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Seminars in Diagnostic Pathology (2010) 27, 77-90

alivary gland-type tumors of the breast: a spectrum ofenign and malignant tumors including “triple negativearcinomas” of low malignant potentialaria P. Foschini, MD,a Thomas Krausz, MD, FRCPathb

rom the aDepartment of Hematology and Oncology, Section of Anatomic Pathology at Bellaria Hospital,L. and A. Seragnoli” University of Bologna, Bologna, Italy; and the
Department of Pathology, University of Chicago, Chicago, Illinois.
Salivary gland-type neoplasms of the breast are uncommon and comprise numerous entities analogousto that more commonly seen in salivary glands. The clinicopathologic spectrum ranges from benign tomalignant but there are important differences as compared with those of their salivary counterpart. Inthe breast, benign adenomyoepithelioma is recognized in addition to malignant one, whereas in thesalivary gland a histologically similar tumor is designated as epithelial-myoepithelial carcinomawithout a separate benign subgroup. Mammary adenoid cystic carcinoma is a low-grade neoplasmcompared with its salivary equivalent. It is also important to appreciate that in contrast to “triplenegative” conventional breast carcinomas with aggressive course, most salivary-type malignant breastneoplasms behave in a low-grade manner. Most of these tumors are capable of differentiating alongboth epithelial and myoepithelial lines, but the amount of each lineage-component varies from case tocase, contributing to diagnostic difficulties. Well established examples of this group include pleomor-phic adenoma, adenomyoepithelioma, and adenoid cystic carcinoma. Another family of salivarygland-type mammary epithelial neoplasms is devoid of myoepithelial cells. Key examples includemucoepidermoid carcinoma and acinic cell carcinoma. The number of cases of salivary gland-typemammary neoplasms in the published data is constantly increasing but some of the rarest subtypes likepolymorphous low-grade adenocarcinoma and oncocytic carcinoma are “struggling” to become clini-cally relevant entities in line with those occurring more frequently in salivary glands.© 2010 Elsevier Inc. All rights reserved.

KEYWORDSBreast;Triple negativecarcinoma;Adenomyoepithelioma;Adenoid cysticcarcinoma;Mucoepidermoidcarcinoma

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Salivary gland-type tumors of the breast are rare benignnd malignant neoplasms with a broad histologic spectrumnalogous to that more commonly seen in salivary glands.1,2

he basic morphologic structure of the tubulo acinar exo-rine glands of the breast and salivary glands perhaps ac-ount for the occurrence of identical tumor types,3 whereas

This work was partly financed with grants from the University ofologna (RFO).

Address reprint requests and correspondence: Maria P. Foschini,D, Anatomia Patologica, Università di Bologna, Ospedale Bellaria, Vialtura 3, 40139 Bologna, Italy.

eE-mail address: [email protected].

740-2570/$ -see front matter © 2010 Elsevier Inc. All rights reserved.oi:10.1053/j.semdp.2009.12.007

he specialization of the acinar cells to secrete milk vs salivand the difference of hormone receptor expression in thesergans explains, at least in part, the clinicopathologic dif-erences. The published data on salivary gland-type tumorsf the breast mostly consist of small series or case reports,ence data on their frequency and clinical behavior areather limited. However, the number of these tumor entitiesas trebled since the first review on this topic in 1970.4

amiliarity with these rare tumor types and distinguishinghem from their mimics is important not only for prognos-ication but also for selecting the correct therapy. This is
xemplified by the fact that even though the malignant
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78 Seminars in Diagnostic Pathology, Vol 27, No 1, February 2010

umors in this group are immunohistochemically “tripleegative,” most of them, in contrast to the more commonasal-like mammary carcinomas, tend to behave in a low-rade manner.

The purpose of the present article is not to review all thereviously published data but to provide an update onelected salivary gland-type breast tumors.

Salivary gland–type tumors of the breast have been di-ided into 2 main groups: tumors with myoepithelial dif-erentiation and tumors devoid of myoepithelial differenti-tion.2

Breast tumors with myoepithelial differentiation consti-ute a wide spectrum of lesions ranging from benign to

alignant neoplasms. Benign breast tumors with myoep-thelial differentiation are represented by pleomorphicdenoma (PA), benign adeno myoepithelioma, and myo-pithelioma. Malignant tumors comprise adenoid cysticarcinoma (AdCC), malignant adenomyoepithelioma thatas a broad histologic spectrum, and pure malignant myo-pithelioma.2,5

leomorphic adenoma

lthough PA is the most frequent tumor of the salivaryland, it is only rarely seen in the breast. It usually affectsdult female patients aged 19-85 years. Rare cases haveeen reported in males.6-8 PA of the breast is most fre-uently located in the periareolar region, and probablyrises from large lactiferous ducts. It is almost alwaysolitary. On mammographic examination, PA can mimic aarcinoma9,10 mainly because of the presence of irregularalcifications. Similarly, a suspicion of malignancy mayrise on examination of cytologic smears.11,12

On histology, PA of the breast is similar to that ofalivary glands and has a broad morphologic spectrumFigure 1). Specifically, it presents as a neoplastic prolifer-tion composed of ductules, sheets, nests, and cords ofpithelial and myoepithelial cells intermixed with mesen-hymal elements in a myxoid, myxohyalinized, or myxo-hondroid background. Focal papillomatous areas may beeen in some of the cases. The phenotype of the neoplasticyoepithelial cells, similar to myoepithelioma and adeno-yoepithelioma, is not always epithelioid but can be spin-

le or plasmacytoid with a “hyaline” cytoplasm.13 Theyoepithelial cells may form a fine reticular growth pattern.

n most examples, scattered double-layered glandular struc-ures lined by luminal epithelial cells beneath which are thebluminal myoepithelial cells which may have clear cyto-lasm are also seen. Focal squamous and/or sebaceousetaplasia may also be observed. The distinction of PA

rom adenomyoepithelioma or even from AdCC can beifficult on a small biopsy material. Islands of well-formedartilage, as the most common mesenchymal component,ith or without ossification/calcification are usually also
resent. Occasionally, neoplastic cartilage is the major com- m
onent of the tumor. PA of the breast is surrounded by ahin, but sometimes incomplete, pseudocapsule.

In most PAs of the salivary gland, chromosomal aberra-ions can be demonstrated.14-18 The most common rear-angements involve 8q12 containing the target gene PLAG1r 12q13-15 with the target gene HMGA2. Other sporadiclonal changes have also been documented. The detection ofLAG1 and HMGA2 translocations by reverse transcriptaseolymerase chain reaction (RT-PCR) or fluorescence in situybridization may potentially aid in diagnosis. It remains toe seen whether the same chromosomal aberrations can bedentified in mammary PAs.19

Mammary PA behaves in a benign manner (malignantransformation is extremely rare, see in the following para-raphs). Recurrences may occur, especially in cases with

igure 1 (A) Pleomorphic adenoma presenting as a multinodu-ar lesion. (B) Pleomorphic adenoma of the breast with chondro-yxoid stroma.

ultinodular growth pattern or in those that are incom-

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79Foschini and Krausz Salivary Gland-Type Tumors of the Breast

letely excised; therefore, adequate surgery and follow-upre recommended.20

Malignant transformation is a well-known phenomenonn salivary gland PA, whereas in the breast it has beenescribed in 3 cases only.21 Carcinoma ex-PA of the breastas observed in 3 female patients, aged 86, 60, and 57ears, respectively. In case 2, the nodule had been detecteduring screening mammography, whereas cases 1 and 3resented with palpable nodule which appeared a fewonths before surgery. On histology, all 3 cases showed

reas of typical PA with areas of malignant transformationn the form of IDC, grade 322 associated with features ofatrix producing metaplastic carcinoma. In case 3, areas of

hondrosarcomatous differentiation were seen and in situuctal carcinoma was also identified. The malignant trans-ormation was located mainly at the periphery of the tumor.n immunohistochemistry, the malignant component showed

ocal positivity for p63 and S-100, in addition to a strongnd diffuse positivity for p53. Immunohistochemical stain-ng was negative for estrogen receptor and human epidermalrowth factor receptor 2 (HER-2).

The cases of carcinoma ex-PA described in the breasthare several features with the salivary gland counterpart,ncluding strong positivity for p53. However, salivary glandases of carcinoma ex-PA are often characterized by a longistory of lump persisting up to 30 years and a prognosislosely related with the local extent of the tumor, specifi-ally whether it is intracapsular or extended beyond theapsule. In addition, the malignant areas are associated withmplification of the HER-2 gene.23

None of the 3 cases were associated with metastasesither to axillary lymph nodes or to distant sites. Case 3eceived chemotherapy. Follow-up, even if limited, wasneventful.

denoid cystic carcinoma

dCC is defined as “an epimyoepithelial carcinoma of lowalignant potential, histologically similar to the salivary

land counterpart.”24

Breast AdCC is rare, constituting �1% of all breastumors.1,25-27 Most of the reported cases affect adult femaleatients, even if rare cases have been described in males andhildren.28

AdCC presents as a palpable nodule/mass, most fre-uently located in the upper quadrants or periareolar region,f variable size.2,24,27 In recent years, cases detected duringammographic screening programs are on records. Care

hould be taken in the interpretation of mammograms be-ause breast AdCC can mimic benign lesions.29 Fine needlespiration cytology (FNAC) can help to reach a correctiagnosis. On FNAC, mammary AdCC is very similar to thealivary gland counterpart, being characterized by 3-dimen-ional clusters of cells arranged around small cystic spaces,
ontaining mucin. Neoplastic cells have uniform and bland h
uclei. In addition, small spheres of amorphous material areresent. Mucicarmine and Alcian blue staining help to con-rm the mucinous material.30 Histologic features are similar

o those of AdCC affecting the salivary glands. Specifically,dCC is composed of epithelial and basal-myoepithelial

ells organized in cribriform, tubular (including compressedubular), and solid patterns (Figure 2A-C). Neoplastic cellsre somewhat polarized around 2 types of oval or roundedpaces: true glandular spaces and pseudolumens. Epithelialells surround true glandular spaces containing epithelial-ype neutral mucin, confirmed by Periodic acid-SchiffPAS) after diastase staining. On hematoxylin and eosinxamination, the epithelial cells surrounding true glandularpaces have round nuclei and eosinophilic cytoplasm.

Basal-myoepithelial cells surround pseudolumens filledith acidic stromal mucosubstance, highlighted by Alcianlue staining, which is hyaluronidase sensitive. In addition,hese spaces may contain rare capillaries with adjacenttrands of collagen consistent with the concept that theseudolumens are the consequence of invagination of theeritumoral stroma. Some of these spaces are partly orompletely obliterated by “hyaline cylinders” composed ofnvaginated basement membrane material confirmed by col-agen IV (Figure 2) and laminin immunostains, and byltrastructural studies.1,24 On hematoxylin and eosin exam-nation, basal-myoepithelial cells have hyperchromatic, an-ular nuclei and a thin rim of pale or clear cytoplasm.

Immunohistochemistry can help to recognize the differ-nt cell types and their distribution. Epithelial cells areositive with low molecular weight cytokeratin (CK)7 andpithelial membrane antigen (EMA), whereas basal-myoep-thelial cells are better highlighted by high molecular weightytokeratins (CK5/6, CK14) and by other myoepithelialarkers like p63, calponin, smooth muscle actin (SMA),

nd smooth muscle myosin heavy chain. Collagen IV andaminin immunoreact both with the peritumoral basementembrane and its invaginated form filling the pseudolu-ens (hyaline cylinders). The immunohistochemical profile

s of practical value in the differential diagnosis, with theore frequent types of breast carcinomas showing cribri-

orm architecture as cribriform invasive carcinoma, muci-ous carcinoma, and polymorphous low-grade adenocarci-oma. The differential diagnosis of AdCC on small biopsyaterial also includes cellular variant of PA and adenomyo-

pithelioma. Furthermore, CD117 (c-kit) positivity, well-nown in salivary AdCC, is maintained also in breastdCC.31,32 Arpino et al27 reported positivity for estrogen

eceptor (ER) in 46% and progesterone receptor (PR) in6% of their cases of AdCC. These data are in contrast withther studies because most of the reported cases of breastdCC were immunohistochemically ER, PR, and HER-2egative. Differences may be related to the method ofetection, as Arpino et al based their data on biochemicalssay of the tumor where samples can also contain normallandular epithelium entrapped within the tumor. Immuno-
istochemical negativity for ER and PR can be an additional

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In addition to the classical tubular or cribriform archi-ecture, breast AdCC can show prominent solid features.hin and Rosen33 described 9 cases of AdCC of the breastainly composed of cells with basaloid features arranged in

olid nests. High mitotic count (�5 mitoses per 10 highower fields) was observed. Axillary dissection was per-ormed in 6 cases, in 2 of which metastases were detected.espite the apparent aggressive morphologic features, no

urther metastases appeared during the reported follow-upmean, 28 months, range, 2-88 months).

AdCC of the breast can show all the spectrum of featuresbserved in cases affecting the salivary glands, includingocal squamous and sebaceous differentiation.2,24,25

Salivary gland AdCC can transform into a high-gradedenocarcinoma (hgAdCC)34-37 leading to death of the pa-

igure 2 Adenoid cystic carcinoma (AdCC) of the breast can sdCC with tubular growth, (C) AdCC with cribriform features, (D

n AdCC.

ient within 5 years.37 Similarly, a case of AdCC of the a

reast containing areas of “ordinary” IDC and ductal carci-oma in situ (DCIS) has been observed.38 The patient, a3-year-old woman, presented with a 4 cm mass located inhe right breast. Radical mastectomy with axillary dissec-ion was performed. Of the 22 axillary lymph nodes, 1howed metastasis at presentation. Bone and lung metasta-es appeared 40 months after surgery. On histology, theumor showed typical features of AdCC, intermingled withDC-DCIS, both expressing c-kit. Both AdCC and IDC-CIS shared some genetic alterations as identified by array

omparative genomic hybridization. Most probably, thisase represents an example of transformation along lines ofuminal cells into ordinary DCIS and IDC, similar to thehenomenon described in salivary glands as “high graderansformation.” Recently, Noske et al39 described a case ofreast carcinoma showing features of multidirectional dif-erentiation, comprising AdCC, a spindle cell carcinoma

arious architectural patterns: (A) Solid and cribriform areas, (B)agen IV immunostaining confirms basal membrane invaginations

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nd melanoma further supporting the concept that one or

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ore cellular clones can acquire molecular alterations, lead-ng to more aggressive transformation.

Ro et al40 performed the tumor grading according to theriteria accepted for salivary gland AdCC and stated that G3ases (solid growth pattern) have a higher rate of metastasesnd recurrences. This result was not confirmed by Lamovect al,25 and Kleer and Oberman.41 Grading mammary AdCCccording to the criteria currently used in cases of breastarcinomas,22 AdCC results as a grade 1 tumor. Accord-ngly, the prognosis of mammary AdCC is usually good.ocal recurrences can appear, mainly related to inadequate

ocal treatment.27 Metastases are rare2,24,27 and usually ap-ear after up to 10 years. It is generally accepted that AdCCf the breast should be treated with simple mastectomy,ith no axillary dissection. However, Shin and Rosen33

eported 9 cases of solid variant of mammary AdCC, withymph node metastasis detected in 2 of the 6 patients inhom lymph node dissection was performed. They con-

luded that axillary lymph node dissection should be per-ormed in patients with these features. As a general caution,he diagnosis of solid variant of AdCC is difficult, thereforetringent diagnostic criteria must be applied to excludeimics of this tumor type. Death related to the tumor has

een occasionally described and limited to those cases thatould not receive radical surgical treatment. The case ofreast AdCC with DCIS-IDC showed a biological behaviorore aggressive than that observed in AdCC of the breast,

s the patient developed lung and bone metastases;38 how-ver, tumor progression was not as rapid as observed inalivary glands AdCC with high grade transformation.37

denomyoepithelioma

denomyoepithelioma (AME) is a biphasic, epithelial—yoepithelilal tumor with a predominant proliferation of

henotypically variable myoepithelial cells around rela-ively small epithelial-lined glandular spaces. In salivaryland, the AME is designated as epithelial-myoepithelialarcinoma and at present, no benign variant is recognized.n the breast, most AMEs behave in a benign manner butalignant transformation may occur (malignant AME) in

ome. AME of the breast was originally described by Ham-erl in 19704 and subsequently characterized by Kiaer etl42 and Eusebi et al.43 During the last 3 decades, numerousrticles have been published (more than 150 cases de-cribed) with the aim of defining the several morphologicubtypes and the clinical features.24

AME usually affects adult female patients, most of themged �50 years.2 Only rare cases have been described inale patients.44,45 AME can present as a nodule, having

ircumscribed borders, varying in size from 1 to 10 cm.5,24

he dominant neoplastic mass may be surrounded bymaller satellite nodules.24

Preoperative diagnosis of AME may be problematic.
nterpretation of FNAC can be difficult because of the great c
ariety of cellular phenotypes and architectural diversityescribed.46 In contrast, core needle biopsy may constituten important tool for a correct preoperative diagnosis47

ecause the biphasic differentiation of the tumor is morepparent and can be supported by immunohistochemicaltudies (Figure 3A).

On histology, AME may exhibit tubular, papillary, solid,r a combination of growth patterns. It is typically charac-erized by excess proliferation of phenotypically diverseyoepithelial cells in close association with glandular struc-

ures lined by epithelial cells. In some examples, the glan-ular structures are formed by 2 phenotypically distinct cellayers. The inner cell layer lining the glandular lumina isomposed of eosinophilic epithelial cells, whereas the outerell layer is typically composed of clear myoepithelial cells.ore frequently, the myoepithelial component is multilay-

red and may form sheets, variably sized nests, or trabecu-ae, resulting in fields composed entirely of myoepithelial

igure 3 Adenomyoepithelioma (AME) in needle biopsy. (A)ow power view. Inset: at higher power a growth of neoplasticells arranged in glandular structures is visible. Inset: immunohis-ochemical staining with smooth muscle actin highlights the myo-pithelial cells. (B) AME with squamous differentiation.

ells. The phenotypic diversity of the myoepithelial cells is

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triking. Some tumors are composed of predominantly spin-le-shaped myoepithelial cells, whereas in others there areostly polygonal cells with clear, eosinophilic, or oncocytic

ytoplasm and, rarely, plasmacytoid myoepithelial cellsith hyaline cytoplasm. Accordingly, AMEs can be sub-

lassified as spindle cell, tubular, and lobulated variants. Inddition, AME can present a variety of other morphologiceatures, such as sebaceous, squamous (Figure 3B), or apo-rine metaplasia in the epithelial component and chondroidr myoid metaplasia in the myoepithelial component. Inontrast to malignant adenomyoepitheliomas, mitotic fig-res are rare (�3 mitoses per 10 high power fields) andeither nuclear atypia nor destructive invasive growth pat-ern is present.

Immunohistochemistry confirms the different nature ofhe 2-cell components. The eosinophilic cells lining thelandular lumina are immunoreactive with markers of epi-helial cell differentiation, (low molecular weight CK, CK7nd CK19, EMA and the apocrine marker, gross cysticisease fluid protein (GCDFP)-15). The clear cells are im-unoreactive with markers of myoepithelial differentiation

SMA, calponin, muscle-specific actin, p63, CK14).48

Breast tumors showing myoepithelial cell differentiationsually do not express estrogen, PRs, or HER-2 amplifica-ion. Nevertheless, exceptions to this rule may occur. Re-ently, we observed a case of AME, affecting a 78-year-oldady, showing diffuse ER expression in both epithelial andyoepithelial cells.Differential diagnoses include PA, hidradenoma, myoep-

thelioma, and matrix-producing carcinoma arising in AME.he histologic resemblance to clear cell hidradenoma isspecially close. Hamperl4 regarded mammary hidrade-oma as a variant of adenomyoepithelioma; however, Az-opardi1 stated “it would be wise to reserve judgement onhis point.” Mammary hidradenomas have been described inoth superficial (especially periareolar) and deep mammaryarenchymal location. Ohi et al49 have reviewed 17 exam-les from the published data. Obviously, those cases whichccur in superficial location have to be distinguished fromhose derived from cutaneous appendages. Histologically,ven though they are biphasic like AMEs, they more fre-uently show perivascular hyalinization, and the abluminalultilayered clear cells have a more uniform, regular ap-

earance with sharp cells borders and monotonous rounduclei than that of myoepithelial cells in AMEs. Limitedmmunohistochemical studies showed that the absence ofey myoepithelial markers (SMA, myosin heavy chain,alponin) in hidradenomas in contrast to AMEs of thereast, which, if confirmed can help in the differentialiagnosis, especially of deeply located examples. Clear cellidradenomas of the breast, whether one regards them asariants of AMEs or not, are benign tumors. About 50% ofutaneous hidradenomas have the t(11;19) resulting inORC1-MAML2 fusion, representing the same transloca-

ion which occurs in mucoepidermoid carcinoma (MEC)
nd Warthin’s tumor. Interestingly, this translocation was t
lso demonstrated in a deeply located hidradenoma of thereast.50

Most of the reported cases behave in benign manner;herefore, in the last edition of the Armed Forces Institute ofathology atlas on breast tumors, the term “benign AME”as been introduced. Local recurrences are possible andhey appear most frequently when excision is incomplete.omplete excision is usually curative.

Malignancy arising in AME has been described in noewer than 40 cases24 (Figure 4). It is becoming evident thatoth epithelial and myoepithelial components can undergoalignant transformation, even if myoepithelial cells areore frequently involved. The malignant neoplasms arising

n AME can be classified as myoepithelial carcinoma, epi-helial carcinoma, malignant epithelial and myoepithelialomponents, sarcoma, and carcinosarcoma.24 In a previ-usly reported series,51 AME was associated with syringo-atous carcinoma (3 cases) and sarcomatoid carcinoma (3

igure 4 AME associated with malignant myoepithelioma. (A)he overgrowth of malignant spindle cells is seen in the left partf the picture. (B) AME showing features of atypia and mitoses in
he myoepithelial cells.

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ases). In addition, in 1 case (case 2 of the series) there wassmall area of mucoid carcinoma.On histology the malignant transformation can be obvi-

us but in some cases it is subtle. In the latter instance, theumber of mitotic figures is an important diagnostic clue:hen they exceed 3 per 10 high power fields there is an

ncreased risk of local recurrences and metastases.24 Inddition, the malignant myoepithelial cells also show highuclear cytoplasmic ratio and a degree of nuclear pleomor-hism. The malignant component frequently shows mor-hologic and immunohistochemical profile of malignantyoepithelioma.Prognosis worsens when malignant features are asso-

iated with AME. In the latter case, local recurrences andistant metastases are expected. Malignant myoepitheli-mas are generally low-grade neoplasms, but high gradexamples do occur. Nevertheless, in the series referred toarlier in the text, no recurrences or metastases werebserved in the 5 cases treated with mastectomy oruadrantectomy. By contrast, recurrences and lung me-astases appeared in the case treated with lumpectomynly. Therefore, it appears that radical surgery is a crucialart of the treatment of AME, even in cases of malignantransformation.

enign myoepithelioma

M is a very rare spindle-cell tumor devoid of any glandularifferentiation and it is regarded conceptually as the pureyoepithelial end of the differentiation spectrum among theore common adenomyoepitheliomas.24,52-55 Histologically,

ven though it resembles smooth muscle tumors, it has theefining immunophenotype of myoepithelial cells. The neo-lasm also shows histologic overlap with the “overgrown”pindled myoepithelial components of adenomyoepithelioma.M should also be distinguished from myoepitheliosis,hich is a multifocal, often microscopic proliferation of

pindle to cuboid cells in the region of terminal duct lobularnit.55 Breast BMs are circumscribed tumors, have no ornly very rare mitotic figures, and show no atypical cyto-ogic features. Immunohistochemistry and electron mi-roscopy can help in differentiating myoepithelioma fromther breast tumors (leiomyoma, spindle cell carcinoma, spin-le cell sarcoma, myofibroblastoma, metastatic spindleell melanoma) exhibiting spindle phenotype.

Pure myoepithelial neoplasms composed of polygonalather than spindle phenotype do also occur, though theirncidence is even lower than that of spindle cell myoepithe-iomas. Histologically, they have a nodular or alveolarrowth pattern with close resemblance to clear cell myoep-thelial neoplasms of salivary glands.

The prognosis of BM is excellent. Only 1 case was
eported to recur 3 times,54 but no metastases are on record. c
alignant myoepithelioma/myoepithelialarcinoma

s described earlier in the text, areas of MM can appear inases of AME.2,55 In addition, cases of pure MM (alsoermed myoepithelial cell carcinoma) without a precursorenign tumor24 can rarely occur in the breast. Pure MM ofhe breast presents as a painless nodule/mass, affecting adultemale patients. Morphologic features vary greatly. Most ofhe cases are composed of atypical, mitotically active spin-le cells, with elongated eosinophilic cytoplasm. The spin-led tumor cells appear to emanate from the myoepithelialells of ductules entrapped in the periphery of the neo-lasm.24 Mitotic activity is usually not more than 4 mitoseser 10 high power fields. In addition, cases showing areas ofpithelioid, clear, and plasmacytoid cells and cases withocal squamous differentiation have been described.56,57 Onare occasions, MM can present a predominantly intra-uctal growth pattern.2 Rare cases of MM with oncocyticeatures have also been reported.2,58 Myoepithelial cellifferentiation can be easily demonstrated by appropriatemmunohistochemical markers.56

The differential diagnosis of MM is broad and includes aariety of sarcomatoid carcinomas, fibromatosis, and otheryofibroblastic lesions. The spindle tumor cells emanating

rom the ductular myoepithelial layer is the most usefuleature in distinguishing MM from spindle squamous car-inoma because immunoreactivity of markers overlaps be-ween the 2 tumor types. There is accumulating evidencehat squamous, fibromatosis-like, and myoepithelial carci-omas are related and should be separated from spindle celldenocarcinoma of epithelial origin.24

A case of MM was associated with DCIS and IDC.59 Theame case, studied by means of comparative genomic hy-ridization, showed that the MM component had a numberf chromosomal gains and losses lower than that of theuctal carcinomatous component.60 Furthermore, it wasemonstrated that the ductal component and the MM com-onent shared an alteration on chromosome 17q, suggestingcommon pathway of transformation.60,61 This hypothesis

s further supported by the observation that myoepithelialell differentiation can be observed in cases of IDC grade.62-64 These latter cases are composed of markedly atypicalells, with large nuclei and prominent nucleoli, arranged inolid sheets with central necrosis. Immunohistochemistryan demonstrate focal areas of myoepithelial differentiation.

Prognosis of MM is generally poor, and local recurrencesnd metastases can appear when appropriate follow-up in-ormation is available.5,24 According to the data reported bysuda et al,64 MM typically metastasizes to the lungs andrain.

Tumors devoid of myoepithelial differentiation compriseEC, acinic cell carcinoma (ACC), and oncocytic carci-

oma (OC). In addition, cases of polymorphous adenocar-
inoma (PLA) have been added recently.

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ucoepidermoid carcinoma

EC was originally described in the salivary glands byoote and coworkers65 as a tumor composed of basaloid,pidermoid, mucous, and intermediate cells. They recog-ized cases of low and high malignant potential. Since theriginal description, MEC has been encountered in severalrgans, including the breast. Low-grade MEC of the breastas originally described by Patchefsky et al in 1979.66

ubsequently, the whole spectrum of MEC, low and highrade, has been reported to occur in the mammary gland.2,67

Despite the long time elapsed since its first description,EC is still one of the rarest tumors of the mammary gland

nd our knowledge is based mainly on single case reports orhort series. Curiously, MEC has been hardly mentioned inajor textbooks of breast pathology. A recent review67 lists

nly 28 cases reported to date in the data published innglish language. All reported cases affected adult femaleatients aged 27-80 years.

Low-grade MEC (Figure 5) can present as a solid orystic, well circumscribed breast mass. When the tumor isocated in the retro-areolar region, nipple discharge can behe first presentation. FNAC shows an admixture of mucousells and cells with ample eosinophilic cytoplasm.68 Correctytologic interpretation of FNAC features may be difficultecause of the rarity of mammary MEC.

On histology, low-grade MEC shows all the same fea-ures observed in salivary gland cases. Diagnosis should beased on the presence of the different cell types, basaloid,ucous, intermediate, and epidermoid cells. On low power

iew, basaloid cells are seen to be located at the peripheryf the neoplastic nests. Basaloid cells are small and haveentrally located round nuclei with coarse chromatin. Inter-ediate cells maintain the round central nucleus but have aore abundant eosinophilic cytoplasm. Epidermoid cells

ave polygonal shape, abundant eosinophilic cytoplasm,nd central nucleus. Intermediate and epidermoid cells areocated in the central part of the neoplastic nests, where theyonstitute the solid areas. No features of true keratinizationre seen. Mucous cells are relatively large cells with paleytoplasm and peripherally displaced nuclei. The cytoplasms filled with sialomucin, demonstrated by PAS after diastase,ucicarmine, or Alcian blue (pH 2.5) stains. Mucous cells areore numerous in the lining of the cystic spaces together with

olumnar cells showing eosinophilic cytoplasm. MEC of thereast may have an in situ component.67,69

Histologic diagnosis is more difficult in cases of high-rade MEC, as typical features are not well defined. Casesf high-grade MEC reported in the published data morerequently present as solid tumors characterized on histol-gy by a mixture of mucous-secreting cells, cells withvidence of epidermoid differentiation and intermediateells. Difference with adenosquamous carcinoma is notlways clear. In the World Health Organization book onreast pathology,70 adenosquamous carcinoma and MECre considered together. According to the criteria adopted in
ases of salivary gland MEC, true keratinization, with squa- s
ous pearl formation, should exclude the diagnosis of MECnd favor the diagnosis of adenosquamous carcinomas. It islso important to remember that rare cases of mammarydenomyoepithelioma71 and hidradenoma may show focalucinous and squamous differentiation, mimicking MEC.50

his is especially interesting in the light of the finding of theame translocation in MECs and in 50% of clear cell hidra-enomas (see the preceding as well as the following para-raphs). Four cases of PA arising in salivary glands withucinous and squamous differentiation have also been de-

igure 5 Mucoepidermoid carcinoma. (A) Low-grade mucoepi-ermoid carcinoma with prominent intraductal growth. (B) Theame case at higher power is composed of an admixture of basal,pidermoid, and mucous secreting cells.

cribed.72

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On immunohistochemistry, each cell type of MEC has apecific profile.69 CK7 stains intermediate, epidermoid, anducinous cells, whereas it is absent in basaloid cells. CK14

nd p63 immunoreact with basaloid and intermediate cells.nti-mitochondrial antigen antibody stains the basaloid and

ntermediate cells in 2 of 4 cases tested.69 Markers ofyoepithelial cell differentiation (calponin and SMA) are

egative in the neoplastic cells. These latter markers areseful to demonstrate the in situ component when it isresent. At low power view the positivity for CK7 is mainlyocated at the center of the neoplastic nests, whereas CK14ositive cells are mainly located at their periphery. Thismmunohistochemical profile is quite similar to what wasreviously described in MEC of the salivary glands aszoning pattern.”73 In contrast to salivary gland cases, MECf the breast shows less frequent and less intense positivityor antimitochondrial antigen. Interestingly, the zoning pat-ern was maintained in the case of high-grade MEC in-luded in the series of Di Tommaso et al.69 A similar patternas previously described by Luchtrach and Moll74 who

ound that low molecular weight CKs were expressedainly in mucous and “nonsquamous” cells, while the strat-

fied-epithelium-type CKs 5, 6, 14, 16, and 17 were mainlyetected in epidermoid cells.

Immunohistochemical staining for estrogen and PRs aresually negative. Only focal positivity for estrogen receptors on record.68

Low-grade salivary gland MEC is characterized by(11;19) translocation being responsible for the CRTC1-

AML2 fusion oncogene.75 Camelo-Piragua et al67 de-cribed a case of mammary MEC that showed a partialeletion of the 11q21 which is the site of the MAML2 gene.

In salivary glands, presence of the fusion gene seemsimited to low-grade MEC and related to a favorable clinicalutcome.75 The same concept cannot be applied in thereast as the case described by Camelo-Piragua et al67

espite the tumor being predominantly intraductal with onlyminor invasive component had a lymph-node metastasis.evertheless, more cases should be studied to really assess

he prognostic value of this molecular alteration.Grading of mammary MEC can be performed either

ccording to the criteria applied to salivary gland tumors orccording to Elston and Ellis22 criteria applied to other typesf mammary carcinomas. Comparison between the 2 grad-ng systems, performed by Di Tommaso et al, leads toimilar results.69

Grading of mammary MEC has relevant prognostic im-lications. Metastases to axillary lymph nodes have beenescribed in 2 of 17 cases of MEC low or intermediaterade, whereas they have been found in 5 of 12 cases ofigh-grade MEC. None of the cases reported as low orntermediate grade MEC died of disease,2,67,69 whereaseath related to the tumor was recorded in 5 of 10 cases ofigh-grade MEC.67 Interestingly, the case reported byjalma et al76 presented as low-grade mammary MEC with

ymph node metastasis and recurred as high-grade MEC. i

espite the recurrence, the patient was alive, with no evi-ence of disease 156 months after surgery.

The morphologic features, together with the distinctivemmunohistochemical profile and the description of theolecular alteration, favor the concept that MEC is a dis-

inct neoplastic entity not only in the salivary gland but alson the breast.

cinic cell carcinoma

CC is defined in the salivary gland as a malignant epithe-ial neoplasm showing acinar cell differentiation, which isharacterized by cytoplasmic zymogen secretory granulesnd immunoreactivity for amylase, lysozyme, and �-1 an-ichymotrypsin.

ACC of the breast was recognized originally by Ron-aroli et al;77 subsequently, only a few cases have beenescribed78-80 and recently reviewed.81 All cases affecteddult female patients. Interestingly, salivary gland acinar-ike differentiation has also been documented in benignreast tissue in a patient who received neoadjuvant chemo-herapy for IDC.82

On histology, ACC of the breast is composed of largeolygonal cells with centrally located round nuclei contain-ng single prominent nucleoli. Neoplastic cells have abun-ant amphophilic cytoplasm filled with coarse granules,ighlighted by PAS stain after diastase digestion. Ultra-tructurally, intracytoplasmic granules have the same fea-ures as the electron dense granules present in the cytoplasmf acinar cells of the parotid. Focal areas of clear cellhenotype may also be present. Mitotic activity varies, butan be to a maximum of 15 mitoses per 10 high powerelds.78 The growth pattern of the tumor can be acinar,icroglandular, microcystic, or solid (Figure 6).Differentiation toward serous acinar cells is demon-

trated with immunohistochemical staining, because theeoplastic cells are positive for salivary gland amylase,ysozyme, and �-1-antichymotrypsin. They are also im-

unoreactive with EMA, S-100 protein, and focally withCDFP-15. Estrogen and PRs and Her-2 are consistentlyegative.

ACC should be differentiated from secretory carcinomaf the breast. From the genetic point of view, ACC does nothow the t(12:15) ETV6-NTRK3 rearrangement typical ofecretory carcinoma.81,83

Axillary lymph node metastases were present in 3 cases;n addition, 2 cases developed metastases to distant organslung and liver). Nevertheless, none of the reported patientsied of disease.

ncocytic carcinoma

C can be defined as a carcinoma composed of �70%ncocytic cells.81,84 OC can arise in several organs, includ-
ng salivary glands and breast.

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True OC should be distinguished from “mitochondrionich” tumors.81,84 This distinction has been suggested byremblay and Pearse,85 who stated that true oncocytes areharacterized by numerous mitochondria occupying almostll the cytoplasm, whereas in mitochondrion rich cells mi-ochondria are grouped at one pole of the cell.

OC usually affects elderly female patients aged �60ears. One case has been described in a male patient.86

According to the original descriptions, OC is character-zed by a proliferation of cells with abundant eosinophilic,ranular cytoplasm (Figure 7A). The nuclei are centrallyocated and show coarse chromatin and prominent nucleo-us. The neoplasm may exhibit both solid and papillaryrchitecture. Ultrastructural examination demonstrates that

igure 6 Acinic cell carcinoma. (A) A case of AC with prom-nent microglandular architecture. (B) Another case of AC withrevalent solid architecture and clear cells.

he cytoplasm of the neoplastic cells is packed with numer- s

us mitochondria. On immunohistochemistry, they aretrongly and diffusely positive with the antimitochondrialntibody. In addition, GCDFP-15 and EMA are frequentlyositive. The strong and diffuse positivity with antimito-hondrial antibody (Figure 7B) is an important feature forhe differential diagnosis, with breast carcinomas showingndocrine and apocrine differentiation. ER, PR, and Her-2ositivity are variable.

The number of OC of the breast reported in the publishedata is too low to reach conclusion about the clinico-patho-ogic spectrum. Ragazzi et al87 reviewed a consecutiveeries of 84 mammary carcinomas to determine the inci-ence of OC. Immunohistochemical study was performedn all the cases with antimitochondrial antibody, and GC-FP-15, chromogranin, ER, PR, AR, HER-2, CK7, CK14,MA, and CD68 antibodies. Positivity for the antimito-hondrial antibody was scored based on staining intensity

igure 7 Oncocytic carcinoma. (A) Oncocytic carcinoma isomposed of cells with eosinophilic granular cytoplasm. (B) Im-unohistochemical staining with anti mitochondrion antigen is

trongly positive in the neoplastic cells.

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nd percentage of positive cells (�70% 3�: OC; �70%�/2�: mitochondrion-rich). Ragazzi et al87 reclassified 19f 84 as OC, whereas 10 of 84 breast cancers (BCs) wereeclassified as “mitochondrion-rich.”

This preliminary data indicate that the incidence of OCf the breast has been underestimated and that this type ofarcinoma has distinct morphologic and immunohistochem-cal features suggesting that it constitutes a distinct entity.

Data presently available on prognosis and treatment aretill scanty to reach any conclusion.

olymorphous adenocarcinoma

vans and Batsakis88 described a malignant tumor arising inhe intraoral minor salivary glands, very similar to lobularnvasive carcinoma of the breast. Subsequent reports betterefined the morphologic spectrum of this entity, leading tohe term “polymorphous low grade adenocarcinomaPLGA)” of salivary glands.89 Although polymorphous lowrade adenocarcinoma mainly affects the intraoral salivarylands, occasional reports describe it in the parotid, lung,kin, vulva, and vagina. Recently, Asioli et al90 described 3ases arising in the mammary gland. All 3 patients weredult females aged 37, 55, and 74 years, respectively. Tu-ors presented as firm nodules, ranging from 1.5 to 4 cm inaximum diameter.On histology, the tumors showed a central solid area

urrounded by a peripheral rim of alveolar and cribriformtructures as well as single neoplastic cells arranged inIndian file” (Figure 8A and B). Neoplastic cells had round,entral nuclei. Atypical mitotic figures were frequent. Noecrosis was present.

On immunohistochemistry neoplastic cells were stronglyositive for BCL-2 (Figure 8C), whereas positivity for CK7nd E-cadherin was faint. Negative results were obtainedith the following antibodies: EMA, CK14, CD117 (c-kit),ER-2, ER, and PR.Differential diagnosis includes invasive lobular carci-

oma and AdCC. Invasive lobular carcinoma should bexcluded because CK7 is weakly positive, E-cadherin, evenhough faint, is still maintained, whereas ER and PR recep-ors are negative in PLA. AdCC should be excluded becauseLA lacks the classic biphasic components of epithelial andasal-myoepithelial cells; in addition, CD117 is consistentlyegative.

Prognosis is difficult to establish as the number of theeported cases is very small. Case 1 of the original seriesied of widespread metastatic disease 3 years after diagno-is. Cases 2 and 3 were alive with no evidence of disease,ut follow-up was limited to a few months. In view of theggressive behavior demonstrated from case 1, at this stage,he term “low grade” should be avoided in cases occurringrimarily in the breast. Further studies are necessary to
etermine the biology of PLA occurring in the breast. fi
igure 8 Polymorphous adenocarcinoma. (A) The tumor isomposed of a central solid area, surrounded by cells arranged inests. (B) At higher power neoplastic cells are arranged in “indian
le.” (C) Neoplastic cells are strongly positive for BCL-2.

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onclusions

alivary gland-type neoplasms of the breast are rare andnclude both benign and malignant tumors. In view of theirarity combined with broad morphologic spectrum, theyften cause diagnostic dilemmas. Even though they areistologically analogous to the more common counterpartsccurring in salivary glands, there are significant differencesn their biological behavior. The correct diagnosis is impor-ant not only for prognostic purposes, but also for selectinghe appropriate therapy. It is also important conceptually tory to place them in the relatively new, evolving “molecularlassification” of breast tumors.

During the last decade, molecular studies coupled with aore detailed immunohistochemical characterization of

reast tumors have lead to a new classification havingmportant implications for clinical management and thera-eutic options. Six main types of breast carcinomas aremerging, each having a specific morphologic and immu-ohistochemical profile91 leading to specific therapeutic op-ions. From the practical point of view, oncologists separateluminal” and “basaloid” carcinomas. Basaloid carcinomasre characterized by a “triple negative” (negative for ER,R, and HER-2) immunohistochemical profile. On H&Eorphology, the “basaloid carcinomas” correspond more

requently to poorly differentiated, aggressive carcinomas.However, breast tumors analogous to those occurring

ore frequently in salivary glands usually do not expressR, PR, or HER-2 amplification and in contrast to othertriple negative” basal-like breast carcinomas, some of themehave in a low-grade manner. Therefore, “triple negativ-ty” in breast carcinomas does not automatically signal aighly aggressive neoplasm because some of the salivaryland-type breast carcinomas like AdCC, majority of ma-ignant adenomyoepitheliomas, and low-grade MEC shoulde regarded as low-grade neoplasms. In these cases, aggres-ive chemotherapeutic treatments are unnecessary.

In summary, a careful and correct morphologic diagnosisf breast carcinomas of special types is important for correctanagement of the patients.

eferences

1. Azzopardi JG: Problems in breast pathology, in Azzopardi JG, Ben-nington JL (eds): Major Problems in Pathology. London, United King-dom, WB Saunders, 1979

2. Foschini MP, Reis-Filho J, Eusebi V, et al: Salivary gland-like tu-mours of the breast: Surgical and molecular pathology. J Clin Pathol56:497-506, 2003

3. Bennett AK, Mills SE, Wick MR: Salivary-type neoplasms of thebreast and lung. Semin Diagn Pathol 20:279-304, 2003

4. Hamperl H: The myothelia (myoepithelial cells). Normal state; regres-sive changes; hyperplasia; tumors. Curr Top Pathol 53:161-220, 1970

5. Foschini MP, Eusebi V: Carcinomas of the breast showing myoepi-thelial cell differentiation. A review of the literature. Virchows Arch432:303-310, 1998

6. Narita T, Matsuda K: Pleomorphic adenoma of the breast: Case report
and review of the literature. Pathol Int 45:441-447, 1995
7. Simha MR, Doctor VM, Udawadia TE. Mixed tumor of salivary glandtype of the male breast. Indian J Cancer 28:14-17, 1992

8. Makek M, von Hochstetter AR: Pleomorphic adenoma of the humanbreast. J Surg Oncol 14:281-286, 1980

9. Agnantis NJ, Maounis N, Priovolou-Papaevangelou M, et al: Pleomor-phic adenoma of the human female breast. Pathol Res Pract 188:235-240, 1992

0. Mizukami Y, Takayama T, Takemura A: Pleomorphic adenoma of thebreast. Radiat Med 26:442-445, 2008

1. Parham DM, Evans A: Pleomorphic adenoma of the breast, a potentialfor the misdiagnosis of malignancy on fine needle aspiration (FNA).Cytopathology 9:343-348, 1998

2. Iyengar P, Cody HS, Brogi E: Pleomorphic adenoma of the breast:Case report and review of the literature. Diagn Cytopathol 33:416-420,2005

3. Lomax-Smith JD, Azzopardi JG: The hyaline cell: A distinctive fea-ture of “mixed” salivary tumours. Histopathology 2:77-92, 1978

4. Geurts JM, Schoenmakers EF, Röijer E, et al: Identification of NFIBas recurrent translocation partner gene of HMGIC in pleomorphicadenomas. Oncogene 16:865-878, 1998

5. Åström AK, Voz AL, Kas K, et al: Conserved mechanism of PLAG1activation in salivary gland tumors with and without chromosome8q12 abnormalities: Identification of SII as a new fusion partner gene.Cancer Res 59:918-923, 1999

6. Voz ML, Agten NS, Van de Ven WJ, et al: PLAG1, the maintranslocation target in pleomorphic adenoma of the salivary glands, isa positive regulator of IGF-II. Cancer Res 60:106-113, 2000

7. Van Dyck F, Declercq J, Braem CV, et al: PLAG1, the prototype of thePLAG gene family: Versatility in tumour development [review]. Int JOncol 30:765-774, 2007

8. Persson F, Andren Y, Winnes M, et al: High-resolution genomicprofiling of adenomas and carcinomas in salivary glands reveals am-plification, rearrangement, and fusion of HMGA2. Genes Chromo-somes Cancer 48:69-82, 2009

9. Sato K, Ueda Y, Shimasaki M, et al: Pleomorphic adenoma (benignmixed tumor) of the breast: A case report and review of the literature.Pathol Res Pract 201:333-339, 2005

0. John BJ, Griffiths C, Ebbs SR: Pleomorphic adenoma of the breastshould be excised with a cuff of normal tissue. Breast J 13:418-420,2007

1. Hayes MM, Lesack D, Gilardet C, et al: Carcinoma ex-pleomorphicadenoma of the breast. Report of three cases suggesting a relationshipto metaplastic carcinoma of matrix producing type. Virchows Arch446:142-169, 2005

2. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer.I. The value of histological grade in breast cancer: Experience from alarge study with long-term follow-up. Histopathology 19:403-410,1991

3. Di Palma S, Skalova A, Vanìèek T, et al: Non-invasive (intracapsular)carcinoma ex pleomorphic adenoma: Recognition of focal carcinomaby HER-2/neu and MIB1 immunohistochemistry. Histopathology 46:144-152, 2005

4. Tavassoli FA, Eusebi V: Tumours of the Mammary Gland, Series 4.Washington, DC, Armed Forces Institute of Pathology, 2009

5. Lamovec J, Uz-Krazovec M, Zidar A, et al: Adenoid cystic carcinomaof the breast: A histologic, cytologic and immunohistochemical study.Semin Diagn Pathol 6:153-164, 1989

6. Bauer E, Sumpio E, Jennings TA, et al: Adenoid cystic carcinoma ofthe breast data from the Connecticut Tumour Registry and a review ofthe literature. Am J Surg 205:295-301, 1987

7. Arpino G, Clark GM, Mohsin S, et al: Adenoid cystic carcinoma of thebreast. Molecular markers, treatment and clinical outcome. Cancer94:2119-2127, 2002

8. Miliauskas JR, Leong AS: Adenoid cystic carcinoma in a juvenilemale breast. Pathology 23:298-301, 1991

9. Okamoto Y, Sumiyama Y, Arima Y, et al: A case of adenoid cysticcarcinoma (ACC) of the breast and review of the utility of preoperative
imaging diagnose. Breast Cancer 8:84-89, 2001

3

3

3

3

3

3

3

3

3

3

4

4

4

4

4

4

4

4

4

4

5

5

5

5

5

5

5

5

5

5

6

6

6

6

6

6

6

6

6

6

7

7

7

7

7

7

7

7


0. Gupta RK, Green C, Naran S, et al: Cytology of adenoid cysticcarcinoma of the breast. Diagn Cytopathol 20:82-84, 1999

1. Mastropasqua MG, Maiorano E, Pruneri G, et al: Immunoreactivity forc-kit and p63 as an adjunct in the diagnosis of adenoid cystic carci-noma of the breast. Mod Pathol 18:1277-1282, 2005

2. Azoulai A, Lae M, Freneaux P, et al: KIT is highly expressed inadenoid cystic carcinoma of the breast, a basal-like carcinoma asso-ciated with a favorable outcome. Mod Pathol 18:1623-1631, 2005

3. Shin SJ, Rosen PP: Solid variant of mammary adenoid cystic carci-noma with basaloid features: A study of nine cases. Am J Surg Pathol26:413-420, 2002

4. Cheuk W, Chan JK, Ngan RK: Dedifferentiation in adenoid cysticcarcinoma of salivary gland: An uncommon complication associatedwith an accelerated clinical course. Am J Surg Pathol 23:465-472,1999

5. Chau Y, Hongyo T, Aozasa K, et al: Dedifferentiation of adenoidcystic carcinoma: Report of a case implicating p53 mutation. HumPathol 32:1403-1407, 2001

6. Nagao T, Gaffey TA, Serizawa H, et al: Dedifferentiated adenoidcystic carcinoma: A clinicopathologic study of 6 cases. Mod Pathol16:1265-1272, 2003

7. Seethala RR, Hunt JL, Baloch ZW, et al: Adenoid cystic carcinomawith high-grade transformation: A report of 11 cases and a review ofthe literature. Am J Surg Pathol 31:1683-1694, 2007

8. Righi A, Morandi L, Lenzi M, et al: Adenoid cystic carcinoma of thebreast associated with invasive ductal carcinoma: A case report. IntJ Surg Pathol [Epub ahead of print]

9. Noske A, Schwabe M, Pahl S, et al: Report of a metaplastic carcinomaof the breast with multidirectional differentiation: An adenoid cysticcarcinoma, a spindle cell carcinoma and melanoma. Virchows Arch452:575-579, 2008

0. Ro JY, Silva EG, Gallager HS: Adenoid cystic carcinoma of the breast.Hum Pathol 18:1276-1281, 1987

1. Kleer CG, Oberman HA: Adenoid cystic carcinoma of the breast:Value of histologic grading and proliferative activity. Am J SurgPathol 22:569-575, 1998

2. Kiaer H, Nielsen B, Paulsen S, et al: Adenomyoepithelial adenosis andlow grade malignant adenomyoepithelioma of the breast. VirchowsArch A Pathol Anat Histol 405:55-67, 1984

3. Eusebi V, Casadei GP, Bussolati G, et al: Adenomyoepitheliom of thebreast with a distinctive type of apocrine adenosis. Histopathology11:305-315, 1987

4. Tamura G, Monma N, Suzuki Y, et al: Adenomyoepithelioma (myo-epithelioma) of the breast in a male. Hum Pathol 24:678-681, 1993

5. Berna JD, Arcas I, Ballester A, et al: Adenomyoepithelioma of thebreast in a male. Am J Roentegnol 169:917-918, 1997

6. Kurashina M: Fine needle aspiration cytology of benign and malignantadenomyoepithelioma of the breast. Report of two cases. Diagn Cy-topathol 26:29-34, 2002

7. Yahara T, Yamaguchi R, Yokoyama G, et al: Adenomyoepitheliomaof the breast diagnosed by a mammotome biopsy: Report of a case.Surg Today 38:144-146, 2008

8. McLaren BK, Smith J, Schuyler PA, et al: Adenomyoepitheliomaclinical, histologic, and immunohistologic evaluation of a series ofrelated lesions. Am J Surg Pathol 29:1294-1299, 2005

9. Ohi Y, Umekita Y, Rai Y, et al: Clear cell hidradenoma of the breast:A case report and review of the literature. Breast Cancer 14:307-311,2007

0. Kazakov DV, Vanecek T, Mukensnabl P, et al: Skin-type hidradenomaof the breast parenchyma with t(11;19) translocation: Hidradenoma ofthe breast. Am J Dematopathol 29:457-461, 2007

1. Foschini MP, Pizzicannella G, Peterse JL, et al: Adenomyoepitheliomaof the breast associated with low-grade adenosquamous and sarcoma-toid carcinomas. Virchows Arch 427:243-250, 1995

2. Hikino H, Nagaoka S, Miura H, et al: Benign myoepithelioma of thebreast: Origin and development. Pathol Int 59:422-426, 2009

3. Toth J: Benign human mammary myoepithelioma. Virchows Arch A
Pathol Anat Histol 374:263-269, 1977
4. Enghardt MH, Hale JH: An epithelial spindle cell breast tumor ofmyoepithelial origin. An immunohistochemical and ultrastructuralstudy. Virchows Arch A Pathol Anat Histol 416:177-184, 1989

5. Tavassoli FA: Myoepithelial lesions of the breast. Myoepitheliosis,adenomyoepithelioma and myoepithelial carcinoma. Am J Surg Pathol15:554-568, 1991

6. Lakhani SR, O’Hare MJ, Managhan P, et al: Malignant myoepitheli-oma (myoepithelial carcinoma) of the breast: A detailed cytokeratinstudy. J Clin Pathol 48:164-167, 1995

7. Cartagena N Jr, Cabello-Inchausti B, Willis I, et al: Clear cell myo-epithelial neoplasm of the breast. Hum Pathol 19:1239-1243, 1988

8. Damiani S, Dina RE, Eusebi V: Eosinophilic and granular cell tumorsof the breast. Semin Diagn Pathol 16:117-125, 1997

9. Scarpellini F, Usellini L, Foschini MP: Malignant myoepitheliomaassociated with ductal carcinoma in situ and invasive. Description of acase and review of the literature. Pathologica 89:420-424, 1997

0. Jones C, Foschini MP, Chaggar R, et al: Comparative genomic hy-bridization analysis of myoepithelial carcinoma of the breast. LabInvest 80:831-836, 2000

1. Jones C, Nonni AV, Fulford L, et al: CGH analysis of ductal carci-noma of the breast with basaloid/myoepithelial cell differentiation.Br J Cancer 85:422-427, 2001

2. Damiani S, Riccioni L, Pasquinelli G, et al: Poorly differentiatedmyoepithelial rich cell carcinoma of the breast. Histopathology 30:542-548, 1997

3. Tsuda H, Tanabe T, Hasegowa T, et al: Myoepithelial differentiationin high grade invasive ductal carcinomas with large central acellularzones. Hum Pathol 30:1134-1139, 1999

4. Tsuda H, Tanabe T, Hasegowa T, et al: Large central acellular zonesindicating myoepithelial tumor differentiation in high grade invasiveductal carcinomas as marker of predisposition to lung and brainmetastases. Am J Surg Pathol 24:197-202, 2000

5. Stewart FW, Foote FW, Becker WF: Muco-epidermoid tumors ofsalivary glands. Ann Surg 122:820-844, 1945

6. Patchefsky AS, Frauenhoffer CM, Krall RA: Low-grade mucoepider-moid carcinoma of the breast. Arch Pathol Lab Med 103:196-198,1979

7. Camelo-Piragua SI, Habib C, Kanumuri P, et al: Mucoepidermoidcarcinoma of the breast share cytogenetic abnormality with mucoepi-dermoid carcinoma of the salivary gland: A case report with molecularanalysis and review of the literature. Hum Pathol 40:1887-892, 2009

8. Horii R, Akiyama F, Ikenaga M, et al: Muco-epidermoid carcinoma ofthe breast. Pathol Int 56:549-553, 2006

9. Di Tommaso L, Foschini MP, Ragazzini T, et al: Mucoepidermoidcarcinoma of the breast. Virchows Arch 444:13-19, 2004

0. Tavassoli FA, Devilee P (eds): World Health Organization Classifica-tion of Tumours: Tumours of the Breast and Female Genital Organs.Lyon, France, IARC Press, 2003

1. Rosen PP: Rosen’s Breast Pathology, (ed 3). Philadelphia, PA:Wolters Kluwer Lippincott Williams & Wilkins, 2009

2. Guo SP, Cheuk W, Chan JK: Pleomorphic adenoma with mucinousand squamous differentiation: A mimicker of mucoepidermoid carci-noma. Int J Surg Pathol 17:335-337, 2009

3. Foschini MP, Marucci G, Eusebi V: Low grade mucoepidermoidcarcinoma of salivary glands: Characteristic immunohistochemicalprofile and evidence of striated duct differentiation. Virchows Arch440:536-542, 2002

4. Luchtrach H, Moll R: Mucoepidermoid mammary carcinoma. Immu-nohistochemical and biochemical analyses of intermediate filaments.Virchows Arch 416:105-113, 1989

5. O’Neill ID: t(11;19) translocation and CRTC1-MAML2 fusion onco-gene in mucoepidermoid carcinoma. Oral Oncol 45:2-9, 2009

6. Tjalma WA, Verslegers IO, De Loecker PA, et al: Low and high grademucoepidermoid carcinomas of the breast. Eur J Gynaecol Oncol23:423-425, 2002

7. Roncaroli F, Lamovec J, Zidar A, et al: Acinic cell-like carcinoma of
the breast. Virchows Arch 429:69-74, 1996

7

7

8

8

8

8

8

8

8

8

8

8

9

9


8. Schmitt FC, Ribeiro CA, Alvarenga S, et al: Primary acinic-cell likecarcinoma of the breast—A variant with good prognosis? Histopathol-ogy 36:286-289, 2000

9. Damiani S, Pasquinelli G, Lamovec J, et al: Acinic cell carcinoma ofthe breast: An immunohistochemical and ultrastructural study. Vir-chows Arch 437:74-81, 2000

0. Coyne JD, Dervon PA: Primary acinic carcinoma of the breast. J ClinPathol 55:545-547, 2002

1. Foschini MP, Eusebi V: Rare (new) entities of the breast and medul-lary carcinoma. Pathology 41:48-56, 2009

2. Matoso A, Easley SE, Gnepp DR, et al: Salivary gland acinar-likedifferentiation of the breast. Histopathology 4:262-263, 2009

3. Lambros MB, Tan DS, Jones RL: Genomic profile of a secretory breastcancer with an ETV6-NTRK3 duplication. J Clin Pathol 67:604-612,2009

4. Damiani S, Eusebi V, Losi L, et al: Oncocytic carcinoma (malignantoncocytoma) of the breast. Am J Surg Pathol 22:221-230, 1998

5. Tremblay G, Pearse AG: A cytochemical study of oxidative enzymesin the parathyroid oxyphil cell and their functional significance. Br J
Exp Pathol 40:66-70, 1959
6. Costa MJ, Silverberg SG: Oncocytic carcinoma of the male breast.Arch Pathol Lab Med 113:1396-1399, 1989

7. Ragazzi M, Reis-Filho JS, De Biase D, et al: Characterization ofoncocytic breast carcinoma. Oral Presentation 22nd Congress Eu-ropean Congress of Pathology. Virchows Archives 455:S33, 2009(suppl 1)

8. Evans HL, Batsakis JG: Polymorphous low-grade adenocarcinoma ofminor salivary glands. A study of 14 cases of a distinctive neoplasm.Cancer 53:935-942, 1984

9. Evans HL, Luna MA: Polymorphous low-grade adenocarcinoma: Astudy of 40 cases with long-term follow up and an evaluation of theimportance of papillary areas. Am J Surg Pathol 24:1319-1328, 2000

0. Asioli S, Marucci G, Ficarra G, et al: Polymorphous adenocarci-noma of the breast. Report of three cases. Virchows Arch 448:29-34, 2006

1. Abd El-Rehim DM, Ball G, Pinder SE, et al: High-throughput proteinexpression analysis using tissue microarray technology of a largewell-characterised series identifies biologically distinct classes ofbreast cancer confirming recent cDNA expression analyses. Int J
Cancer 116:340-350, 2005

salivary gland-type tumors of the breast: a spectrum of ... · salivary gland-type tumors of the...

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