenomas. 3. Clinical presentation. The majority of phyllodes tumors are detected as palpable masses, or as an abnormal mammographic finding. 4. Pathology. (A) Gross findings. Grossly, the phyllodes tumors are round to oval, well-circumscribed multinodular masses with a grayish white appearance; it is often received as a shelled-out specimen. (B) Microscopic findings. Microscopically, phyllodes tumors display a characteristic leaf-like architecture. They feature elongated cleft-like spaces that contain papillary projections of epithelial-lined stroma with varying degrees of hyperplasia and atypia. There is a wide spectrum of microscopic appearances that ranges from resembling a benign fibroadenoma to a high-grade sarcoma. Phyllodes tumors are classified as benign, borderline, or malignant. BENIGN PHYLLODES TUMOR. Benign phyllodes tumors are characterized by increased stromal cellularity (compared to fibroadenoma) with mild to moderate cellular atypia, circumscribed tumor margins and low mitotic rate. Borderline tumors have a greater degree of stromal cellularity and atypia, a moderately high mitotic rate, and microscopic infiltrative borders. MALIGNANT PHYLLODES TUMOR. Malignant phyllodes tumors are characterized by marked stromal cellularity and atypia, infiltrative margins, and high mitotic rate. They may be difficult to distinguish from other soft-tissue sarcomas and may have foci of mesenchymal differentiation. 4 5. Molecular genetics. Somatic mutations of the MED12 (Mediator complex subunit 12) gene have been identified in about 70% of phyllodes tumors. The mutational spectrum is similar to that of fibroadenomas, supporting an underlying commonality in pathogenesis. 6. Imaging studies. The typical appearance of a phyllodes tumor on mammography is a large, rounded, well-circumscribed mass with smooth margins, resembling a fibroadenoma. On ultrasound, phyllodes tumors are lobulated with smooth margins, and hypoechoic. 7. Behavior. Phyllodes tumors are capable of a diverse range of biologic behavior. About 70% of these tumors are benign; they behave similarly to benign fibroadenomas. They recur locally following excision without wide margins in 15% of cases. At the other end of the spectrum are malignant phyllodes tumors (5%), which undergo mainly hematogenous spread, the proportion of patients with lymph node metastases being <1%. Phyllodes tumor metastases transform histologically into sarcomatous lesions that lack an epithelial component. 8. Principles of treatment. Phyllodes tumors must be excised with wide margins or by mastectomy to avoid local recurrences. Axillary lymph node dissection is not indicated. Adjuvant radiotherapy decreases local recurrences after breast conserving surgery. NEOPLASMS ARISING FROM INTERLOBULAR STROMA. Tumors that arise from the interlobular stroma of the breast are composed of stromal cells without an accompanying epithelial component. 1. Pseudoangiomatous stromal hyperplasia. (A) Definition. Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of interlobular fibroblasts and myofibroblasts. (B) Clinical presentation. PASH occurs in pre-menopausal women. Age ranges from 12 to 65 years. Most commonly PASH occurs as an incidental finding adjacent to other benign or malignant breast lesions but can present as a discrete, painless, mobile mass, clinically indistinguishable from a fibroadenoma. (C) Pathology. The lesion ranges in size and has well-demarcated borders. It is firm and rubbery with a smooth external surface. The cut surface consists of homogeneous, fibrous, tan tissue. Microscopically, PASH consists of interanastamosing angulated and slit-like spaces lined by slender spindle cells and surrounded by dense collagenous stroma. The spindle cells lack atypia, show no mitotic activity and the slit spaces are empty. The slits are probably a fixation artifact induced by the retraction of the collagenous stroma. The spindle cells have the ultrastructural characteristic of myofibroblasts. They express CD34, vimentin, smooth muscle actin, and desmin. (D) Imaging studies. Radiologically, PASH appears as a well-circumscribed mass, not associated with calcification. Ultrasound examination reveals a well-defined hypoechoic lesion. (E) Principles of treatment. Wide local excision is the treatment of choice. 2. Fibromatosis. (A) Definition. Fibromatosis is an infiltrating spindle cell proliferation composed of fibroblastic and myofibroblastic cells. 5 (B) Clinical presentation. Fibromatosis presents predominantly as a painless, palpable, firm or hard mass, which may be accompanied by skin dimpling and nipple retraction. Fibromatosis can occur at any age, most commonly in the forties. (C) Pathology. Grossly, fibromatosis is an irregular area of white/tan fibrous tissue. The lesion margins are infiltrative and difficult to discern on gross examination. The cut surface reveals a firm tumor that is gray yellow to gray white in color. The lesion may range in size from less 1 -10 cm. Microscopically, fibromatosis is characterized by bland spindle-shaped or oval cells arranged in broad sheets or fascicles and interlacing bundles, producing a storiform or herringbone pattern. The lesion irregularly infiltrates the adjacent breast parenchyma. Cellular atypia is absent and mitoses are uncommon. (D) Imaging studies. Mammography may not reveal any abnormality, although a stellate lesion that mimics carcinoma may be identified. Rarely the lesion presents with dense mammographic calcifications. 3. Myofibroblastoma. (A) Definition. Myofibroblastoma (MFB) of the breast is a benign tumor that is thought to arise from cells of the mammary stroma with myofibroblastic and myoid differentiation. (B) Clinical presentation. The MFB is encountered mainly in older men and postmenopausal women aged between 40 and 87 years. It presents as a solitary, slowly growing painless mass. (C) Pathology. MFB is a well-circumscribed tumor ranging in size from 1 cm to 10 cm. The mass is firm and rubbery with a bulging gray to white, whorled cut surface. Microscopically, the tumor is composed of an admixture of oval to spindle-shaped cells arranged in fascicles and numerous interspersed thick bands of eosinophilic collagen. The tumor has pushing borders. Mitoses are rare. Electron microscopy studies have shown a variable admixture of undifferentiated mesenchymal cells, fibroblasts, myofibroblasts, and smooth muscle cells. (D) Imaging studies. Ultrasonography shows a well-circumscribed, homogeneous, slightly hypoechoic mass. Mammography reveals a well-circumscribed, round to oval mass devoid of calcifications NON-EPITHELIAL BREAST MALIGNANCIES. Non-epithelial primary breast malignancies account for <5% of breast neoplasms and between 0.5% and 2% are metastases to the breast. • The most common non-epithelial primary breast malignancies are lymphomas, followed by sarcomas and malignant melanoma. Most primary breast lymphomas are either diffuse large B-cell non-Hodgkin lymphoma or primary MALT-type lymphoma. Rare T-cell lymphomas may arise in association with breast implants, possibly due to chronic inflammation, which is known to stimulate lymphoma development in other contexts. • The most common sarcoma of the breast is angiosarcoma. Angiosarcoma presents as a primary tumor of the breast or as secondary lesions that are most commonly associated with previous radiotherapy. Primary angiosarcoma has been observed in women aged 30-50 years and develops without a known 6 precursor. In contrast, secondary angiosarcoma presents in older women (median age 67-71 years) following a median of 10.5 years after radiotherapy for breast cancer. • Lymphangiosarcoma of the upper limb is a rare malignant tumor that develops in post-mastectomy patients with long-standing lymphedema (Stewart Treves syndrome). • Malignant tumors may arise from the skin and dermis of the breast. Examples include dermatofibrosarcoma protuberans and malignant melanoma. These tumors are identical to their counterparts found in skin elsewhere. • Metastases to the breast are rare and most commonly arise from multiple myelomas and ovarian cancers. 7