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Unusual Tumors of the Breast

umor Growth Characteristicshe days of routine radical, or even modified radical mastectomy, haveeen replaced in large part by the less morbid lumpectomy and recon-truction. It has been said that routine radiation only benefits 30% ofatients, with 60% who would do well without it and 10% who wouldecur regardless of radiation therapy. Thus, recent trials have focused onetermining what patients would be suited for surgical extirpation alone.n that regard, surgical pathology becomes extremely important and evenor carcinomas of the usual type we catalog in extreme detail size, grade,uclear grade, lymphovascular invasion, size, and grade of any in situomponent, multifocality versus multicentricity, hormone receptors, Her--neu amplification, width of the margin, and nodal status. Probably 95%f breast tumors can be easily cataloged in this way. Five percent fall intoategories that we do not often encounter and thus our intent is to discussheir unique clinical presentations, pathology, and treatment. We havelassified the tumors into unusual carcinomas that represent differentia-ion from mammary carcinomas, malignant mesenchymal or pure stromalumors, metastatic carcinomas, tumors of lymphoid or hematopoieticrigin, myoepithelial tumors, phylloides tumors that contain both epithe-ial and stromal elements, and benign stromal tumors of the breast. Finallye will discuss some unusual presentations of breast cancer.

nusual Carcinomas

etaplastic Breast CarcinomaClinical Presentation. Metaplastic breast carcinoma first described in881 is a rare type of invasive ductal carcinoma (IDC) representing lesshan 5% of breast cancers.1-3 The range of age at the time of diagnosis isimilar to that of the usual type of IDC, with two thirds of patients beingostmenopausal. Most of these tumors manifest as small palpable massesnd are well-demarcated hypoechoic lesions on imaging (Fig 1), typical
f IDC, and have been reported to be as large as 21 cm.4,5
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In the largest series to date from the National Cancer Data Base (NCDB)hese lesions are less likely to metastasize to lymph nodes even though theyre thought to be more aggressive than the average IDC.6

Pathology. Metaplastic breast carcinoma is usually poorly differentiatedut demonstrates both epithelial and mesenchymal components.7 Most ofhese tumors show small foci of squamous metaplasia. Some cases canemonstrate sarcomatous differentiation as well and can be confused witharcomas. Extensive sampling will identify foci of epithelial differentiation inetaplastic carcinoma. Spindle cell carcinoma should be considered aonophasic variant of this tumor. The spindle cells may vary from aarkedly pleomorphic cell population to bland fibroblastic appearance

esembling fibromatosis (Fig 2). To establish the diagnosis a battery ofmmunostains may be necessary. The spindle cell component usually shows

range of positivity with various cytokeratin stains including 34�E12,AM5.2, MNF116, CK7, CK19, and CK20.7,8 These tumors do not have

eceptors for estrogen or progesterone and do not demonstrate Her-2-neumplification.Treatment. Patients are usually treated with resection, lumpectomy, and

adiation or mastectomy based on the size of tumor, with sentinel lymph

IG 1. (A) The arrow indicates a fairly well demarcated lesion on mammography. (B) The angularargins of the cancer with hypoechoic shadowing on ultrasound.

ode biopsy, followed by chemotherapy.6,9-12

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ow Grade Adenosquamous CarcinomaClinical Presentation. Low grade adenosquamous carcinoma might beetter classified as a low grade variant of metaplastic carcinoma first

IG 2. Metaplastic breast carcinoma showing moderately cellular, mitotic active stroma with malignantpithelial nests showing squamous differentiation. Original magnification, 40�. (Color version of figure isvailable online.)

IG 3. Prominent squamous differentiation is noted in a background of slightly hypercellular stroma containingnfiltrating glandular elements. Original magnification, 40�. (Color version of figure is available online.)

escribed by Rosen and Ernsberger in 1987.13-15 Patients usually mani-


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est clinically with either an abnormal mammogram or a clinicallyalpable mass. Tumor size has been reported from 1.5 to 8 cm.15

Pathology. These tumors can originate from an intraductal papilloma, aocus of sclerosing adenosis, or a radial scar. Pia-Foschini and colleaguesescribed the tumor as having an inner layer of epithelial cells and anuter layer of myoepithelial cells within a layer of stroma.7,14-16 Theseumors are also biphasic and show both epithelial and mesenchymalomponents. The mesenchymal component of this tumor shows rareitotic figures and contains foci of prominent squamous differentiation

Fig 3). Foci of glandular differentiation are also present. Myoepithelialifferentiation is preserved in these foci. These tumors do not usuallyxpress estrogen or progesterone. Drudis and colleagues reported that theumor stains for p53, Her-2-neu, and cathepsin D.17 The squamousomponent of the tumor shows prominent positivity with CK5/6. Theyoepithelial component may show positivity for actin. The preservedyoepithelial layer shows reactivity with calponin and S-100.Prognosis. These tumors can recur locally, but they do not metastasize

o the lymph nodes. The treatment of choice is wide local resectionollowed by radiation therapy. Local recurrence would necessitate aastectomy.14,18

nvasive Micropapillary CarcinomaClinical Presentation. Invasive micropapillary carcinoma is an un-sually aggressive form of breast cancer. This cancer was once termedpseudopapillary serous-like breast carcinoma” due to its resemblanceo a variant of ovarian cancer (see Fig 30). Clinically, patients presentn the 25- to 80-year-old range. They more likely than not present with

palpable mass accompanied by the mammographic appearance of aypical IDC. Luna-More and colleagues19 reviewed 986 breast cancerases and reported that micropapillary carcinoma was present in 2.7%f the cases. Tumor sizes vary from 0.3 to 10 cm,20,21 with largeresions having greater than 50% micropapillary growth within theumor.20 Patients with this tumor are more likely to have metastaticisease to the axilla. According to some studies they also have a higherropensity for recurrence, reported as high as 90% in a 24-monthollow-up period.22

Pathology. Thor and colleagues23 showed genetic loss of the shortrm of chromosome 8 in 16 cases of invasive micropapillary carci-oma. The cells of this tumor are arranged in tight clusters and areurrounded by clear spaces (Fig 4). Nassar22 described these spaces as
esembling small dilated lymphatic channels. This may be the reason

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or the high lymphovascular invasion (15% to 80%) seen with thisype of tumor.22 In fact, lymphovascular invasion may predict metas-ases to the lymph nodes suggested in 1 study as frequently as 80% to0% of the cases.24 The micropapillary feature is present in variousuantities ranging from a rare pure form to a more mixed tumor.20,22,24,25

ettinato and colleagues21 described the morphologic features of 62 cases ofnvasive micropapillary carcinoma. Eighty-seven percent were staged atrade 3, 47% had psammoma bodies, 63% showed focal to massiveymphovascular permeation, 32% were ER�, 20% PR�, 95% Her-2-neuverexpression, 70% expressed p53, and 90% had nodal metastases.eventy-one percent of patients had local recurrence within 60 months and9% died of disease within 10 years.Treatment. Treatment for this aggressive tumor is currently mastectomyith sentinel lymph node biopsy and modified radical mastectomy as

ndicated, followed by chemotherapy. Liberal use of chest wall radiations recommended due to the high recurrence rate, particularly if the tumors larger than 5 cm or has more than 4 positive lymph nodes.

pocrine Breast CarcinomaClinical Presentation. The incidence of apocrine carcinoma of the breast

anges from 0.3% to 4% of IDC.26,27 The age of presentation ranges from 19o 86 years and the clinical presentation of apocrine carcinoma as a mass oralcifications is very similar to that of invasive breast cancer.28

Pathology. The term apocrine change in the breast is usually used to

IG 4. Representative micrographs of a pure micropapillary carcinoma of the breast composed oficropapillary small cell clusters surrounded by empty spaces (A) and displaying the typical inside-outrowth pattern as highlighted by EMA staining (B). (Reprinted with permission from Marchiò et al.273)Color version of figure is available online.)

escribe metaplastic changes that may involve ductal or lobular units.


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hese changes can be seen involving benign cysts, tubular adenoma, focif sclerosing adenosis, radial scars, fibroadenomas, hamartomas, andapillomas. The diagnosis of apocrine carcinoma should be used onlyhen apocrine features involve most or all of the mammary carci-oma28 (Fig 5). Apocrine ductal carcinoma in situ (DCIS) is perhapsne of the most underrecognized changes in breast pathology.29,30

oth low grade and high grade DCIS with apocrine type cells can beeen. The great majority of these lesions are grade 3 and show markeduclear pleomorphism. They may also show prominent nucleoli. Somef the cases show comedo-type necrosis. Moinfar and colleagueseported a series of 12 cases of mammary carcinoma with apocrineifferentiation in which 58% were ER negative and PR negative andndrogen receptor positive.31 Matsuo and colleagues found thatlthough p53 and Her-2 amplification was similar to that in IDC, Bcl-2nd MIB-1 were lower when compared with IDC.27

Treatment and Prognosis. Treatment for apocrine breast carcinomaepends on stage and patient preference and is the same as for IDC anday include conservative breast surgery or mastectomy.30 Prognosis is

ased on grade and stage at presentation with these lesions tending toe more aggressive.

quamous Cell Carcinoma of the BreastClinical Presentation. Pure squamous cell carcinoma of the breast

SCC) is an exceedingly rare tumor first described by Troell in

IG 5. Invasive apocrine carcinoma. (A) Low power magnification demonstrating invasive aprocrinearcinoma with a small focus of intraductal apocrine carcinoma showing micropapillary fronds.riginal magnification, 40�. (B) Cells with abundant eosinophilic granular cytoplasm. Originalagnification, 200�. (Color version of figure is available online.)

908.32,33 These tumors should be distinguished from ductal carcino-


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as with foci of squamous metaplasia and metaplastic carcinomas.he incidence may be as low as 0.04% to 0.075% with only 100 cases

eported in the literature.34,35 The mean age of patients at presentations slightly younger than that of IDC of the usual type at 54 years.35

ssentially all patients present with large (average 5 cm) palpableasses.35 Up to two thirds of these lesions have been found to be

ystic on presentation.35 Nair and colleagues recently reported 6 casesf this tumor presenting as an abscess.36 Mammography will show anrregular mass but ultrasound demonstrates the cystic nature of thisumor33 (Fig 6).Metastases to the axilla are less common than with IDC with one review

eporting axillary metastases in 22% of patients.33,34,37

Pathology. It is theorized that primary squamous cell carcinoma of thereast derives from squamous metaplasia of the ductal epithelium,erhaps induced by excess cyclic adenine nucleotide and prostaglan-in38,39 (Fig 7). Weigel and colleagues listed 3 requirements for aiagnosis of squamous cell carcinoma of the breast: 1) other forms ofreast cancer must be ruled out, 2) SCC cannot be found at another siten the body as a suspicious source of metastases (common sources of

etastases include lung, esophagus, head and neck, cervix, and bladder),

IG 6. Squamous cell carcinoma. (A) An irregular mass on mammogram. (B) Concordant irregularass on ultrasound with irregular shadowing. A cystic component was not found in thisatient.

nd 3) the skin cannot be involved.35 The presence of associated DCIS at


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he site confirms breast origin. Squamous metaplasia and metaplasticarcinoma must also be ruled out. Extensive sampling of the excisedesion is necessary to determine if the tumor is a metaplastic carcinomaith squamous differentiation or a pure squamous carcinoma.34,40 Estro-en and progesterone receptors for squamous cell carcinoma of the breastre predominantly negative.33,41

Treatment and Prognosis. The fact that these tumors can manifest asbscesses dictates that all abscess cavities be routinely biopsied. Becausehese tumors are usually large at presentation, primary systemic chemo-herapy is often recommended to downstage the tumor. Cysplatin and-FU are effective in both SCC and adenocarcinomas of the breast.33,34,42

lthough SCC is a radiosensitive tumor, the effectiveness of radiationherapy in this setting has been questioned.40

euroendocrine CarcinomaClinical Presentation. The tumors usually manifest as painless palpableasses that are firm and mobile.43 Patients range in age from 28 to 79

ears. Zekioglu and colleagues reported 12 patients with a range in tumorize from 0.8 to 7.0 cm with a median of 2.35 cm. These tumors are oftenssociated with a bloody nipple discharge.43,44 (Fig 8) According toosen, the diagnosis of small cell variant of neuroendocrine carcinoma of

he breast is valid only when nonmammary sites have been excluded or ann situ component is seen on histological examination.45,46

Pathology. Sapino and colleagues described 5 categories of morpho-ogic and immunophenotypic characteristics of neuroendocrine breastarcinoma including solid cohesive, alveolar, small cell, solid papillary,

IG 7. Squamous cell carcinoma. (A) Low magnification of a cystic space lined by a well-differentiatedquamous epithelium. Original magnification, 40�. (B and C) Higher magnification nuclearrowding; frequent mitotic figures are also present. B also shows broad-based infiltrate to theurrounding tissue. (B) Original magnification, 200�. (C) Original magnification, 400�. (Colorersion of figure is available online.)

nd cellular mucinous.47 Production of mucin has been shown to correlate


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ith a better prognosis.48,49 The solid cohesive pattern is composed ofarge clear cells with plasmacytoid features that show an infiltrativerowth pattern. Alveolar shows large clear cells with infiltrative pattern.he solid papillary is composed of plasmacytoid or spindled cells thathow expansile growth pattern. In the category of cellular mucinousarcinoma, the neoplastic cells form cribriform or solid islands within theucous lakes. These cells also show intracytoplasmic mucin. The last

ategory of neuroendocrine carcinomas resembles oat cell undifferenti-ted carcinoma of the lung. This latter category shows unusually highumbers of mitotic figures and frequent apoptosis (Fig 9). Neuroendo-rine carcinomas are the result of differentiation of IDC rather thanrising from preexisting neuroendocrine cells. Small cell neuroendocrinearcinoma is notorious for inconsistency in expression of neuroendocrinearkers; that is why the morphologic presentation is so important.50

euroendocrine markers such as immunoreactivity with S-100, chromo-ranin and synoptophysin should be detected in more than 50% of tumor

IG 8. Neuroendocrine carcinoma is frequently associated with a bloody nipple discharge. (Colorersion of figure is available online.)

ells before a tumor is classified as a neuroendocrine carcinoma.47 The


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umors may react with neuron-specific enolase and cytokeratin (AE1/E3, CAM5.2, CK7)45,51 and TTF-1.52

Treatment and Prognosis. No standard treatment regimen exists forhese tumors. The oat cell variant should be treated according to thetandard protocol of oat cell carcinoma of the lung.53 The remaining casesre usually mammary carcinomas that show only focal neuroendocrineifferentiation and can be treated according to standard breast protocol.hese tumors, with the exception of small cell carcinoma, variably expressstrogen and progesterone receptor. Mirza and colleagues found only 33% to0% have positivity for ER and PR receptors.54 Amplification of Her-2-neus typically absent. It is believed that the small cell variant otherwise knowns undifferentiated neuroendocrine carcinoma has the poorest prognosis.55,56

ncocytic CarcinomaClinical Presentation. As of this publication, only 4 cases of true

IG 9. Small cell carcinoma. Low power shows diffuse infiltrate by a poorly differentiated carcinoma;igher magnification shows marked increased nucleus to cytoplasmic ratio, frequent mitotic figures,nd apoptotic bodies. Original magnification, 40� (A), 400� (B), 100� (C), and 400� (D). (Colorersion of figure is available online.)

ncocytic carcinoma of the breast have been reported in the literature.57,58


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wo cases were female, and 2 cases were male. All patients were olderhan 60 and all had a palpable breast mass on clinical presentation.15

Pathology. Although rare, oncocytic carcinoma of the breast can beonfused with apocrine carcinoma, as it was originally described asuch.15,59 According to Rosen, these tumors have abundant mitochondriat the ultrastructural level and do not react with gross cystic disease fluidrotein-15 (GCDFP-15) as apocrine cells do.20 The cells do not haveyoepithelial differentiation and they contain fine eosinophillic gran-

les15,59 (Fig 10). They share immunohistochemistry with antimitochon-rial antibody that should be used to delineate them from apocrine cellslong with GCDFP-15.15,20,57

Treatment and Prognosis. Due to the rarity of described cases ofncocytic breast carcinoma, it is difficult to determine the prognosis. Aingle case reported a disease-free survival of 7 years after a modifiedadical mastectomy.58 This is in contrast to oncocytomas arising at otherites.57 There are too few data to evaluate the usefulness of chemotherapy

IG 10. Neuroendocrine carcinoma. (A) Solid nests containing eosinophilic granular cells. (B) Theranularity of the cytoplasm is pronounced. In some areas, nuclei are more pleomorphic than in the othercases. (C) Antiepithelial membrane antigen antibody outlines the luminal border of the neoplastic

ells and highlights their functional “polarization.” (D) Most cells are stained intensely with thentimitochondrion antibody. The cribriform structure of this tumor is evident. (Reprinted withermission from Damiani et al.57)

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ecretory Breast CarcinomaClinical Presentation. Secretory breast carcinoma was first described in966 in 7 patients, all under 15 years of age. McDivitt therefore coinedhe term—juvenile breast carcinoma.60 It is now known that they canccur in women from age 3 to 73 years. They also rarely occur inen.20,61 Like fibroadenomas the clinical presentation usually consists ofwell-circumscribed mass often in the subareolar position.62,63

Pathology. Secretory carcinomas manifest grossly as white, gritty,rregular, and firm nodules.63 Microscopically, they are well circum-cribed with areas of invasion to the surrounding tissue (Fig 11). Threeeparate patterns with varying combinations are known: a microcysticattern, a tubular pattern, and a more solid pattern.64,65 The neoplastic cellshow mild nuclear atypia, and prominent eosinophilic secretions with rareitoses.20,62,63,66,67 The cells stain with periodic acid Schiff, �-lactalbumin,-100, and carcinoembryonic antigen (CEA).20,62,67 Estrogen and progester-ne receptor studies are usually negative.62,63

Treatment and Prognosis. Secretory carcinoma usually has a goodrognosis.65,68 Surgical excision is the primary treatment for this tumor.ptions have ranged from modified radical mastectomy to wide local

xcision.62 Costa and colleagues felt that the past reported high incidencef local recurrence is most likely due to inadequate excision of therimary tumor rather than the aggressive nature of the tumor. To date,here is still no consensus as to whether chemotherapy or postoperative

IG 11. (A) Secretory carcinoma, demonstrating a well-demarcated mass predominantly composedf solid nests of neoplastic cells. Original magnification, 40�. (B) At the periphery this tumor showsicrocystic pattern with prominent eosinophilic secretions. Original magnification, 200�. (Colorersion of figure is available online.)

adiation is necessary.66,69,70


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ntracystic Papillary CarcinomasClinical Presentation. Intracystic papillary carcinoma accounts for.5% to 1% of all newly diagnosed breast cancers. Approximately 40% to0% of them are associated with ductal carcinoma in situ. They are alsoarely associated with an invasive carcinoma. This tumor usually presentsn elderly women as a mass lesion and bloody nipple discharge.ltrasound imaging shows an intracystic tumor with an indistinct marginemonstrating both anechoic (cystic) and echogenic (solid) componentst ultrasonography (US) (Fig 12). Ultrasonography is used to identify and

IG 12. Ultrasound of intracystic papillary carcinoma demonstrates an intracystic tumor.

IG 13. (A) Intracystic papillary carcinoma. Low magnification showing proliferation of uniformeoplastic cells within a cystic space with thin delicate fibrovascular cores. Original magnifica-ion, 40�. This tumor also showed adjacent foci of ductal carcinoma in situ and a single focus ofnvasive carcinoma. Original magnification, 200� (B). (Color version of figure is availablenline.)

haracterize such masses and to guide percutaneous biopsy.71


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Pathology. Intracystic papillary carcinoma (IPC) of the breast hasraditionally been considered to be a variant of ductal carcinoma in situDCIS). Traditionally, tumors classified as IPC show delicate fibrovas-ular cords lined by uniform epithelial cells (Fig 13). Some lesionsategorized histologically as IPC are truly in situ carcinomas, whereasthers might represent circumscribed or encapsulated nodules of invasiveapillary carcinoma. A third category is papillomas that show foci ofribriform intraductal carcinoma. The presence and distribution of ayoepithelial cell layer using immunohistochemistry for p63, calponin,

nd smooth muscle actin can distinguish some of these lesions as trulyoninvasive carcinoma versus invasive that show an intracystic growthattern. Almost all cases classified as IPC are estrogen positive and haveow proliferation index.

Treatment and Prognosis. Most of these lesions have an excellentrognosis with adequate local therapy alone. Treatment for intracysticapillary carcinoma is complete resection without axillary sampling asong as there is no invasive component present.72-75 Presence of invasionhould dictate nodal sampling. Adjuvant radiation is considered standard

IG 14. Mammogram of adenocystic carcinoma demonstrates almost a ground glass type of solidass in the absence of calcifications.

ut is often omitted for this indolent tumor.


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denocystic CarcinomaClinical Presentation. Adenoid cystic carcinoma of the breast, firstescribed by Robin and Laboulbene in 1853, is a very rare tumor.76

antamaria and colleagues retrospectively reviewed medical records ofatients treated for adenoid cystic carcinoma of the breast and found thatost patients were postmenopausal (50 to 64 years old) and presented withpainful lump.77 On mammography, they can appear as a lobulated,

ell-defined mass, or ill defined, but without calcifications77 (Fig 14). Veryarely do these tumors metastasize to the axilla.78

Pathology. Histologically, this tumor has a glandular tubular appear-nce.77 From a database of 50,000 patients, Arpino and colleagues79

dentified 28 patients with adenocystic carcinoma for which clinicalollow-up and biologic information was available. Most tumors had lowrade features and 46% were ER positive, and 35% were PR positive.his statement is incorrect. All cases seen at our institution are estrogennd progesterone negative. This is in keeping with most publishederies. Recently, Rabban and colleagues found that the cribriformattern of adenoid cystic carcinoma (Fig 15) can be confused withollagenous spherulosis.80 The 2 tumors can be distinguished, in thatdenoid cystic carcinoma does not express calponin and smoothuscle myosin heavy chain.80

Treatment and Prognosis. Adenoid cystic carcinoma of the breast isonsidered a rare entity with a comparatively favorable prognosis.perber and colleagues81 evaluated the clinical course and outcome of 99atients by meta-analysis. Recurrence-free 10-year survival was calculated at5% following mastectomy and at 46% after breast conserving therapy (P �.05). A majority of the local recurrences and nearly all distant metastases

IG 15. Adenocystic carcinoma. (A) Infiltrating epithelial process. Original magnification, 20�. (B)rominent cribriform pattern of neoplastic cells. (C) Diffuse p63 expression of the tumor cells. Originalagnification, 200�. (Color version of figure is available online.)

ccurred 5 years or later after initial treatment. Arpino and colleagues


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oncluded that adenoid cystic carcinomas of the breast have very favorableiologic characteristics and, consistent with this, an excellent prognosis. Inhis more recent, although smaller series, these authors maintained good localontrol could be achieved by either lumpectomy with radiation or by simpleastectomy, as there were no local recurrences in their series. Based on the

ery low incidence of axillary lymph node metastases, lymph node dissectionas not recommended, although a sentinel lymphadenectomy seems pru-ent.79 Due to the small size of all these reports, no definitive recommenda-ions can be made.78

cinic Cell Carcinoma of the BreastClinical Presentation. Acinic cell carcinoma of the breast is one of theore recently classified tumors. Only 10 cases have been reported in the

iterature.82-88 Patients range in age from 35 to 80 years old.83 All patients toate have presented with a palpable mass that has a concordant well-circum-cribed mass on mammography. Tumor size ranges from 2 to 5 cm.83,88

Pathology. Salivary gland-like tumors occur in the breast as both thereast and salivary glands are modified sweat gland.82 The differentialiagnosis, however, includes adenoid cystic, low grade adenosqua-ous, oncocytic, mucoepidermoid, and adenomyoepitheliomas tu-ors.83 There is a microglandular growth pattern that is similar toicroglandular adenosis83,84 (Fig 16). The cytoplasm has small

gyrophilic, eosinophilic granules, small, round nuclei, and no mito-es.82 Acinic cell tumors of the breast stain positively for antily-ozyme, �1-antichymotrypsin, anti-S-100 protein, and antiepithelialembrane antigen.83,86 Egan noted that salivary gland amylase is aarker specific for acinar cell differentiation.83,89

Treatment and Prognosis. Surgical treatment has ranged from breastonserving therapy to modified radical mastectomy.86 Medical treatmentonsists mainly of chemotherapy. Since the estrogen, progesterone, andndrogen receptors are always negative, no hormonal therapy has beenecommended. Peintinger and colleagues reported the longest follow-upo date of only 10 years.86 Not withstanding a few cases of localecurrence and distant metastases, there seems to be an overall favorablerognosis for this type of tumor.88

alignant Mesenchymal Neoplasms

steosarcoma of the BreastClinical Presentation. In a review of the Mayo Clinic database records
f patients with primary breast sarcomas, essentially all will manifest with

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IG 16. Acinic cell carcinoma. (A) Mammographic findings. Mammography revealed a well-emarcated mass without microcalcifications. (B) Cytological findings of the Giemsa stain. Cytologyhowed a monotonous cell population with an abundant coarse granular cytoplasm and round nucleirranged in 3D clusters (bar, 25 �m). (C) Gross findings of the tumor. The tumor was well defined,inkish gray, and hemorrhaging slightly. (D) Histopathological appearance of the tumor (hematoxylinnd eosin [H&E]). Histologically, the tumor was composed of neoplastic cells with faintly basophilicnd abundant cytoplasms resembling serous acinic cells of the major salivary glands (bar, 200 �m).E) Histological findings of the neoplastic cells (H&E). The tumor was predominantly made up of aonotonous proliferation of cells resembling acinic cells with a finely granular cytoplasm. Some neoplasticells had a clear cytoplasm. These 2 types of neoplastic cells were intermixed in some portions (bar, 50m). (F) Immunohistochemistry. Neoplastic cells are positive with antiamylase (bar, 50 �m). (Reprinted
ith permission from Tanahashi et al.88) (Color version of figure is available online.)

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palpable mass at a mean age of 45 years.90 Osteosarcoma of the breasts an exceedingly rare tumor, the incidence of which is estimated to beess than 1 per 1000 malignant tumors of the breast.90,91 A review bydem and colleagues described this lesion as well circumscribed, havingodular or pushing margins.90 Fine needle aspiration or core biopsy cane used to identify malignancy.92

Pathology. It is important to distinguish primary breast osteosarcoma fromalignant phyllodes tumor and metaplastic sarcoma with osseous/cartilagi-

ous differentiation91 (Fig 17). These lesions have been reported to occuroncurrently.93 Bahrami and colleagues have recently delineated both ahondroblastic and a osteoblastic variant of primary osteosarcoma of thereast.91 These cases were not immunoreactive for AE1/AE3, CAM5.2,K903, EMA, CEA, CK5/6, p63, and CD34 and as such can be helpful in

uling out metaplastic carcinoma.91,94

Treatment and Prognosis. The consensus of reports seems to be thatsteosarcoma tends to be highly aggressive with a propensity for earlyecurrence.91,95 The treatment of primary breast osteosarcomas is com-arable to other soft tissue sarcomas.90 This tumor usually spreadsematogenously with rare metastases to the axillary lymph nodes.91,96

reatment consists of wide local excision versus mastectomy based on theize of the tumor as well as the breast.90,96,97 Radiation is reserved for

IG 17. Hematoxylin and eosin stain shows an osteosarcoma of the breast with numerous giant cellsnd malignant osteoid. Original magnification, 40�. (Color version of figure is available online.)

nresectable tumors and tumors with positive margins.97


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IG 18. Malignant fibrous histiocytoma of the breast. (A) Physical examination revealed a lobulated giantumor in the left breast, 20 cm in size, with ulceration. (B) Computed tomographic scan of the chest. The leftreast was replaced by a hypodense lesion with tumor necrosis and muscle invasion. (Reprinted with permission
rom Ajisaka et al.103)
IG 19. (A) Photomicrograph of malignant fibrous histiocytoma with hematoxylin and eosin staining. Diffuseroliferation of small tumor cells and delicate collagen fibers with myxoid matrix were observed (�100). (B)hotomicrograph of the tumor stained immunohistochemically positive with antibody to CD34 (�400).
Reprinted with permission from Ajisaka et al.103) (Color version of figure is available online.)
IG 20. Fibrosarcoma of the breast on gross anatomical dissection. (Color version of figure is
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alignant Fibrous Histiocytoma and Fibrosarcoma

Clinical Presentation. Sarcomas of the breast are rare. The most

ommon sarcomas are angiosarcomas followed by malignant fibrousistiocytoma (MFH) and fibrosarcoma (Fig 18). Many of these patientsave a previous history of radiation to the chest wall often more than 15ears prior. Women tend to present with an enlarging sometimes painfulass. Ages range from 24 to 93 years, with an average of 59 years.98 A

tudy by Jones and colleagues indicated that younger patients tend to haveower grade tumors while older patients tended to have higher gradeumors.98,99

Pathology. Primary malignant fibrous histiocytoma and other types ofare sarcomas should only be considered after one has excluded bothetaplastic carcinoma and a malignant phyllodes tumor.100,101 Malignantbrous histiocytoma is composed of a storiform growth pattern of spindleells that show marked pleomorphism (Fig 19). Occasional multinucle-ted giant cells and tumor necrosis may also be seen. Fibrosarcomas aresually lower grade. They are composed of uniform spindle cells thatrow with a herringbone pattern98 (Figs 20 and 21). As with all spindleell lesions of the breast, immunohistochemistry is critical in the abilityo diagnose the lesions properly staining positive for CD34.102

Treatment and Prognosis. Surgical excision of these tumors remainshe most important therapy. Since axillary metastases are rare, lymph

IG 21. Desmoplastic fibrosarcoma shows uniform fiboblastic proliferation. Original magnification,00�. (Color version of figure is available online.)

ode dissection is not warranted unless clinically positive nodes are


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resent.98,103 According to Patel and colleagues and others, myxoid MFHesponds well to chemotherapy.103,104

iposarcoma of the BreastClinical Presentation. Liposarcoma of the breast was first described byeumann in 1862.105 Today we know that primary breast liposarcoma

ccounts for 3% to 24% of breast sarcomas exclusive of cystosarcomahyllodes.106 The majority of patients are female and present with areast mass that varies from 1 cm to larger than 40 cm.107

Pathology. Enzinger and colleagues classified 4 categories of lipo-arcoma: 1) well differentiated, 2) myxoid, 3) round cell, and 4)leomorphic type.108 The grade of the tumor is prognostic and theell-differentiated category falls into the low grade form. Intermedi-

te grade includes the myxoid category, and the high grade lesionsnclude round cell and pleomorphic types.106 Histologically, theell-differentiated form has hyperchromatic nuclei, lymphocytes, aatrix of fibrosis and lipomatous mix. Myxoid tumors tend to have aore prominent capillary pattern, whereas round cell lesions are more

ndifferentiated with lipoblasts. The pleomorphic type cells have aixture of multinucleated lipoblasts.106

Treatment and Prognosis. As with other soft tissue sarcomas, 3rognostic features should be considered: 1) tumor contour—pushing,nfiltrating, or indeterminant, 2) degree of atypia, and 3) the number ofitoses per high power field.109 Treatment for these tumors is best served

y wide local excision or mastectomy. Since nodal metastases are rare,xillary node dissections are not necessary. There is no prospectivevidence that radiation or chemotherapy is beneficial.

eiomyosarcomaClinical Presentation. Patients can present with large (average 4 cm)ecrotic masses that appear to be smooth walled on mammogram. Figure2 shows a computed tomographic (CT) scan from a case report by Vund colleagues that shows no invasion of the chest wall.110 The diagnosiss easily made by core biopsy. Care must be taken to rule out metastasesrom a primary uterine leiomyosarcoma.110

Pathology. Most leiomyosarcomas of the breast originate from bloodessels or the smooth muscle of the nipple-areolar complex.110,111 Micro-copically, the tumor appears as bundles of smooth muscle fibrils withylindrical nuclear hyperchromasia, pleomorphism, and mitoses (Fig 23). Immu-
ohistochemical stains are positive for smooth muscle desmin and actin.110

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Treatment and Prognosis. Simple mastectomy appears to be thereatment of choice for leiomyosarcomas of the breast since local failureith lumpectomy alone was 53% versus 8% with mastectomy. Axillaryetastases are extremely rare making axillary node dissection unneces-

ary. Follow-up with chest radiographs to survey for pulmonary metas-ases should be routine.112 Prognosis is poor, with approximately 25% ofatients dying of metastatic sarcoma.

habdomyosarcoma of the BreastClinical Presentation. Primary rhabdomyosarcoma of the breast wasrst discussed by Bilroth in 1860.113 According to Hays and colleagues,

he incidence is only 0.2% although in children the prevalence may be asigh as 4% to 8% of all soft tissue tumors.114,115 Adult cases are evenore rare.116 The age at presentation ranges from 14 to 17 years with aean of 15 years.115 Size at presentation ranges from 3 to 21 cm (Fig 24),

nd even though axilla are often clinically negative, they are oftenathologically positive.117

Pathology. Rhabdomyosarcoma has 2 distinct subtypes: embryonal andlveolar. The Intergroup Rhabdomyosarcoma Study Group found 7 casesf primary rhabdomyosarcoma when they reviewed cases from 1972 to992.115,117 They found that only 1 of the 7 patients had the embryonalype whereas 6 had the alveolar type.115 Histologically, the cells tend toe small and round with easily identifiable mitoses (Fig 24). Ancillarymmunohistochemistry is critical in the diagnosis since these tumors are

IG 22. (A) Computed tomographic scan of leiomyosarcoma demonstrates a smooth homogenousass without invasion into the chest wall. (B) Leiomyosarcoma of the right breast manifests with aecrotic mass. (Reprinted with permission from Vu et al,110 Copyright © 2006, American Medicalssociation. All rights reserved.) (Color version of figure is available online.)

niversally immunoreactive to desmin and myogenin.115


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Treatment and Prognosis. Since the tumor is relatively rare, managementuestions remain to be answered. Appropriate management begins withstablishing the correct pathologic diagnosis, histologic subtype, primary site,xtent of disease, and extent of resection. Cooperative groups throughout Northmerica and Europe have defined risk-benefit treatment based on these factors,

ncluding a coordinated management plan of surgery, chemotherapy, and usuallyadiotherapy.115,118 Enrollment on clinical trial for this rare tumor is encouraged.

yofibroblastomaClinical Presentation. Myofibroblastoma is a benign tumorous prolif-

ration of myofibroblasts. Predominantly male patients present with aedian age of 65 years with a palpable solid lesion46 (Fig 25).Pathology. The tumor consists mainly of spindle cells that have

yoplasmic actin-like microfilaments with elongated nuclei and perinu-

IG 23. Histologic features of primary leiomyosarcoma of the breast. (A) The tumor was composed ofnterlacing fascicles of spindle cells without epithelial elements. (B) The spindle-shaped tumor cellshow eosinophilic cytoplasm, fusiform hyperchromatic nuclei, and mitotic figures. The tumor cells aretrongly immunoreactive to markers of muscle differentiation such as (C) muscle specific actin and (D)esmin. (Reprinted with permission from Lee et al.274) (Color version of figure is available online.)

lear cyoplasmic vacuoles (Fig 26). These clusters of cells are usually


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eparated by bands of collagen. These tumors usually stain with antibodyo actin.46,119

Treatment and Prognosis. Myofibroblastomas tend to be very favor-ble, requiring only excision.119

alignant Schwannoma of the BreastClinical Presentation. Malignant schwannoma of the breast is an

xceedingly rare tumor that, according to Uchida and colleagues, has onlycases reported in the literature.120 Whether benign or malignant, these

umors are difficult to diagnose before surgery. Patients with a mean age ofresentation of 47 years commonly present with a slow growing mass,sually in the upper outer quadrant of the breast.120,121 Benign schwannomasange in size from a few millimeters to 11 cm. Malignant schwannomassually manifest at a very large size. Anything smaller than 2 cm should beuspicious for a diagnosis of sarcoma.120-124

Pathology. Schwannomas of the breast grossly have a thick fibrous

IG 24. (A) Primary embryonal rhabdomyosarcoma of the breast encompassing most of the breast.B) Histology demonstrates small round cells with frequent mitoses. (Reprinted with permission from Dailva et al.275)

apsule surrounding the tumor probably due to the nerve sheath origin.


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longated spindle cells are seen arranged as Verocay bodies or in aalisading fashion121 (Fig 27). There are only rare mitotic cells. Theumor cells stain positive for S-100.121 Malignant schwannomas usually

IG 25. Radiological findings of myofibroblastoma (malignant fibrous histiocytoma). (A) Ultrasonog-aphy revealed a well-circumscribed, dis-homogeneous, 3-cm nodule in the superficial parenchyma ofhe left breast. (B) Mammographic examination confirmed a nodular and dis-homogeneous mass withircumscribed margins. Hypodense areas within the mass were interpreted as fatty tissue. (Reprintedith permission from Magro et al.119)

IG 26. Myofibroblastoma. Cohesive spindle cells without intervening stroma, and with interspersedosinophilic collagen bands. Original magnification, 200�. (Color version of figure is available online.)

how marked pleomorphism and numerous mitotic figures.


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Treatment. To date, only excisional breast biopsy has been performedn patients with schwannoma of the breast. No additional treatment haseen offered in the literature.

hondrosarcoma of the BreastClinical Presentation. Chondrosarcoma rarely manifests as a primary

umor of the breast. Only 5 to 10 cases have been reported in theiterature.125 The age at presentation averages 55 years.126 Essentiallyll cases have presented with freely mobile, large breast massesveraging 10 cm in size.125,126 Mammography may reveal calcifica-ions and ultrasound shows the typical posterior shadowing of IDC126

Fig 28).

Pathology. Chondrosarcoma tumors of the breast arise from breasttroma and not bone or cartilage. They have cellular atypia and

IG 27. Malignant schwannoma. Alternating hyper- and hypocellular areas of tumor withalisading spindle shaped cells and intervening myxoid areas (hematoxylin and eosin �200).ells are diffusely positive for S-100. (Reprinted with permission from Dhingra et al.276) (Colorersion of figure is available online.)

leomorphism with a variable mitotic rate125,126 (Fig 29). Before a


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iagnosis of a primary chondrosarcoma is established, a malignanthylloides tumor and metaplastic carcinoma must be ruled out.125 Inddition, care must be taken that the tumor does not represent anxtraskeletal myxoid chondrosarcoma that can arise from a rib andanifest as a breast mass.Treatment and Prognosis. Gupta and colleagues reported a patientho presented with a clinically palpable node; however, in case

eports to date, no patient has had pathologically positive lymphodes.125,126 Patients may undergo modified radical mastectomy;owever, wide local excision is acceptable. Preoperative chemother-py (5-FU, adriamycin, and cyclophosphamide) may be instituted butn a single case report showed only a partial response.125 Targetedherapy using hormonal therapy may be useful, depending on the

IG 28. Chondrosarcoma. Mammography of the right breast shows a hyperdense mass containingacrocalcifications. (Reprinted with permission from Verfaillie et al.277)

strogen sensitivity of the tumor.127


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etastatic CarcinomasClinical Presentation. The incidence of metastatic neoplasm to thereast is increasing. This is partly due to more effective treatmentesulting in longer term survival of various cancers, and partly due toverall survival. Ovarian, predominantly papillary serous carcinoma,terine, leiomyosarcoma, gastrointestinal tract, colonic adenocarcinoma,idney, renal cell carcinoma, medullary thyroid, melanoma, sarcoma,nd lung metastases have all been reported in the breast. Lung,arcinoid, renal, and ovary are among the most common sites of origino manifest as breast metastases.128-130 One must consider a metastaticrigin in the patient with a known extramammary primary especiallyhen unusually heavy tumor burden is present, when there is aiagnosis of invasive malignant melanoma, prolonged course ofancer, or known sites of local or distant sites of recurrent cancer. Inhildren, medulloblastomas, rhabdomyosarcoma, and neuroblastomasave been reported.The clinical presentation is different from primary breast cancers in that

he patient may feel multiple masses or have multiple fairly well-ircumscribed masses of different size on mammogram or ultra-ound129,131 (Fig 30). The usual spiculations and calcifications seen withnvasive adenocarcinoma of the breast are not present on mammogram.

IG 29. Chondroid component of the tumoral mass. The cartilage cells show signs of malignancy, cellularnd nuclei polymorphism, and a high mitotic rate. (Reprinted with permission from Verfaillie et al.277)

hese masses may manifest as hyperechoic on ultrasound rather than the


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sual hypoechoic appearance of mammary carcinoma. Metastases in thepsilateral lymph nodes are unusual but can occur, particularly withvarian cancer (Fig 31).Pathology. A combination of the clinical history, attention to the

ytomorphological features, and suspicion in cases with other knownetastatic sites should alert the surgeon and pathologist to a nonbreast

rigin. This diagnosis can be confirmed using ancillary immunohistochem-cal studies. A fine needle or needle core biopsy should be performed foriagnosis, but it is advisable to obtain enough tissue for ancillary tests.129,132

ytologic features allow metastatic disease to be suspected in almost one halff metastatic cancers manifesting in the breast. Metastatic adenocarcinomas,elanomas, and sarcoma often require immunohistochemistry to differen-

iate breast origin from metastatic cancer.130 Demonstrating in situarcinoma will confirm the breast origin of questionable lesions, butbsence does not confirm metastatic origin. Lymphatic tumor embolian occur with primary or metastatic breast cancer. Preferentially oneould like to confirm the diagnosis with one or more confirmatoryositive stains and in addition one or more negative stains. A largeumber of neoplasms may show aberrant expression. In our experi-nce, 100% of primary breast carcinomas of various types expressancytokeratin AE1/AE3. Both mammary carcinoma and lobulararcinoma show strong positivity for pancytokeratin. The level ofxpression is significantly lower in spindle cell carcinomas andetaplastic carcinomas. With an exception of epitheloid sarcomas and

ynovial sarcoma, which show cytokeratin positivity, none of the

IG 30. Metastatic papillary serous carcinoma from the ovary to the breast. (A) Ultrasoundemonstrates multiple fairly well circumscribed multifocal lesions of the breast. (B) Hematoxylin andosin stain of metastatic papillary serous carcinoma to the breast. Original magnification, 40�.Color version of figure is available online.)

arcomas show any positivity with pancytokeratin. Approximately


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0% of primary breast carcinomas express GCFD-15.130 Papillaryerous carcinomas of the ovary not only can metastasize to the breast,ut can also cause lymph node metastases. Almost all of these tumorshow strong diffuse cytoplasmic staining with CA-125. They do notxpress GCDF-15.130 TTF-1 is a very helpful marker in distinguishingetastatic adenocarcinoma from primary breast cancer. Primary breast

ancers, with the rare exception of small cell carcinomas of the breast, do notxpress TTF-1. All small cell carcinomas of the breast should be consideredo be metastases unless no other primary sites such as lung or skin can beetected. Metastatic malignant melanomas express Mart-1 and HMB-45.133

Treatment and Prognosis. As a general rule one must always excludemetastatic neoplasm in a patient with preexisting history of carcinoma.istinguishing between a primary breast tumor and metastasis is critical

or treatment and may require panendoscopy and body scans. Systemicreatment of the primary is more appropriate than mastectomy. Lumpec-omy is usually sufficient for a single lesion, but mastectomy and/oradiation may be appropriate to control the chest wall with multicentric

IG 31. Metastatic axillary lymph node from a papillary serous carcinoma of the ovary. Two-imensional ultrasound of the axilla demonstrates a positive axillary lymph node due to its round andypoechoic nature and absence of a central white stripe.

umors or in the case of heavy tumor burden.


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umors of Lymphoid or Hematopoietic Origin

ymphoma/LeukemiaClinical Presentation. For a diagnosis of primary mammary non-odgkins’ lymphoma (PNHL) or leukemia the disease should be

imited to the breast with no evidence of systemic disease. Secondarynvolvement of the breast by hematopoietic malignancies is moreommon and is almost always accompanied by regional or systemicisease.134 Fewer than 0.5% of all malignant lymphomas and approx-mately 2% of extranodal lymphomas involve the breast.134 Theverage age of onset is 55 years with bilateral disease being present in0% of patients (Figs 32 and 33). Nearly one half of the patients willave involved nodes associated with a solitary mass that manifests notnlike a usual breast cancer and can also be associated with breastancer in the same patient.135 Mammographically, breast cancers ofematopoietic or lymphoid origin usually manifest no differently thanarcinomas of ductal origin although leukemia can present as a diffusenfiltrate. There is no association between specific subtypes of lym-homa and specific mammographic or sonographic findings. They doot present with calcifications.136 Figure 33 demonstrates a large-cell lymphoma with necrotic center. Benign intramammary lymphodes have a well-circumscribed appearance on ultrasound with aucent center and a hyperechoic hilar stripe. Intramammary lymph

IG 32. Lymphoma in the cleavage of breast with a superficial nodular mass. (Color version of figures available online.)

odes with metastatic disease appear hypoehoic with loss of the hilar


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tripe and smooth borders. What is much more commonly seen isrimary breast cancer following mantle irradiation for Hodgkin’symphoma.137 Needle core biopsy is recommended for diagnosis tobtain adequate sample size to be able to perform the necessaryncillary tests.Pathology. Primary lymphomas of the breast are a heterogeneous groupf lymphomas. Most primary lymphomas of the breast have morphologiceatures of a poorly differentiated neoplasm. These types of neoplasticells usually diffusely infiltrate the stroma. They may show entrapment ofenign ductal and lobular structures. A battery of immunostains isecessary to establish the diagnosis. These tumors express leukocyteommon antigen CD45. A great majority of these lymphomas are diffusearge B-cell and they express CD20 (Fig 34). Other types of lymphomane may encounter in breast are Burkitt’s lymphoma, follicular center cellymphoma, and lymphoma of mucosa-associated lymphoid tissue. Flowytometric studies might be crucial in diagnosis.135 In addition, on coreiopsy, pseudolymphoma can be mistaken for fragments of intramam-ary lymph node. The rare Hodgkin’s lymphoma can be diagnosed by the

IG 33. Magnetic resonance imaging scan of the breast in a patient presenting with a B-cellymphoma.

resence of Reed-Sternberg cells.


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Treatment and Prognosis. Distinguishing between a primary breastumor and lymphoma is critical for treatment since the systemic treatmentegimens differ. Bilaterality of disease and the international prognosticndex (IPI) are 2 prognostic factors.138 In the past, lumpectomy andadiation or mastectomy were thought to be the most appropriate for localreatment; however, more recently a combination of chemotherapy andadiotherapy has been advocated. Most patients are treated with chemo-herapy (MACOP-B regimen), radiotherapy, and for CD20-positiveisease, rituximab. Combined modality treatment together confer anmproved median survival of 6.5 years over any single treatmentodality.138

lasmacytomaClinical Presentation. Extramedullary plasmacytoma is defined as an

xtraosseous proliferation of neoplastic plasma cells without clinicalvidence of bone or bone marrow involvement.139 These are rare and canppear as solitary palpable lesions (Fig 35) in the breast, but in activeyeloma, it is more common to see the patient present with multiple

esions in the breast (Fig 36). A core biopsy is sufficient to make theiagnosis. When the breast is the only presenting symptom, then stagingagnetic resonance imaging (MRI) of the spine and pelvis is the gold

tandard imaging technique for the detection of bone marrow involve-ent to rule out myeloma, although positron emission tomography–CT

PET-CT) appears just as sensitive in recent studies and has the addeddvantage of total body screening.140

Pathology. Although there are significant differences in terms ofocation and clinical behaviors between multiple myeloma and plasma-ytoma, the cells are really morphologically the same (Fig 37). Histologic

IG 34. Lymphoma of the breast. The tissue is diffusely infiltrated by a relatively uniform neoplastic cellopulation. Original magnification, 40� (A), 200� (B), and 200� (C). (Color version of figure isvailable online.)

xamination of a biopsy specimen will show diffuse sheets of monomor-


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hous plasmacytoid cells with abundant eosinophilic cells with giantuclei and prominent nucleoli with mitotic figures. These cells will stainith anti-� light chain, CD43. Further criteria for diagnosis are biopsy-

IG 35. Plasmacyoma of the breast. (Color version of figure is available online.)

IG 36. Mammogram demonstrates the multiple masses that can be seen with plasmacytoma.

roven extramedullary plasmacytoma with a normal bone marrow with-


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ut evidence of clonal plasma cells and absence of end-organ damageeing negative for Bence Jones protein.141

Treatment. After ruling out systemic disease, a single plasmacytomaan be excised. Multiple myelomas may require a mastectomy andnvolvement of the axillary nodes has been reported, so at least a sentinelode biopsy should be performed in a clinically negative axilla and a leveland II dissection in a clinically positive axilla.142 If systemic disease isresent, chemotherapy is warranted and local therapy, in this instance, isnnecessary.

yoepithelial Lesions

denomyoepitheliomaClinical Presentation. These are rare predominantly solitary, unilateral,ainless, well-circumscribed, noncalcified masses usually seen on mam-ogram. Occasionally they occur centrally. Rare, cutaneous adenomyo-

pitheliomas have been described. These tumors occur in women age 24o 82 years old.16 The average age of presentation is 60 years with aolitary, unilateral, painless mass that can measure from 1 to 7 cm.16

maging studies such as mammography and ultrasound are similar topithelial carcinomas but nonspecific.143 The cytologic features of this

IG 37. Histology of plasmacytoma of the breast. Atypical plasma cells show enlarged eccentricuclei, basophilic cytoplasm, high nuclei-cytoplasm ratio, and mitosis. (Color version of figure isvailable online.)

esion are not well defined. The cytologic features of a case of adeno-


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yoepthelioma characterized by hypercellularity and the presence ofany atypical epithelial cells can lead to the erroneous diagnosis of

denocarcinoma. A needle core biopsy and not fine needle biopsy shoulde used for diagnosis.Pathology. Adenomyoepithelioma is characterized by satellite nod-les of proliferative glands lined by a dual population of cells.143 Theesion forms glands where, on standard immunohistochemical stain-ng, the inner cells appear as epithelial, whereas the cells of the outerayer, that typically have abundant, clear cytoplasm, are interpreted asyoepithelial144 (Fig 38). Squamous, apocrine, and sebaceous meta-

lasia may be focally seen. Many of the cells show foci of spindle cellroliferation. These cells are usually of myoid differentiation. Theultinodular character of the lesion and peripheral intraductal exten-

ion contribute to local recurrence. Approximately one half the casesre estrogen positive.Adenomyoepithelioma can frequently mimic the cytologic featuresf a number of benign and malignant breast lesions and can easily beonfused with carcinoma.144 Preferentially, these lesions should beiagnosed by core needle biopsy rather than fine needle biopsy. Theresence of myoid and epithelial components can be verified bymmunohistochemistry. The majority of adenomyoepitheliomas of thereast are benign. Occasionally, the epithelial component may showalignant differentiation. Carcinomatous components may metasta-

ize to the axillary lymph nodes. The myomatous component may giveise to leiomyosarcomas.Treatment and Prognosis. Adenomyoepithelioma is usually benign and

an be treated by wide local excision, although it does appear to beocally aggressive with multiple recurrences reported at the site ofrior local excision.16 Local excision may be repeated. More aggres-ive therapies such as mastectomy, irradiation, or axillary lymph nodeissection are not appropriate for this benign lesion.

alignant AdenomyoepitheliomaClinical Presentation. Malignant myoepitheliomas are exceedingly

are tumors with little more than 12 cases reported in the literature.he age of presentation ranges from 25 to 81 years, with the majority

ocated in the central portion of the breast and microcalcifications onammography.145 Adenomyoepithelial tumors and myoepithelial car-

inomas of the breast are primarily defined by the presence ofeoplastic cells with a myoepithelial immunophenotype. Current
lassification schemes, developed by Tavassoli and others, are based

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IG 38. Conventional histology and immunostaining of 2 benign adenomyoepitheliomas of the breastA, C, E, G: biphasic; B, D, F: monophasic). Panel A shows a prominent tubular component, whereasn B a spindle-cell architecture predominates (A, hematoxylin and eosin [H&E], magnification �20; D,&E, magnification �20). (C and D) Distribution patterns of basal cytokeratin expression that are

antamount to the proportion of tumor cells (immunostaining for Ck5/6, magnification �20). (E and F)xpression of sm �-actin (immunostaining for SMA, magnification �20) with a distribution similar toormal breast tissue in biphasic benign adenomyoepithelioma. (G) Double immunofluorescence stainingCk5/6 green, Ck8/18 red, �40) with prominent abluminal swarming of Ck5/6-positive cells. Theroliferating glandular epithelium consists of differentiated (red signal) and less differentiated (hybridignal) glandular cells. (H) Double immunofluorescence staining (Ck5 red, SMA green, �63) of aonophasic, malignant myoepithelial tumor with many cells coexpressing SMA and high moleculareigh Ck5. Note some less differentiated cells that express mainly Ck5 and some better differentiatedells with a predominance of SMA expression (green signal). (Reprinted with permission from
ungermann et al.146) (Color version of figure is available online.)

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n purely descriptive features and an assessment of individualrognosis is still problematic.146,147

Pathology. Biphasic ductal and myoepithelial lesions of the breast arencommon. A majority of these rare lesions behave in a benign fashion.alignancy is rare, and preferentially involves the epithelial component

Fig 39). Malignancy in both epithelial and myoepithelial components isven more rare. We report such a case, employing the use of a range ofytokeratins and myoepithelial markers to delineate the extent of eachomponent. In addition, we apply the relatively novel technique of multi-mmunolabeling combined with Adobe Photoshop imaging to highlighthe different components of the neoplasm on the same tissue section.hese ancillary tests can provide much needed information about theontribution of epithelial or myoepithelial components to malignantumors, hence providing the gateway to further study into their histogen-sis and natural history.148

Treatment and Prognosis. These tumors are still quite rare; thereforeata regarding prognosis and treatment have not been defined. To date,reatment for malignant myoepithelioma is wide local excision.145 Hor-

onal therapy will not be effective since these tumors rarely expressstrogen or progesterone receptors.145

hylloides TumorsClinical Presentation. Phylloides tumor, a fleshy tumor with leaf-like

ppearance, was first described in 1838 by Johannes Müller as cystosar-oma phyllodes. The first metastatic case was discussed in an article in themerican Journal of Cancer by Lee and Pack, in 1931.149-151 The SEERatabase states an incidence of 2.1 per 1 million women.150 This isonsistent with an occurrence rate of 0.3% to 1.0% of all breasteoplasms.152 In a review by Chaney and colleagues, of 101 patientsiagnosed with a phylloides tumor, the age ranged from 10 to 86 years oldith a median age of 45.153,154 Population-based studies have shown

ignificantly higher incidence in younger Asian and Hispanic thanon-Hispanic whites. Foreign-born Hispanics have a 3- to 4-fold higherisk for phylloides than Hispanic women born in the United States.155

Patients usually present with a rapidly enlarging palpable mass (Fig 40).he lesions range in size from small to 40 cm.150,152,153 On physicalxamination they are smooth, round, and firm, often mobile and painless.xillary node metastases are rare despite the size these tumors can

chieve.156 Mammography will usually show a rounded, lobulated,
harply defined, opaque mass (Fig 40). Ultrasound studies also show a

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IG 39. Conventional histology and immunostaining of 2 malignant adenomyoepitheliomas of thereast. A, C, and E show a biphasic malignant adenomyoepithelial tumor with distinct tubularormations, whereas B, D, and F show a monophasic adenomyoepithelial carcinoma with diffusenfiltration of adipose tissue (hematoxylin and eosin, magnification �20). C and D display distributionatterns of basal cytokeratin expression that are tantamount to the proportion of tumor cellsimmunostaining for Ck5/6, magnification �20). E and F show expression of SMA in a more irregularistribution compared with normal breast tissue in the malignant biphasic lesion and a rather diffuseattern in monophasic lesions. A prominent mitotic figure is marked in F (arrow; magnification �20).
Reprinted with permission from Hungermann et al.146) (Color version of figure is available online.)

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ell-defined mass that might be inhomogeneous.157 They may also showhe cystic component.156

Pathology. Phylloides tumors are circumscribed masses that are notncapsulated. The cut surface shows a firm, bulging gray to tan tissueith foci of degeneration, necrosis, and infarction (Fig 41). Papillary

tructures or leaflets can be grossly identified.156 Microscopically, phyl-oides tumors at least focally show elongated epithelial lined clefts.hylloides tumors are usually classified as benign, borderline, andalignant,158 but even so these distinctions remain somehow ambiguous.he benign phylloides resemble intracanalicular fibroadenoma. Phyl-

oides tumors show increased cellularity and expansion of the stromalomponent. The mitotic index is very low in benign phylloides, less than

to 2/10 HPF. Lipomatous and osseous metaplasia has been seen inenign phylloides tumors. Occasional multinucleated giant cells withuclear hyperchromasia can also be seen in benign phylloides. Malignanthylloides show prominent stromal overgrowth. The mitotic index isbove 5/10 HPF. Malignant phylloides usually are larger and infiltrate tohe surrounding tissue. Borderline phylloides show infiltrative bordersicroscopically and have a mitotic index of 2 to 5/10 HPF.150,159 Many

hylloides tumors show marked epithelial proliferation. Atypical epithe-

IG 40. Phylloides tumor of the breast. (A) Patient with large phylloides tumor taking up almost onealf of the breast. (B) Mammography in a patient with a smaller phylloides tumor manifesting as aell-circumscribed mass. (Color version of figure is available online.)

ial proliferation is, at times, extreme.157


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Treatment and Prognosis. Older literature suggests that phylloidesumors may be highly unpredictable. However, recent publicationsndicate that one can predict the outcome of these tumors. In a studyonducted at M.D. Anderson, investigators found local failure in only 4%f benign and borderline phylloides tumors. In this study, most cases withocal recurrence were large (�5 cm). This study and others recommendomplete surgical excision with a wide margin of 1 to 2 cm wheneverossible.150 Telli and colleagues found that positive margins were theost powerful predictor of local recurrence.156 Radiation therapy is

ontroversial, but Khan and Badve indicate it may be useful with highrade tumors.150 Chaney and Telli and colleagues state that radiation isot necessary if the margins are greater than 1 cm and have shown thattromal overgrowth is the strongest predictor of distant metastases andverall outcomes.153,156 None of the published studies have found any

IG 41. Phylloides tumor. (A) Gross tumor bisected. (B) Epithelial leaflet-like pattern with markedlyellular stroma. Original magnification, 20�. (C) Stromal overgrowth with frequent mitotic figures.riginal magnification, 40�. (D) Original magnification, 200�. (Color version of figure is availablenline.)

ndication for axillary sampling in these patients.


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ascular Tumors

ngiosarcoma of the BreastClinical Presentation. Angiosarcoma of the breast is one of a hetero-eneous mixture of neoplasms ranging from benign to malignant. Theumor size varies greatly and has been reported from 1 cm to more than0 cm.20 The incidence of primary angiosarcoma is between 0.02% and.05% per year.160 Angiolipoma is a rather benign form of the neoplasmet must be excised due to the concern that it may contain a focus ofngiosarcoma. Secondary angiosarcoma is histologically similar butanifests clinically after primary treatment with radiation therapy.orburger reported that secondary angiosarcoma has an incidence of.01% to 0.02% per year (Figs 42 and 43) and that radiation therapy-ssociated angiosarcomas behave as aggressively as radiation therapy-aïve angiosarcomas.160 Stewart-Treves syndrome is a complication ofong-standing lymphedema commonly seen in postmastectomy and/oradiation therapy patients. Hemorrhagic tumor-like masses erupt on thepper arm and forearms of patients with chronic lymphedema.20

Pathology. A suggested causative factor for angiosarcoma has beenymphedema, even with primary forms.20,161 Schreiber and colleaguesostulated that obstruction of lymph tissue allowed for increased collateralessels that excrete vascular growth factors, which could lead to malignantransformation.162 Histologic features of angiosarcoma of the breast areraded from low to high based on the presence or absence of specificatterns. These include: lesions involving the breast parenchyma, anastomos-ng vascular channels, hyperchromatic endothelial cells, endothelial tufting,apillary formations, solid and spindle cell foci, mitoses, blood lakes, and

IG 42. Angiogenic sarcoma occurring in an irradiated breast after mastectomy (A), and in an armith lymphedema (B). (Color version of figure is available online.)

ecrosis163-165 (Fig 44). Angiolipoma can be confused with its malignant


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ounterpart by predominance of spindle cells and is why this benign lesionust be excised completely.20

Treatment and Prognosis. Radical ablative surgery following diag-osis confers the best prognosis for these patients.166 Treatment for

IG 43. Angiosarcoma occurring in a breast conservation patient. (Color version of figure is availablenline.)

IG 44. Angiosarcoma of the breast showing anastomosing vascular spaces lined by plumpndothelial cells with occasional papillary tufting. Original magnification, 200�. (Color version ofgure is available online.)

ngiosarcoma of any etiology has commonly been either simple


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astectomy or wide local excision. The incidence of local recurrences high, such that simple mastectomy should be the primary treatmentf choice for most sarcomas of the breast. Monroe and colleaguesalculated a recurrence rate of 84% within 1 year of surgicalreatment.167 Some have even advocated radiation before mastectomy.xillary metastases are rare. Despite this, angiosarcoma has a poorrognosis with frequent metastases to the lung. Three-year survivalas been quoted at 14% and is similar in both primary and secondaryumors.167-169 Paclitaxel is known to show promise with other tissueorms of angiosarcomas, but there is little known about the responsen this rare tumor after primary breast cancer treatment.

emangiopericytoma of the BreastClinical Presentation. This lesion is another of the soft tissue

arcomas that can arise in breast tissue. It was first described by Stoutn 1942.170,171 It will usually manifest as an enlarging but painless

ass that is well circumscribed and firm.1 Approximately 30 casesave been described in the literature with 1 of them documenting anccurrence in the axilla.172 The age of presentation ranges from 5 to0 years with the majority presenting in the fifth and sixth decades.173

n ultrasound, the tumor is described as having a heterogeneous echoattern and often a large vascular pedicle can be found within the

IG 45. Hemangiopericytoma. Mammogram demonstrates an ill-defined, well-circumscribed, inho-ogeneous lesion in the left lower lateral quadrant. No calcifications were present. Ultrasound showssolid, inhomogeneous mass, predominantly hypoechoic and partly well-circumscribed, partly

ll-defined borders. (Reprinted with permission from Buecker et al.171)

ass174 (Fig 45).


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Pathology. Histologically, this tumor is composed of round, plump,nd spindle cells proliferating around vascular channels (Fig 46).hese vessels commonly show a staghorn pattern.171 The mitotic

ndex is typically low.173 The tumor cells are polymorph fusiformells with indistinct cytoplasmic borders, form sinusoidal vessels, andxpress CD31, CD34, CD117, CD99, and vimentin.171

Treatment. These tumors usually do not metastasize. The optimalreatment is wide local excision as lymph node involvement is rare.

astectomy might be necessary for exceptionally large cases or in casesith local recurrence.175,176

emangioma of the BreastClinical Presentation. Hemangioma of the breast is found in 1.2% ofastectomies for breast carcinoma. Hemangiomas are divided into

erilobular, parenchymal, nonparenchymal or subcutaneous, and ve-ous types. Venous hemangiomas are extremely rare.177-180 Theseenign lesions are usually divided into cavernous or venous typesased on the size of the involved vessels. Recent publications suggesthat many of these tumors may indeed represent vascular malforma-ion.181,182 Hemangiomas are considered a vascular tumor that must beistinguished from angiolipomas and angiosarcomas. Patients range inge from 10 to 67 years old and the vessels can range from 7 to 50 mmn diameter.178 There is an infantile category of this tumor that haseen found to be associated with the Hox A5 gene, but these tend toegress spontaneously and are not excised.177 Hemangiomas can alsoe seen on mammogram as multilobulated well-circumscribed masses.n ultrasound the lesions are hypoechoic with echogenic flecks

rom the calcifications.183 The calcifications are often found withinhleboliths.180,184

Pathology. Perilobular hemangiomas occur in the extralobulartroma of the breast (Fig 47). Parenchymal hemangiomas are micro-copically composed of dilated channels filled with red blood cells,nd vary greatly in size. Venous hemangiomas are composed ofenous channels with disorganized vascular proliferation. Subcutane-us hemangiomas are located superficial to the anterior pectoral fascian the subcutaneous fat and are distinguishable from sebaceous cystsecause they do not involve the skin. Staining for CD34, a vascularndothelial marker, confirms the tumor’s vascular origin and aids in
dentifying the luminal endothelial cells.185

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IG 46. Histological findings of hemangiopericytoma. (A) Low power view shows the characteristicascular pattern of hemangiopericytoma consisting of anatomizing vessels with marked variations inaliber and cystic changes (hematoxylin and eosin [H&E], �25). (B) Strong expression of the vasculararker CD34 by all tumor cells (�25). (C) High power view showing polymorph fusiform cells with

ndistinct cytoplasmic borders forming sinusoidal vessels (H&E, �400). (Reprinted with permission
rom Buecker et al.171) (Color version of figure is available online.)

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Treatment. Venous hemangioma is not likely to develop into anngiosarcoma so it is recommended to follow rather than excise. Rapidrowth would necessitate wide local excision.

enign Stromal Tumors of the Breast

ibromatosis of the BreastClinical Presentation. Fibromatosis in the breast is a low grade, spindle

ell proliferation composed of fibroblasts.186 These stromal tumors canlinically and radiographically mimic breast cancer. Also known as extra-bdominal desmoid tumors, they have a tendency to recur.187 The etiology istill unclear; however, reports exist of desmoids arising in the breast afterrauma, especially surgical in nature, as well as after the placement of breastmplants.187 There is also an association with familial adenomatousolyposis.188 This is a rare entity accounting for fewer than 0.2% of allreast tumors.189 Patients range in age from 13 to 83 years.187,189 Thelinical presentation is usually a discrete breast mass that is often tender.ammographically they can mimic carcinoma. They appear as dense,

piculated masses and, on ultrasound, they appear irregular and hypo-choic187 (Fig 48). Sizes range from 2.5 to 3.0 cm.

Pathology. Desmoid tumors are composed of uniform spindle cells thatnfiltrate the stroma and surround preexisting lobular and ductal struc-

IG 47. Hemangioma. (A) Hematoxylin and eosin–stained slide (original magnification �100). The massonsists of thick-walled irregular vascular channels with smooth muscle walls of varying thickness, thusuggesting a venous hemangioma. (B) Immunohistochemical staining for CD34 (original magnification �200).taining for CD34, a vascular endothelial marker, reveals strong reactivity in the flattened luminal-liningndothelial cells, confirming the tumor’s vascular origin. (Reprinted with permission from Kim et al.185) (Colorersion of figure is available online.)

ures.188,190 They have various amounts of collagen. Tumor cells show


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ssentially no cytologic atypia. The mitotic index is less than 3/10PF188,189,191 (Fig 49). According to Schwarz and colleagues, expressionf estrogen and progesterone receptors is uncommon.189 Many of theases show focal lymphocytic infiltrate.Treatment and Prognosis. Fibromatosis is best treated surgically. Due

o the infiltrative nature, wide margins are preferred since recurrence ratesan range from 18% to 27% within 2 years of excision.187,189 Potential

IG 48. (A) A 25-year-old lactating woman with a desmoid tumor of left breast. Sonographymage shows irregular, hypoechoic mass with indistinct margins. Tumor is confined to the breastarenchyma and does not involve retromammary structures. (B) Power Doppler sonography

mage shows increased vascularity especially in periphery of lesion. (Color version of figure isvailable online.)

IG 49. A 25-year-old lactating woman with a desmoid tumor of left breast. Photomicrograph showsesion microscopically is composed of bland-appearing fibroblasts of moderate cellularity withoutppreciable mitotic activity (hematoxylin and eosin, �200). (Reprinted with permission from themerican Journal of Roentgenology from Erguvan-Dogan et al.278) (Color version of figure is availablenline.)

reatment in the future may include the use of nonsteroidal anti-


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nflammatory drugs (NSAIDs), but the mechanism of action is notlear.187,189

ranular Cell TumorsClinical Presentation. Abrikossof was the first to describe granular cell

umors in the breast in 1931.192 Granular cell tumors can occur in womenges 17 to 74 years old. Patients usually present with a solitary firm,ainless mass.193 Rare patients have multiple masses.194 They can occurn the axilla as well as anywhere in the breast parenchyma. Superficialesions can cause skin retraction. On mammography these tumors arendistinguishable from IDC. Ultrasound studies show a solid mass withosterior shadowing that resembles carcinoma.195

Pathology. With rare exceptions, granular cell tumors are considered to bebenign neoplasm of myoblastic origin. Morphologically, these tumors are

omposed of nests and sheets of cells with abundant eosinophilic granulesFig 50). Variable amounts of collagen are present in the surrounding stroma.he nuclei are usually uniform and small. They may show inconspicuousucleoli. Compared with infiltrating apocrine carcinomas, these cells areegative for cytokeratin. They diffusely and strongly express S-100. Granularell tumors do not express estrogen or progesterone.196

Treatment and Prognosis. Local excision is the treatment of choice. Ifncompletely excised, these tumors may recur. On rare occasions theseumors have metastasized. The morphologic features of the cases thatave metastasized are indistinguishable from the others.197,198

seudoangiomatous Hyperplasia (PASH)Clinical Presentation. Vuitch and colleagues were the first to describeatients with pseudoangiomatous hyperplasia (PASH). Patients usually

IG 50. Granular cell tumor of the breast shows diffuse infiltration of the stroma by uniform cellopulation with abundant granular cytoplasm. Original magnification, 20� (A), 400� (B), and00� (C). (Color version of figure is available online.)

resent with a unilateral palpable breast mass and range in age from teens


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o mid-50s.199 Patients can present with a rapidly growing mass,specially in young patients.200,201 Ibrahim and colleagues reported thatorphologic features of PASH could be detected microscopically in 23%

f benign and malignant breast lesions.202 Pure nodular or diffuse patternsf PASH are rare.202 Pseudoangiomatous hyperplasia is also a frequentnding associated with gynecomastia. The nodular and diffuse pattern ofASH is thought to be hormonally responsive. Pseudoangiomatousyperplasia occurs in pre-, peri-, and postmenopausal women who haveaken hormonal replacement.203 These tumors are usually progesteroneositive.202 On mammographic examination they appear predominantlys well-demarcated masses without calcification. Occasionally they man-fest as irregular spiculated masses.204

Pathology. Nodular and diffuse PASH usually presents as a well-ircumscribed firm gray white mass. Histologically, they are composed ofnastomosing spaces lined by endothelial-like cells in a dense collagenoustroma (Fig 51). These cells do not express endothelial markers such as factorIII or ULEX. They predominantly show myofibroblastic differentiation and

s such they express CD34 and vimentin. These myofibroblastic cellsxpress progesterone receptor by immunohistochemistry.205 It is crucialo distinguish these lesions from low grade angiosarcomas since they areasily misdiagnosed. The slit-like anastomosing spaces of angiosarcomasre lined by bland appearing endothelial cells. As such they do expressndothelial markers. Low grade angiosarcomas usually show red bloodells within the anastomosing spaces.206

Treatment and Prognosis. The nodular and diffuse pattern of PASH is

IG 51. Pseudoangiomatous hyperplasia, with fibrotic stroma showing diffuse complex network ofpaces involving perilobular and interlobular spaces. Original magnification, 20� (A) and 200� (B).Color version of figure is available online.)

hought to represent a highly exaggerated manifestation of physiologic


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hanges commonly seen in both benign and malignant breast lesions. Theajority of these nodular and diffuse cases are treated by local excision.

t is thought that incomplete resection may result in local recurrence.ccasionally mastectomies have been performed in patients with multiple

ecurrences or in patients who presented with unusually large deformingasses. There is also at least one report of successful treatment with

amoxifen.207,208

yringomatous AdenomaClinical Presentation. Syringomatous adenoma of the nipple was firstescribed by Rosen in 1983.209 Patients usually present with a subareolarass ranging from 0.5 to 3.5 cm in size. They can be painful and they can

ause nipple discharge. Most reported cases are in women age 11 to 76ears of age. The median age at presentation is 46 years.210,211

Pathology. Histologically, syringomatous adenomas are composed ofmall attenuated duct-like structures lined by a double layer of flattenedpithelial cells (Fig 52). Many of these ductal structures appear commahaped. In some areas they may merge with larger ducts. The backgroundtroma consists of dense collagenous stroma. Some of these tumors showprominent infiltrative pattern. The small ductal structures can infiltrate

he muscle, but they do not show any perineural invasion. They canxtend to the epidermis. These tumors are thought to be of probableccrine origin.212,213

Treatment and Prognosis. These tumors are considered benign, but

IG 52. Nipple adenoma. Image shows branching ductal structures lined by uniform basophilic cells.hese cells are usually connected to epidermis and can form small cystic spaces which contain deeplyosinophilic secretion. (Color version of figure is available online.)

hey can recur especially if they are incompletely excised. Low grade


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denosquamous carcinoma and tubular carcinoma should be consideredn the differential diagnosis. Tubular carcinoma clearly lacks any myo-pithelial component seen in these tumors.

eiomyomaClinical Presentation. Leiomyomas of the breast parenchyma are

xceedingly rare in contrast to those arising near the muscle-richubareolar plexus. Case reports are predominantly in postmenopausalomen. They appear much the same as a fibroadenoma, with a circum-

cribed mammographic appearance and homogenous and hypoechoic onltrasound and may have a central tumor vessel (Fig 53).Pathology. Leiomyomas must be differentiated from other benign

tromal tumors of the breast such as fibroadenomas and cystosarcomahylloides. Histologically, fibroadenomas and benign phylloides tumorsemonstrate both epithelial and stromal components, whereas leiomyomas made up of only stromal elements of smooth muscle differentiationFig 54). It can be difficult to differentiate stromal predominant cystosar-oma phylloides from leiomyomas, especially in needle core biopsies,nd extensive sectioning and immunohistochemistry for the epithelial

IG 53. Leiomyoma. Well-circumscribed mass on mammogram (A) and ultrasound (B) that appearsenign and virtually indistinguishable from a fibroadenoma. (Reprinted with permission fromourbagher et al.279)

omponent will aid in the definitive diagnosis.


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Treatment and Prognosis. Simple excision is adequate treatment forhese tumors. Local recurrence is virtually unknown.

eurofibromaClinical Presentation. Neurofibroma of the breast is an especially rare

umor outside of a diagnosis of neurofibromatosis I (NF1) or vonecklinghausen’s disease. Once the neurofibromas appear on the trunk,

he breast examination is difficult and often ignored. This can lead to aigher incidence of breast cancer without self-breast examination. Neu-ofibromatosis I is also a hallmark of unilateral or bilateral gynecomastia,specially in African American men between the ages of 14 and 15.5ears.214 Women with long-standing NF1 can present with grosslynvolved breast tissue with extensive neurofibromatosis. The tumors cane large but mostly painless.215

Pathology. Neurofibromas have a central distribution and appear asutaneous hyperpigmented lesions.215 The lesions are well circumscribedith moderately cellular and focally pleomorphic nucleoli surrounding

rregular spindle cells216 (Fig 55). The cells lack an epithelial componentnd demonstrate positivity for S-100.216

Treatment and Prognosis. With neurofibromas of the breast, the initialreatment should be biopsy of the lesion to confer a correct diagnosisnd treatment.214 Having a low recurrence rate, complete excision isonsidered the standard of care. Patients, especially women with NF1, shoulde considered high risk for breast cancer, at 8.4% by age 50.217 Lumpectomyollowed by radiation therapy carries a significant risk of developing soft

IG 54. Leiomyoma of the breast parenchyma shows uniform cytoplasmic staining for smooth musclectin. (Color version of figure is available online.)

issue sarcoma in these patients.218


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nusual Presentations of Breast Cancer

ammary Paget’s DiseaseClinical Presentation. Paget’s disease of the nipple was originallyescribed by Sir James Paget in 1874. Paget’s disease can occur in 1% to% of breast cancer patients.219,220 The peak incidence is thought to be 50o 60 years of age. The great majority of these lesions manifest as a redcaling lesion involving the nipple (Fig 56), but it can also extend to thereolar region. On rare occasion, Paget’s disease extends to the adjacentpidermis. Most patients present with itching and pain. Some patients alsohow nipple discharge. Approximately 50% to 60% of the cases aressociated with a palpable mass. More than 75% of them may have annvasive carcinoma. Mammography and physical examination couldreatly underestimate the size of the tumor.221 Several publications havehown that MRI is capable of delineating the extent of the disease.222

ess than 1% of Paget’s disease cases occur in men.Unusual Presentation. In several recent case presentations, pigmentedammary Paget’s disease is described in older women.223 In addition, a

ase of mammary Paget’s is described occurring in a woman with prioristory of simple mastectomy.224

Pathology. This neoplastic process is characterized by the presence of

IG 55. Neurofibroma. Photomicrograph of the resected neurofibroma shows spindle cells withharacteristic elongated, wavy nuclei (hematoxylin and eosin, magnification �20). (Reprinted withermission from Jeyaretna et al.216) (Color version of figure is available online.)

arge neoplastic cells as single or in groups at the dermal-epidermal


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unction (Fig 57). Some of the cells may form small glandular spaces;thers infiltrate the epidermis. The majority of these cells have largeyperchromatic nuclei with abundant cytoplasm. Most Paget’s cells do notxpress estrogen or progesterone. Most are Her-2-neu positive. Similar toells of the ductal origin these cells express cytokeratin 7 as compared withytokeratin 5/6, which is expressed by the keratinocytes. Since theajority of these cells are ductal in origin, almost all of these cells express-cadherin. Of interest is that approximately 18% of Paget’s cells are-100 positive. Immunohistochemical studies should only be interpretedy light microscopic findings seen on the hematoxylin and eosin–stainedlide.Treatment and Prognosis. Treatment depends on extent of the process

nd presence or absence of invasive cancer. Based on a recent report, 11%f patients diagnosed at one institution presented with a positive sentinelymph node biopsy. These authors highly recommend sentinel lymphode biopsy in all patients with mammary Paget’s disease. These authorsoncur with others that Paget’s disease remains rare but should be treatedimilarly to other “breast cancer.” Sentinel lymph node biopsy should beerformed to evaluate the axilla when invasive disease is identified or aastectomy is planned. Recent publication suggests a similar outcome for

atients who have undergone central lumpectomy followed by radiationnd patients who have undergone mastectomy with limited disease

IG 56. Typical scaly erosion of the nipple in Paget’s disease of the breast. (Color version of figures available online.)

rocess.219-226


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arcinoma Presenting During PregnancyClinical Presentation. Pregnancy-associated breast cancer has beenefined as breast cancer diagnosed during pregnancy or lactation up toyear postpartum.227 The incidence has been reported at 1% to 3%.urrently, the mean age of diagnosis of breast cancer during preg-ancy is between 32 and 34 years.228 Unfortunately, breast cancer canften remain hidden during pregnancy due to difficult clinical exam-nations. The presentation is often similar to nonpregnant patients—aainless mass found by the patient or physician during a clinical breastxamination. Many of these lesions, however, can be obscured byhysiologic changes and lactoceles in the breast.229 Although breastbscesses can occur during pregnancy, missing a diagnosis of inflam-atory breast cancer can be avoided by obtaining a biopsy of the

bscess wall.230 Ultrasound is the preferred method of investigatingreast masses in pregnant women.227 Mammograms have less sensi-ivity during pregnancy and postpartum due to an increase in paren-hymal density but are the best modality to evaluate microcalcifica-ions. Although concern for the fetus is of utmost importance during

IG 57. Paget’s disease of the breast. The skin is infiltrated by large pleomorphic cells. There is ductalarcinoma in situ in the lactiferous duct that is 0.5 cm away from the epidermis. There is atypicaluctal hyperplasia away from the site. Sentinel nodes were negative. Original magnification, 40�

A), 200� (B), and 20� (C). (Color version of figure is available online.)

ny form of radiographic imaging, the ability to protect the patient


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ith shielding is available. Magnetic resonance imaging causes toouch discomfort for the prone pregnant patient and the safety of

adolinium is unknown.231

Pathology. Pathologically, the range of histology between pregnant andonpregnant patients is quite similar, with 90% being some form of ductalarcinoma.227 Pathologically, this portends a higher level of microvascu-ar invasion. Estrogen and progesterone receptors are usually negative ander-2-neu is more commonly positive in pregnant patients as comparedith nonpregnant patients. Due to the larger size at presentation, axillaryetastases are detected between 60% to 70% of the time.227

Treatment and Prognosis. To date, few prospective, randomized trialsave involved patients who have breast cancer and are pregnant oractating. In fact, ethical prospective and randomized studies may not beeasible.228 As with most breast masses, the preferred method ofiagnosis is through an ultrasound-directed core needle biopsy althoughhis carries a risk of fistula, especially if lactation has begun.Kuerer and colleagues have reported similar results in pregnant patientsith stage I or II disease treated with lumpectomy or modified radicalastectomy.232,233 Surgery and/or radiation may be delayed until after

irth. Risks of surgery are increased with pregnant patients and includeot only bleeding and infection but also formation of milk fistulas.234

nly a handful of case reports on sentinel lymph dissection in a pregnantatient have been reported. Despite this there is no clear evidence thatadiolocalization is safe. Since blue dye crosses the placenta, it is notonsidered safe.Due to the higher incidence of later stage at presentation, prognosis

s considered poorer due to the increased incidence of nodal metasta-es. The indications for chemotherapy are identical to those foronpregnant women and chemotherapy can be utilized after the firstrimester.227,228,231

arcinoma Arising in a FibroadenomaClinical Presentation. Fibroadenomas form during the ages of 15 to 25ears.235 These lesions account for 68% of breast masses, and 19% ofbroadenomas have associated fibrocystic changes.236 Malignancy within

hese lesions is less than 1%. Patients who present with a fibroadenomaontaining a malignancy tend to be older, the median being 42.5 years forn situ carcinomas and 47.0 years for invasive carcinomas, ranging from5 to 83 years.237-239 The physical examination commonly demonstrates
firm, mobile mass that can vary in size. Often cancer within the

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broadenoma is not found until excision. Often, people with fibrocysticisease harbor these masses.237

According to the statement of the American College of Pathologists,broadenomas have no increased risk for breast cancer.240 Since theisk of carcinoma within a fibroadenoma is small, 0.02% according toeschenes and colleagues, it is considered to be caused by chance

ather than a causal relationship.238,240-242 Pick calculated a range of.07% to 0.35% for the chance occurrence of lobular carcinoma in situithin a fibroadenoma.237 As with many lesions, age is the bestredictor of the risk of malignancy within a fibroadenoma.242 Fibro-denomas, particularly in older women, tend to have popcorn-likeacrocalcifications and show up well on mammogram240 (Fig 58)

nlike masses containing microcalcifications that carry approximately30% risk of carcinoma. Fibroadenomas in older patients often showense fibrosis. However, these lesions are not always calcified, andherefore, ultrasound may be more useful, especially in youngeromen with dense breast tissue, to look for irregularities and

etrotumoral abnormalities.236,243,244

Pathology. Pick and Iossifides reviewed the types of cancer foundithin fibroadenomas, and they tend to be ductal carcinoma in situ and

obular carcinoma in situ with a lower incidence of invasive ductal andobular carcinomas.237 The histological diagnosis of carcinoma arisingithin a fibroadenoma has been based on criterion that the carcinoma

ells were limited to a well-defined fibroadenoma or only focallyxtended into adjacent stroma or ducts.245 In another review article the

IG 58. Mammogram of a fibroadenoma with an associated invasive ductal carcinoma.

ost common histological type was lobular carcinoma in situ (66.9%),


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ollowed by ductal carcinoma in situ (12.4%), invasive ductal carcinoma11%), and invasive lobular carcinoma (3.4%).238,246 In all publishedata, the incidence of in situ carcinomas is higher than invasive cancerithin fibroadenomas. In 1958, Demtrakopoulos and colleagues found

here is a common derivation of the epithelial components of bothbroadenomas and lobular carcinoma. This may be why there is a higherrequency of carcinoma in situ,237,247 since fibroadenomas develop fromobules, not from a single cell.240

Treatment and Prognosis. A statement by Hughes in 1987 encourageseaving fibroadenomas alone in patients under the age of 25, providedhere is no concern over it and there has been no growth of the mass.owever, he states that the diagnosis of fibroadenoma after the age of 25

s uncertain due to cyclical changes and involution. Biopsy is thenecommended.248 A consensus statement from a clinical update byoussami and colleagues in 2001 states that women with fibroadenomas

re not at a significantly increased risk of developing breast cancer.249 Aonservative approach using a triple assessment of physical examina-ion, imaging, and biopsy is acceptable.240,242,249,250 Fibroadenomasarboring cancer should be treated on the basis of the therapeuticriteria for ordinary carcinoma.238

arcinoma Arising in Axillary Breast Tissue orupernumerary NipplesClinical Presentation. Physicians are mostly familiar with supernumer-

ry nipples that lie most commonly just below the primary breast. Theeported incidence of ectopic breast tissue recognized by the presence oflandular tissue, nipple, areola, or a combination of these is 5.78%.251 Theast majority of cases develop along the mammary ridge, also known as themilk line.” Aberrant breast tissue becomes noticeable and symptomatic onlyfter hormonal stimulation.252 Axillary breast tissue and accessory nipplesre often common findings on clinical examinations. Also known asolythelia (extra nipples) and polymastia (extra breasts) (Fig 59), thencidence ranges from 1% to 6%, being more common in Africanmericans and those of Jewish or Japanese heritage.253 Ectopic breast

issue in the axilla occurs as a result of the failure of resolution of thembryologic mammary ridge, and ectodermal thickening that extendsrom the axilla to the groin.254 Aughsteen and colleagues describe theilk line as an ectodermic thickening between the upper and lower limb

uds during the 6th week of gestation. They classified polythelia andolymastia into 8 categories: I, complete breast with areola and nipple; II,
upernumerary breast with nipple only; III, supernumerary breast with

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reast tissue and areola only; IV, ectopic or aberrant breast tissue only; V,seudomamma consists of fat with areola and nipple; VI, polythelianipples only); VII, areola only (polythelia areolaris); and VIII, patch ofair only (polythelia pilosa).253

Although breast cancer arising as an axillary mass with an occultrimary breast cancer is rare, the incidence is reported at 0.34% to.45%.255,256 The male incidence is equal to the female incidence.20

reast tissue, regardless of anatomic position, is subject to prolifera-ive changes and hormonal stimulation. Ectopic breast tissue isherefore subject to the same diseases as pectoral breast tis-ue.20,254,257 According to Evans and Guyton, of the 90 cases ofctopic breast carcinoma that have been reported, 64 were located inhe axilla.254 There is a reported association of supernumerary nipplesnd renal anomalies.20,258

Pathology. The morphologic features of the majority of breast cancerases arising from extramammary tissue are consistent with an invasiveammary ductal carcinoma in the presence of ductal carcinoma in situ orremnant of normal breast tissue. If one does not identify an in situ

omponent or in the absence of adjacent benign breast tissue, establishingproper diagnosis might be more cumbersome. A great majority of the

eported cases are estrogen positive.259,260

Treatment and Prognosis. Unfortunately, these cases have a much

IG 59. Patient with breast cancer exhibiting an axillary breast with nipple discharge. (Color versionf figure is available online.)

oorer prognosis due to difficult evaluation, early lymph node involve-


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ent, and difficult excision.253,254 Wide excision is equivalent to mas-ectomy along with removal of local nodes. Adjuvant therapy is necessarynly with nodal disease.261 Preoperative lymphoscintogram for theseatients is critical to assess lymphatic drainage in this group of patients.

nflammatory Breast CancerClinical Presentation. Inflammatory breast cancer (IBC) was firstescribed by Sir Charles Bell in 1814 as “a purple color on the skin overhe tumor accompanied by shooting pains.”262 Today, we know that thisapidly developing breast enlargement may or may not be accompaniedy a localized tumor, and pain does not initiate the process until locallydvanced inflammation is evident. Unfortunately, many patients are ofteniagnosed with an infective process and treated with antibiotics due to theimilar presentation of infection and due to the rarity of presentation.nflammatory breast cancer tends to occur in women with a mean age of1 years.263,264 It is an aggressive form of breast cancer that comprises% to 6% of all breast cancer diagnoses—interestingly, 2% to 3% in thenited States, and upwards of 50% in Tunisia, North Africa.263,265 There

s a rapid onset of breast swelling and enlargement with classic peau’orange appearance due to the blockage of dermal lymphatics. Accord-ng to Singletary, 55% to 85% of patients will have axillary or supracla-icular metastases at clinical presentation.266 Risk factors in opposition tooninflammatory breast cancer include age at first birth (younger ageeing at higher risk), high body mass index, and a possible associationith pregnancy and lactation.265 Mammographic and MRI findings

nclude diffuse skin thickening (Fig 60), the presence of trabeculations,

IG 60. Inflammatory breast cancer. (A and B) Patient presenting with a mammogram demonstratingdema of the breast clinically (peau d’orange) and on the mammogram (indicated by the arrows).Color version of figure is available online.)

nd increased breast density, with or without a localized mass.264,267,268


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Pathology. Inflammatory breast cancer demonstrates a high level ofngiogenesis and lymphangiogenesis compared with noninflammatoryreast cancer269 (Fig 61). Involvement of the dermal lymphatics is thetandard for diagnosis. The disease tends to be ER and PR negative, ander-2-neu positive.269,270 E-cadherin is positive in IBC; however, there is

vidence that p53 suffers a missense mutation as well as nuclear exclusion.270

Treatment and Prognosis. Complete staging is critical with IBC sincehe American Joint Committee on Cancer defines it as stage IIIB, IIIC, or IVf metastases are evident.264 The largest study to date for systemic treatmentf IBC showed that 5-FU, doxorubicin, and cyclophosphamide, radiation,ith or without surgery, followed by additional chemotherapy showedverall survival and relapse-free survival of 50% and 31%, respectively.271

leming and colleagues showed a significant advantage to the addition ofastectomy for local control as well as disease free survival and overall

urvival, unless the patient did not respond to initial chemotherapy.266,272 Aodified radical mastectomy with or without delayed reconstruction after

eoadjuvant chemotherapy, followed by radiation therapy, is the treatment ofhoice.266

ummaryThe emergency digital mammogram, MRI, and accurate large core diag-

IG 61. Inflammatory breast cancer. Image shows neoplastic cells within numerous dermal lymphaticpaces. Original magnification, 200�. (Color version of figure is available online.)

osis have emphasized the need for interdisciplinary care and close commu-


nUSun

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ication of the radiologist, pathologist, medical oncologist, and surgeon.ltimately, this will help us prevent overtreatment and needless side effects.uch interdisciplinary care and communication and a working knowledge ofnusual types of tumors and their presentation are the gold standardecessary to achieve optimal care for our breast cancer patients.

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