BRIEF REPORTS
Diagnosis of Adenoid Cystic Carcinoma of the Breast Using Fine-Needle Aspiration Cytology: A Case Report and Review of the Literature Tosun M. Ilkay, M.D.,1* Kir Gozde, M.D.,1 Sarica Ozgur, M.D.,2 and Demirel Dilaver, M.D.3
Adenoid cystic carcinoma (ACC) of the breast is a rare variant of breast malignancy and is associated with an excellent prognosis. ACC accounts for 0.1% of all breast carcinomas. It has favorable biological characteristics and an excellent prognosis. A 77-year-old woman presented with a lump in the right breast. Ultrasonography and mammography showed a 12-mm, welldefined, lobulated mass in the retroareolar region of the right breast. The lump was diagnosed as ACC on the basis of immunohistochemical staining results for c-kit (CD117), musclespecific actin, p63, estrogen receptor, and progesterone receptor using a fine-needle aspiration cytology (FNAC) specimen. This diagnosis was subsequently confirmed by excision biopsy. To the best of our knowledge, this is the first case of ACC of the breast to date to be diagnosed on the basis of immunohistochemical staining of an FNAC cell block material. From our experience, we recommend the usage of cell block material for immunohistochemical studies to accurately diagnose ACC of the breast.
1 Department of Pathology, Umraniye Education and Research Hospital, Istanbul, Turkey 2 Department of Radiology, Umraniye Education and Research Hospital, Istanbul, Turkey 3 Department of Pathology, GATA Haydarpasa Education Hospital, Istanbul, Turkey All of the authors declare that they have all participated in the design, execution, and analysis of the article and that they have approved the final version. Additionally, there are no conflicts of interest in connection with this article, and the material described is not under publication or consideration for publication elsewhere. There are no grants or other funding for all authors. *Correspondence to: Tosun M. Ilkay, M.D., Department of Pathology, Umraniye Education and Research Hospital, Istanbul, Turkey. E-mail: [email protected] Received 18 August 2014; Revised 27 December 2014; Accepted 20 March 2015 DOI: 10.1002/dc.23272 Published online 17 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
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Diagnostic Cytopathology, Vol. 43, No 9
C 2015 Wiley Periodicals, Diagn. Cytopathol. 2015;43:722–726. V Inc.
Key Words: FNAC
adenoid cystic carcinoma; breast cytopathology;
Case Report A 77-year-old woman came to our hospital for a routine checkup. Ultrasonography and mammography showed a 12-mm, well-defined, lobulated mass in the retroareolar region of the right breast (Figs. 1 and 2). There was no obvious palpable mass on physical examination of the breast. Fine-needle aspirations of the mass were performed under ultrasonographic guidance using three passes while maintaining negative pressure. Four smears of aspirated material were prepared; one was air-dried and stained with May–Gruenwald–Giemsa (MGG stain) and three were fixed in 95% ethanol and stained with Papanicolaou stain. For histological analysis, a cell block of the third aspirate was prepared by first fixing it in thin prep solution. After routine tissue processing, it was embedded, cut and stained with hematoxylin–eosin (H&E). A highly cellular smear containing round and branching multilayered clusters of cohesive, small, uniform epithelial cells (Fig. 3), and mucoid globules was obtained (Fig. 4). The cell population was monotonous with small, uniform cells. Nuclei were round to oval and slightly hyperchromatic, with occasional small nucleoli. Cytoplasm in cells was absent or scant and ill-defined. A tendency to lose cell cohesiveness was noticed with a few to moderate number C 2015 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
DIAGNOSIS OF ADENOID CYSTIC CARCINOMA OF THE BREAST
Fig. 1. Ultrasonography showed 12-mm well-defined lobulated hypoechoic and heterogeneous mass. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 3. A highly cellular smear containing round and branching multilayered clusters of cohesive, small, uniform epithelial cells surrounding mucoid globules (Giemsa, x40). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 4. Hyaline globules mimicking collagenous spherulosis (Papanicolaou, x10). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 2. Mammography showed relatively well-defined hyperdense lobulated mass.
of disassociated naked nuclei in the smear background, with a nuclei appearance similar to that of the cells in the groups. There were no free myoepithelial cells. Hematoxylin and eosin-stained sections of cell block preparations from the aspirate showed three-dimensional clusters of uniform ductal cells with a biphasic pattern of tumor cells and both true laminae and pseudocystic spaces. Cell block
material was also evaluated immunohistochemically using the following antibodies: CD117, P63, muscle-specific actin (MSA), estrogen receptor (ER), and progesterone receptor (PR). Details of antibodies and dilutions are shown in Table I. Immunohistochemistry assays were performed on a VENTANA Benchmark XT automated staining instrument according to the manufacturer’s instructions. Immunohistochemical staining showed strong membranous and cytoplasmic immunoreactivity with CD117 (Fig. 5). Basal and myoepithelial cells were positive for p63 (nuclear staining) and MSA (cytoplasmic and membranous staining). ER and PR were negative. Therefore, a cytologic diagnosis of adenoid cystic carcinoma (ACC) was made. The patient underwent wide local excision with sentinel lymph node sampling with frozensection examination. Two sentinal lymph nodes were tumor-free, and no axillary lymph node dissection was performed. The histopathologic examination findings confirmed the cytologic diagnosis (Fig. 6). Diagnostic Cytopathology, Vol. 43, No 9
723
Diagnostic Cytopathology DOI 10.1002/dc
ILKAY ET AL. Table I. Details of Antibodies and Dilutions Antibody Er Pr P63 MSA CD117
Clone
Source
Dilution
EP1 16 I27-I HHF-35 YR145
Gremed Laica Biocare Biocare Cell Marq
1/40 1/50 1/100 1/100 1/200
Fig. 5. Strong cytoplasmic and membranous CD117 immunoreactivity in cell block material (x40). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 6. Histolopathologic specimen shows cribriform architecture with focal basophilic secretion and cylindromatous nodules (H&E, x10). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Discussion ACC of the breast is uncommon, accounting for 0.1% of all breast cancers.1 It has favorable biological characteristics and an excellent prognosis.2,3 The morphological features of ACC are identical to other malignancies that rarely occur in the salivary and lacrimal glands, nasal cavity, lung, trachea, cervix, and Bartholin’s gland.4 Although it is known for its predominance in women, breast ACC may be seen in men.5 Further, although most patients with ACC are usually between 35 and 94 years 724
Diagnostic Cytopathology, Vol. 43, No 9
old, a case of ACC of the breast in a 19-year-old woman was recently reported.6 Patients may present with a slow growing solid mass for months or years without distant spread. Another common feature is intermittent pain and tenderness in the breast mass.3 Mammography and ultrasonography findings vary widely and are not diagnostic. These tumors often appear as a small lobulated nodule with clearly defined margins.7 ACC of the breast has a good prognosis, and early cytologic diagnosis is very important. It should be differentiated from benign conditions, such as collagenous spherulosis (CS), and other malignant conditions, such as invasive cribriform carcinoma.8 CS very often mimics the features of ACC in the breast and demonstrates similar spherical globules admixed with benign ductal epithelial and myoepithelial cells; however, it usually does not form a mass and is limited in extent, involving only a few ducts.9 In contrast to the three-dimensional cell clusters with high nuclearto-cytoplasmic ratios seen in ACC, CS yields cells arranged as two-dimensional sheets with lower nuclearto-cytoplasmic ratios.1,10–12 The naked nuclei of ACC are round and resemble those present in the threedimensional clusters, whereas bipolar naked nuclei are present in CS.13 In addition, CD117 has been reportedly expressed by ACC but not by CS and is considered a helpful marker in the differentiation of these two entities.9,14 In our case, strong membranous and cytoplasmic positivity for CD117 was observed. ACC may be confused with other pathologic conditions of the breast, particularly the cribriform type of invasive ductal carcinoma.15 The presence of extracellular metachromatic globules and second-cell population (myoepihelial) are key cytologic findings helping to exclude cribriform carcinoma.16 In order to make an accurate diagnosis between cribriform carcinoma and ACC, we checked for p63 and MSA positivity on immunohistochemical staining. Besides the lack of expression of ER, PR, and human epidermal growth factor receptor (Her-2/neu), ACCs, in addition, express one or more basal cell markers (e.g., cytokeratins 5, 5/6, 14, and 17).17 Immunhistochemical staining pattern in ACC, CS and invasive cribriform carcinoma was summarized in Table II. ACC offers better prognosis, and therefore, an early diagnosis on the basis of FNAC is significant. Nearly, 35 cases of ACC of the breast have been diagnosed to date by FNAC and reported in the literature (Table III). In earlier reports of ACC of the breast, cytological diagnosis was made and confirmed by histopathological material. There were only two studies in which cell block materials were prepared. Gupta et al. presented their experience with seven cases of ACC of the breast.4 In this study, cell block material was prepared from each aspirate but not stained with immunohistochemical stains. In the study of Szalay et al., immunohistochemical staining for cytokeratin, epithelial
Diagnostic Cytopathology DOI 10.1002/dc
DIAGNOSIS OF ADENOID CYSTIC CARCINOMA OF THE BREAST Table II. Immunohistochemical Different Diagnosis of ACC
CD117 P63 ER/PR
ACC
CS
Invasive cribriform carcinoma
1 (cytoplasmic/membranous) Basal myoepithelial cells (nuclear 1) —
— Basal myoepithelial cells (nuclear 1) 1 (nuclear)
— — 1 (nuclear)
Table III. A Summary of Salient Features in Cases No of cases
CB
IHC
Gupta4 (1999) Sagi25 (2004) Pandya26 (2010) Szalay18 (1996)
7 1 1 1
1(7/7) — — 1
Stanley27 (2006) Culubret13 (1996) Tsuchiya28 (2000) Kuo29 (2008) Okamoto3 (2001) Kasagowa30 (2006) Jain31 (2003) Fargahi32 (2011) Sherigar33 (2006) Wang34 (2012) Lamovec16 (1989) Lee 35 (1991) Malik36 (2007) Cheng37 (2002) Righi38 (2009) Tosun (2014)
6 1 1 1 1 2 1 1 1 1 5 1 1 1 1 1
— — — — — — — —— — — — — — — 1
— — — CK, EMA, col-IV, AML — — — — — — — — — — — — — — — CD117, p63, MSA, ER, PR
References
Cytologic diagnosis
Histological diagnosis
ACC ACC ACC ACC
ACC ACC ACC ACC
ACC SFM SFACC FA SFM ACC ACC ACC SFACC MEDT 2/S, 3/ACC ACC ACC SFAC SFM ACC
ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC
CB: Cell block, IHC: Immunohistochemistry, SFM: Suspicious for malignancy, SFACC: Suspicious for ACC, FA: Fibroadenoma, MEDT: Myoepithelial derived tumor, S: Suspicious feature, SFAC: Suspicious for adenocarcinoma
membrane antigen, collagen IV, and alpha actin smooth muscle was performed on smears and histological sections obtained by excisional biopsy.18 To the best of our knowledge, this is the first case of breast ACC diagnosed on the basis of CD117 immunohistochemical staining of FNAC cell block material. There is no consensus on optimal treatment for patients with ACC of the breast because of the rarity of this condition. It is accepted that local excision as the sole treatment may lead to unacceptably high rates of local recurrence.19 ACC usually presents as a localized disease (stages pT1/2) with a low frequency of axillary lymph node involvement (less than 8%), particularly in tumors smaller than 1.4 cm in diameter.20–23 According to the clinical presentation and overall favorable outcome, most clinicians recommend a breastconserving surgical approach with or without radiotherapy for the treatment of ACC.22,24
Conclusion This case represents the first example of ACC of the breast diagnosed on the basis of CD117 staining on cell block material obtained by FNAC. FNAC is an easy and
quick method for diagnosing breast masses. A cellular smear with uniform, round hyperchromatic cells presenting singly and in loosely cohesive clusters, the absence of myoepithelial cells, and tumor cells surrounding cores and balls of acellular homogeneous material supports the diagnosis of ACC of the breast. It is important to differentiate ACC from CS and other pathologic conditions of the breast. From our experience, we recommend usage of cell block material for immunohistochemical studies to accurately diagnose ACC of the breast.
References 1. Quinodoz IS, Berger SD, Schafer P, Remadi S. Adenoid cystic carcinoma of the breast: Utility of immunocytochemical study with collagen IV on fine needle aspiration. Diagn Cytopathol 1997;16: 442–445. 2. Stahlschmidt J, Liston J, Aslam MM, Carder PJ. Educational case report. Fine needle aspiration cytology of adenoid cystic carcinoma of the breast. Cytopathol 2001;12:266–269. 3. Okamoto Y, Sumiyama Y, Arima Y et al. A case of adenoid cystic carcinoma [ACC] of the breast and review of the utility of preoperative imaging diagnose. Breast Cancer 2001;8:84–89. 4. Gupta RK, Green CC, Naran S. Fine-Needle Aspiration Cytology of Adenoid Cystic Carcinoma of the Breast Diagnostic Cytopathology, Vol 20, No 2 1999. Diagnostic Cytopathology, Vol. 43, No 9
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ILKAY ET AL. 5. Page DL. Adenoid cystic carcinoma of breast, a special histopathologic type with excellent prognosis. Breast Cancer Res Treat 2005; 93:189–190. 6. Delanote S, Van den Broecke R, Schelfhout VR, Serreyn R. Adenoid cystic carcinoma of the breast in a 19-year-old girl. Breast 2003;12:75–77. 7. Bourke AG, Metcalf C, Wylie EJ. Mammographic features of adenoid cystic carcinoma. Australas Radiol. 1994;38:324–325. 8. Jain M, Gautam S. Cytological diagnosis of adenoid cystic carcinoma of breast, a case report. Indian J Pathol Microbiol 1999;42:113–116. 9. Rabban JT, Swain RS, Zaloudek CJ, Chase D, Chen YY. Immunophenotypic overlap between adenoid cystic carcinoma and collagenous spherulosis of the breast: Potential diagnostic pitfalls using myoepithelial markers. Mod Pathol 2006;19:1351–1357. 10. Rosen PP. Rosen’s breast pathology. Philadelphia: Lippincott Williams and Wilkins; 2001. p 114–134, 535–550. 11. Perez SJ, Guillermo PM, Bernal BA, Bermejo RM. Diagnosis of collagenous spherulosis of the breast by fine needle aspiration cytology: A report of two cases. Acta Cytol 1993;37:725–728. 12. Jain S, Kumar N, Sodhani P, Gupta S. Cytology of collagenous spherulosis of the breast: A diagnostic dilemma: Report of three cases. Cytopathology 2002;13:116–120.
States (1977 to 2006): A population-based cohort study. Breast Cancer Res 2010;12:R54. 23. Vranic S, Frkovic-Grazio S, Lamovec J, et al. Adenoid cystic carcinomas of the breast have low Topo IIa expression but frequently overexpress EGFR protein without EGFR gene amplification. Hum Pathol 2010;41:1617–1623. 24. Khanfir K, Kallel A, Villette S, et al. Management of adenoid cystic carcinoma of the breast: A rare cancer network study. Int J Radiat Oncol Biol Phys 2011. 25. Saqi A, Mercado CL, Hamele-Bena D. Adenoid cystic carcinoma of the breast diagnosed by fine-needle aspiration. Diagn Cytopathol 30:271–274. 26. Pandya AN, Shah P, Patel RD, Patel PR. Adenoid cystic carcinoma of breast and the importance of differentiation from collagenous spherulosis by FNAC. J Cytol. 2010;27: 69–70. 27. Stanley MW, Tani EM, Rutquist LE, Skoog L. Adenoid cystic carcinoma of the breast: Diagnosis by fine needle aspiration. Diagn Cytopathol 1993;9:184–187. 28. Tsuchiya A, Nozawa Y, Watanabe T, Kimijima I, Takenoshita S. Adenoid cystic carcinoma of the breast: Report of a case. Surg Today 2000;30:655–657.
13. Culubret M, Roig I. Fine needle aspiration biopsy of adenoid cystic carcinoma of the breast: A case report. Diagn Cytopathol 1996;15: 431–444.
29. Kuo PH, Huang CS, Huang WC, Kuo SH, Wang J. Adenoid cystic carcinoma of the breast arising in a lipoma mimicking hamartoma: Imaging manifestations and review of the literature. Chin J Radiol 2008;33:37–40.
14. Mastropasqua MG, Maiorano E, Pruneri G, Orvieto F, Mazzarol G, Vento AR, VialeG. Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. Mod Pathol 2005;18:1277–1282.
30. Kasagawa T, Suzuki M, Doki T, Fujimori T, Itami M, Takenouchi T, Yamamoto N. Two cases of adenoid cystic carcinoma: Preoperative cytological findings were useful in determining treatment strategy. Breast Cancer 2006;13:112–116.
15. Khalbuss WE. Cytomorphology of rare malignant tumors of the breast. Clin Lab Med 2005;25:761–775.
31. Jain S,Gupta S,Kumar N,Sodhani P. Extracellular hyaline material in association with other cytologic features in aspirates from collagenous spherulosis and adenoid cystic carcinoma of the breast. Acta Cytol 2003;47:381–386.
16. Lamovec J, Us-Krasovec M, Zidar A, Kljun A. Adenoid cystic carcinoma of the breast: A histologic, cytologic, and immunohistochemical study. Semin Diagn Pathol. 1989;6:153–164. 17. Vranic S, Bender R, Palazzo J, Gatalica Z. A review of adenoid cystic carcinoma of the breast with emphasis on its molecular and genetic characteristics. Hum Pathol 2013;44:301–309. 18. Quinodoz IS, Berger SD, Schafer P, Remadi S. Adenoid cystic carcinoma of the breast: Utility of immunocytochemical study with collagen IV on fine-needle aspiration. Diagn Cytopathol 1997;16:442–445. 19. Veeratterapillay R, Veeratterapillay S, Ward E, Khout H, Fasih T. Adenoid cystic carcinoma of the breast: Case report and review of literature. Ann R Coll Surg Engl 2012;94:e137–e138. 20. Glazebrook KN, Reynolds C, Smith RL, Gimenez EI, Boughey JC. Adenoid cystic carcinoma of the breast. AJR Am J Roentgenol. 2010;194:1391–1396. 21. Thompson K, Grabowski J, Saltzstein SL, Sadler GR, Blair SL. Adenoid cystic breast carcinoma: Is axillary staging necessary in all cases? Results from the California Cancer Registry. Breast J 2011; 17: 485–489. 22. Ghabach B, Anderson WF, Curtis RE, Huycke MM, Lavigne JA, Dores GM. Adenoid cystic carcinoma of the breast in the United
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32. Fargahi S, Gu M. Adenoid cystic carcinoma of the breast diagnosed by fine needle aspiration. Cytopathology 2012;23:205–207. 33. Sherigar JM, Finnegan J, McManus D, Lioe TF, Spence RAJ. Extra alivary adenoid cystic carcinoma: Report of two cases. Ulster Med J. 2006;75: 223–225. 34. Wang S, Xiangjun JI, Wei Y, Yu Z, Li N. Adenoid cystic carcinoma of the breast: Review of the literature and report of two cases. Oncol Lett 2012;4:701–704. 35. Lee DW, Jin SY, Kim DJ, Kwon KH. Adenoid cystic carcinoma of the breast: Diagnosis by fine needle aspiration cytology. Korean J Cytopathol 1991;2:160–167. 36. Malik A, Shamus-ul-Bari, Khan A, Amin R, Jan M. Adenoid cystic carcinoma of breast. Internet J Pathol 2007;7. 37. Cheng SB, Li MC, Yeh DM, Liu TJ, Wu CC. Adenoid cystic carcinoma of the breast: Report of a case. Mid Taiwan J Med 2002;7: 109. 38. Righi A, Lenzi M, Morandi L, Flamminio F. Adenoid cystic carcinoma of the breast associated with invasive duct carcinoma: A case report. Int J Surg Pathol 2011;19:230–234.
Diagnosis of Adenoid Cystic Carcinoma of the Breast Using Fine-Needle Aspiration Cytology: A Case Report and Review of the Literature Tosun M. Ilkay, M.D.,1* Kir Gozde, M.D.,1 Sarica Ozgur, M.D.,2 and Demirel Dilaver, M.D.3
Adenoid cystic carcinoma (ACC) of the breast is a rare variant of breast malignancy and is associated with an excellent prognosis. ACC accounts for 0.1% of all breast carcinomas. It has favorable biological characteristics and an excellent prognosis. A 77-year-old woman presented with a lump in the right breast. Ultrasonography and mammography showed a 12-mm, welldefined, lobulated mass in the retroareolar region of the right breast. The lump was diagnosed as ACC on the basis of immunohistochemical staining results for c-kit (CD117), musclespecific actin, p63, estrogen receptor, and progesterone receptor using a fine-needle aspiration cytology (FNAC) specimen. This diagnosis was subsequently confirmed by excision biopsy. To the best of our knowledge, this is the first case of ACC of the breast to date to be diagnosed on the basis of immunohistochemical staining of an FNAC cell block material. From our experience, we recommend the usage of cell block material for immunohistochemical studies to accurately diagnose ACC of the breast.
1 Department of Pathology, Umraniye Education and Research Hospital, Istanbul, Turkey 2 Department of Radiology, Umraniye Education and Research Hospital, Istanbul, Turkey 3 Department of Pathology, GATA Haydarpasa Education Hospital, Istanbul, Turkey All of the authors declare that they have all participated in the design, execution, and analysis of the article and that they have approved the final version. Additionally, there are no conflicts of interest in connection with this article, and the material described is not under publication or consideration for publication elsewhere. There are no grants or other funding for all authors. *Correspondence to: Tosun M. Ilkay, M.D., Department of Pathology, Umraniye Education and Research Hospital, Istanbul, Turkey. E-mail: [email protected] Received 18 August 2014; Revised 27 December 2014; Accepted 20 March 2015 DOI: 10.1002/dc.23272 Published online 17 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
722
Diagnostic Cytopathology, Vol. 43, No 9
C 2015 Wiley Periodicals, Diagn. Cytopathol. 2015;43:722–726. V Inc.
Key Words: FNAC
adenoid cystic carcinoma; breast cytopathology;
Case Report A 77-year-old woman came to our hospital for a routine checkup. Ultrasonography and mammography showed a 12-mm, well-defined, lobulated mass in the retroareolar region of the right breast (Figs. 1 and 2). There was no obvious palpable mass on physical examination of the breast. Fine-needle aspirations of the mass were performed under ultrasonographic guidance using three passes while maintaining negative pressure. Four smears of aspirated material were prepared; one was air-dried and stained with May–Gruenwald–Giemsa (MGG stain) and three were fixed in 95% ethanol and stained with Papanicolaou stain. For histological analysis, a cell block of the third aspirate was prepared by first fixing it in thin prep solution. After routine tissue processing, it was embedded, cut and stained with hematoxylin–eosin (H&E). A highly cellular smear containing round and branching multilayered clusters of cohesive, small, uniform epithelial cells (Fig. 3), and mucoid globules was obtained (Fig. 4). The cell population was monotonous with small, uniform cells. Nuclei were round to oval and slightly hyperchromatic, with occasional small nucleoli. Cytoplasm in cells was absent or scant and ill-defined. A tendency to lose cell cohesiveness was noticed with a few to moderate number C 2015 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
DIAGNOSIS OF ADENOID CYSTIC CARCINOMA OF THE BREAST
Fig. 1. Ultrasonography showed 12-mm well-defined lobulated hypoechoic and heterogeneous mass. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 3. A highly cellular smear containing round and branching multilayered clusters of cohesive, small, uniform epithelial cells surrounding mucoid globules (Giemsa, x40). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 4. Hyaline globules mimicking collagenous spherulosis (Papanicolaou, x10). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 2. Mammography showed relatively well-defined hyperdense lobulated mass.
of disassociated naked nuclei in the smear background, with a nuclei appearance similar to that of the cells in the groups. There were no free myoepithelial cells. Hematoxylin and eosin-stained sections of cell block preparations from the aspirate showed three-dimensional clusters of uniform ductal cells with a biphasic pattern of tumor cells and both true laminae and pseudocystic spaces. Cell block
material was also evaluated immunohistochemically using the following antibodies: CD117, P63, muscle-specific actin (MSA), estrogen receptor (ER), and progesterone receptor (PR). Details of antibodies and dilutions are shown in Table I. Immunohistochemistry assays were performed on a VENTANA Benchmark XT automated staining instrument according to the manufacturer’s instructions. Immunohistochemical staining showed strong membranous and cytoplasmic immunoreactivity with CD117 (Fig. 5). Basal and myoepithelial cells were positive for p63 (nuclear staining) and MSA (cytoplasmic and membranous staining). ER and PR were negative. Therefore, a cytologic diagnosis of adenoid cystic carcinoma (ACC) was made. The patient underwent wide local excision with sentinel lymph node sampling with frozensection examination. Two sentinal lymph nodes were tumor-free, and no axillary lymph node dissection was performed. The histopathologic examination findings confirmed the cytologic diagnosis (Fig. 6). Diagnostic Cytopathology, Vol. 43, No 9
723
Diagnostic Cytopathology DOI 10.1002/dc
ILKAY ET AL. Table I. Details of Antibodies and Dilutions Antibody Er Pr P63 MSA CD117
Clone
Source
Dilution
EP1 16 I27-I HHF-35 YR145
Gremed Laica Biocare Biocare Cell Marq
1/40 1/50 1/100 1/100 1/200
Fig. 5. Strong cytoplasmic and membranous CD117 immunoreactivity in cell block material (x40). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 6. Histolopathologic specimen shows cribriform architecture with focal basophilic secretion and cylindromatous nodules (H&E, x10). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Discussion ACC of the breast is uncommon, accounting for 0.1% of all breast cancers.1 It has favorable biological characteristics and an excellent prognosis.2,3 The morphological features of ACC are identical to other malignancies that rarely occur in the salivary and lacrimal glands, nasal cavity, lung, trachea, cervix, and Bartholin’s gland.4 Although it is known for its predominance in women, breast ACC may be seen in men.5 Further, although most patients with ACC are usually between 35 and 94 years 724
Diagnostic Cytopathology, Vol. 43, No 9
old, a case of ACC of the breast in a 19-year-old woman was recently reported.6 Patients may present with a slow growing solid mass for months or years without distant spread. Another common feature is intermittent pain and tenderness in the breast mass.3 Mammography and ultrasonography findings vary widely and are not diagnostic. These tumors often appear as a small lobulated nodule with clearly defined margins.7 ACC of the breast has a good prognosis, and early cytologic diagnosis is very important. It should be differentiated from benign conditions, such as collagenous spherulosis (CS), and other malignant conditions, such as invasive cribriform carcinoma.8 CS very often mimics the features of ACC in the breast and demonstrates similar spherical globules admixed with benign ductal epithelial and myoepithelial cells; however, it usually does not form a mass and is limited in extent, involving only a few ducts.9 In contrast to the three-dimensional cell clusters with high nuclearto-cytoplasmic ratios seen in ACC, CS yields cells arranged as two-dimensional sheets with lower nuclearto-cytoplasmic ratios.1,10–12 The naked nuclei of ACC are round and resemble those present in the threedimensional clusters, whereas bipolar naked nuclei are present in CS.13 In addition, CD117 has been reportedly expressed by ACC but not by CS and is considered a helpful marker in the differentiation of these two entities.9,14 In our case, strong membranous and cytoplasmic positivity for CD117 was observed. ACC may be confused with other pathologic conditions of the breast, particularly the cribriform type of invasive ductal carcinoma.15 The presence of extracellular metachromatic globules and second-cell population (myoepihelial) are key cytologic findings helping to exclude cribriform carcinoma.16 In order to make an accurate diagnosis between cribriform carcinoma and ACC, we checked for p63 and MSA positivity on immunohistochemical staining. Besides the lack of expression of ER, PR, and human epidermal growth factor receptor (Her-2/neu), ACCs, in addition, express one or more basal cell markers (e.g., cytokeratins 5, 5/6, 14, and 17).17 Immunhistochemical staining pattern in ACC, CS and invasive cribriform carcinoma was summarized in Table II. ACC offers better prognosis, and therefore, an early diagnosis on the basis of FNAC is significant. Nearly, 35 cases of ACC of the breast have been diagnosed to date by FNAC and reported in the literature (Table III). In earlier reports of ACC of the breast, cytological diagnosis was made and confirmed by histopathological material. There were only two studies in which cell block materials were prepared. Gupta et al. presented their experience with seven cases of ACC of the breast.4 In this study, cell block material was prepared from each aspirate but not stained with immunohistochemical stains. In the study of Szalay et al., immunohistochemical staining for cytokeratin, epithelial
Diagnostic Cytopathology DOI 10.1002/dc
DIAGNOSIS OF ADENOID CYSTIC CARCINOMA OF THE BREAST Table II. Immunohistochemical Different Diagnosis of ACC
CD117 P63 ER/PR
ACC
CS
Invasive cribriform carcinoma
1 (cytoplasmic/membranous) Basal myoepithelial cells (nuclear 1) —
— Basal myoepithelial cells (nuclear 1) 1 (nuclear)
— — 1 (nuclear)
Table III. A Summary of Salient Features in Cases No of cases
CB
IHC
Gupta4 (1999) Sagi25 (2004) Pandya26 (2010) Szalay18 (1996)
7 1 1 1
1(7/7) — — 1
Stanley27 (2006) Culubret13 (1996) Tsuchiya28 (2000) Kuo29 (2008) Okamoto3 (2001) Kasagowa30 (2006) Jain31 (2003) Fargahi32 (2011) Sherigar33 (2006) Wang34 (2012) Lamovec16 (1989) Lee 35 (1991) Malik36 (2007) Cheng37 (2002) Righi38 (2009) Tosun (2014)
6 1 1 1 1 2 1 1 1 1 5 1 1 1 1 1
— — — — — — — —— — — — — — — 1
— — — CK, EMA, col-IV, AML — — — — — — — — — — — — — — — CD117, p63, MSA, ER, PR
References
Cytologic diagnosis
Histological diagnosis
ACC ACC ACC ACC
ACC ACC ACC ACC
ACC SFM SFACC FA SFM ACC ACC ACC SFACC MEDT 2/S, 3/ACC ACC ACC SFAC SFM ACC
ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC ACC
CB: Cell block, IHC: Immunohistochemistry, SFM: Suspicious for malignancy, SFACC: Suspicious for ACC, FA: Fibroadenoma, MEDT: Myoepithelial derived tumor, S: Suspicious feature, SFAC: Suspicious for adenocarcinoma
membrane antigen, collagen IV, and alpha actin smooth muscle was performed on smears and histological sections obtained by excisional biopsy.18 To the best of our knowledge, this is the first case of breast ACC diagnosed on the basis of CD117 immunohistochemical staining of FNAC cell block material. There is no consensus on optimal treatment for patients with ACC of the breast because of the rarity of this condition. It is accepted that local excision as the sole treatment may lead to unacceptably high rates of local recurrence.19 ACC usually presents as a localized disease (stages pT1/2) with a low frequency of axillary lymph node involvement (less than 8%), particularly in tumors smaller than 1.4 cm in diameter.20–23 According to the clinical presentation and overall favorable outcome, most clinicians recommend a breastconserving surgical approach with or without radiotherapy for the treatment of ACC.22,24
Conclusion This case represents the first example of ACC of the breast diagnosed on the basis of CD117 staining on cell block material obtained by FNAC. FNAC is an easy and
quick method for diagnosing breast masses. A cellular smear with uniform, round hyperchromatic cells presenting singly and in loosely cohesive clusters, the absence of myoepithelial cells, and tumor cells surrounding cores and balls of acellular homogeneous material supports the diagnosis of ACC of the breast. It is important to differentiate ACC from CS and other pathologic conditions of the breast. From our experience, we recommend usage of cell block material for immunohistochemical studies to accurately diagnose ACC of the breast.
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