—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 2 - Solid Variant of Adenoid Cystic Carcinoma with Basaloid Features

Laura C. Collins
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston MA





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Clinical History
  • A 43 year old female presented with a 2.5 cm right breast mass

  • Overlying skin dimpling was present

  • On imaging the lesion appeared as a well circumscribed, lobulated mass

  • Due to the superficial location of the lesion an excisional biopsy was performed



Case 2 - Figure 1
Low power view of several irregular nests of tumor cells embedded in a fibrotic stroma.
Case 2 - Figure 2
Higher power view showing a solid nest of basaloid appearing cells characterized by large cells with round to oval, hyperchromatic nuclei with scant eosinophilic cytoplasm. Nucleoli are inconspicuous.
Case 2 - Figure 3
High power view showing a cribriform area. On high power the basaloid cells show moderate to marked nuclei atypia. Around some of the lumens the cells appear to have more abundant eosinophilic cytoplasm and normochromatic nuclei. Other lumens contain homogeneous, eosinophilic material.

Case 2 - Figure 4
Low power view showing another area of the tumor which has the appearance, at this power, of having fibrotic material within the solid tumor cell nests.
Case 2 - Figure 5
CK 5/6

Microscopic findings
Low power images of this tumor show solid, irregular nests of basaloid tumor cells infiltrating through a fibrotic stroma. On higher power, the basaloid morphology of the tumor cells is better appreciated. These cells have moderate to marked nuclear atypia and scant cytoplasm. In some of the nests, areas of cribriforming architecture are appreciated. Around some of the lumens ("true lumens") in the cribriform areas, cells with a more epithelial appearance are noted. These cells have more abundant eosinophilic cytoplasm and the nuclei are less hyperchromatic than those in the basaloid cells. Other lumens contain homogeneous, eosinophilic material consistent with basement membrane material.

Immunostains for estrogen and progesterone receptor (ER and PR) were negative. HER2 was not overexpressed in this case. Neuroendocrine markers were performed and were negative. This case showed focal expression with cytokeratin (CK) 5/6.

Differential Diagnosis
Differential diagnostic considerations include:
  • Infiltrating ductal carcinoma NOS This could be an NOS infiltrating ductal carcinoma except for the very basaloid appearance of the tumor cells and the foci that have abundant eosinophilic material within the tumor cell nests. These features should prompt further exploration into whether this might represent a "special type" carcinoma

  • IDC with neuroendocrine/endocrine features At first glance, the solid nested pattern and appearance of the tumor cells may raise the possibility of neuroendocrine carcinoma. But high power examination will reveal the marked nuclei atypia and hyperchromasia. As well the presence of amorphous material in some of the tumor cell nests does not fit with infiltrating carcinoma with neuroendocrine features. The neuroendocrine markers were negative.

  • Solid papillary carcinoma These tumors are composed of single or multiple circumscribed nodules of neoplastic cells with a solid growth pattern. Often difficult to appreciate is the delicate to hyalinized fibrovascular stromal network. Endocrine differentiation is common as is intra- and extra-cellular mucin production [1]. These latter features are not apparent in our case. These tumors are frequently associated with mucinous carcinoma and IDC

  • Small cell carcinoma This tumor has the same morphology as small cell carcinoma at other locations. It may have either a solid nested growth pattern or a more infiltrative pattern. Typically molding, crush artifact and nuclear streaming would be seen [2]. These latter features are not present in the current case.

  • Basal-like carcinoma Strictly speaking basal-like carcinomas are a class of tumor defined through gene expression profiling. Histologic and immunophenotypic correlation of this class of tumors has demonstrated that many are high grade tumors with a brisk mitotic rate; have a solid growth pattern with pushing tumor margins and large zones of geographic necrosis or a central fibrotic focus. These tumors have a triple negative immunophenotype and expression of basal cytokeratins and/or epidermal growth factor receptor (EGFR). In many respects, this case may fit with this description; however, it does not have the very brisk mitotic rate nor the "typical" morphology of a basal-like carcinoma.

  • Solid variant of adenoid cystic carcinoma with basaloid features This is a rare tumor. It most often is a lobulated, unicentric mass and it has a >90% solid growth pattern. The tumor cells have "basaloid" features (as described above). Ductules (or "true" lumens) may be appreciated within the solid tumor cell nests. These ductules are surrounded by larger cells with more eosinophilic cytoplasm. Additionally, cyst-like spaces ("pseudo" lumens) containing homogenous eosinophilic (basement membrane-like) material can usually be identified [3].

Diagnosis:
Solid variant of adenoid cystic carcinoma with basaloid features

Adenoid Cystic Carcinoma
Adenoid cystic carcinomas (ACC) are uncommon tumors, representing only ~0.1% of all breast carcinomas [1]. The reported age at presentation is broad age. ACC presents equally in both breasts with approximately 50% located in the sub-periareolar region [4]. ACC often presents as a discrete nodule, which may be painful. Occasionally overlying skin dimpling may occur. On imaging, ACC is usually a solid mass, with a lobulated appearance [4].

Histopathology
ACC of the breast show the distinctive biphasic pattern of these tumors in other locations. True lumens are lined by epithelial cells that may have varying degrees of glandular, sebaceous and squamous differentiation. These areas of glandular differentiation are thought to represent intercalated ducts and may be subtle. More readily recognizable are the "pseudolumens" which are lined by basaloid (myoepithelial) cells and contain acellular, eosinophilic basement membrane material.

Immunophenotype
ACC of the breast are typically estrogen and progesterone receptor negative and do not show overexpression or amplification of HER2 [5]. These tumors are also c-kit and p63 positive [6, 7, 8]. Cytokeratin (CK) 7 is useful as this antibody highlights the intercalated ducts which may not be readily discernible in the solid variant of ACC.

Grading and Prognosis
Three architectural patterns have been described: cribriform, trabecular-tubular and solid [4]. Some reports have suggested that clinical course is correlated with growth pattern and that tumors with a solid growth pattern exhibit a more aggressive clinical course [9]. This observation has led to the classification of ACC according to the proportion of solid growth (I, no solid growth; II, <30% solid growth; III, >30% solid growth). Tumors with a solid growth pattern have been shown to be larger at presentation and have a greater propensity for local recurrence as well as axillary lymph node metastases [3, 9]. Others have shown no correlation between clinical behavior and tumor grade [10]. Overall, ACC of the breast have a very favorable prognosis with a low rate of axillary lymph node metastasis [9, 10, 11].

Differential Diagnosis of ACC
The differential diagnosis of ACC includes other lesions with a cribriform pattern such as invasive cribriform carcinoma and DCIS. Collagenous spherulosis may also be a differential diagnostic consideration.

Invasive cribriform carcinoma is composed of a single population of malignant epithelial cells. Myoepithelial cells and basement membrane material are absent.

Cribriform DCIS is similarly composed of a single population of malignant epithelial cells, but the tumor cell nests are bounded by a layer of myoepithelial cells. Basement membrane material is absent from the lumens within the cribriform nests.

Collagenous spherulosis is a benign lesion that is frequently found in association with other benign proliferative processes. Like ACC, collagenous spherulosis has a population of myoepithelial cells producing basement membrane material deposited in lumens within the lesion. However, unlike ACC, collagenous spherulosis does not exhibit an invasive growth pattern; it is generally very limited in extent and is usually an incidental finding in a biopsy performed for another reason.

Associated Lesions
Of interest, a number of lesions have been reported in association with ACC or even in transition to ACC. Microglandular adenosis (MGA) is the lesion most often reported in this scenario [12, 13, 14]. Reports have described foci of MGA to be intermingled with ACC. In some cases, the MGA shows a spectrum of changes through atypical MGA and transitioning to ACC. Others have reported ACC in association with tubular adenoma and adenomyoepithelioma. Whether any of these entities represents a precursor lesion (or ACC in situ) is still a matter of debate.

Molecular Pathology
There is very little data on the genetic alterations found in ACC of the breast. One case report found low levels of genetic instability with small deletions on 16p and 17q (in the region of the BRCA1 gene) [15]. The authors speculate whether these findings may suggest a role for additional epigenetic mechanisms or whether the 17q loss may explain the "basal" features of these tumors [15].

With respect to the issue of whether ACC are "basal-like" carcinomas, a recent study evaluating the gene expression profiles of a variety of special-type carcinomas found ACC to localize with tumors of the "basal-like" subtype [16]. The immunophenotype (ER, PR and HER2 negative and basal cytokeratin and c-kit positive) also supports the notion that these tumors belong to the basal-like carcinoma group [6]. However, in contradistinction to most invasive ductal carcinomas in among this subtype, ACC has a very favorable prognosis.

Treatment
Treatment varies with each case. Many smaller well-demarcated lesions can be satisfactorily treated with wide excision alone. Radiation therapy is often given as an adjunct though the benefit of this modality for ACC is unknown. Axillary lymph node dissection is not indicated unless there is clinical evidence of lymph node involvement [10, 11]. Sentinel lymph node sampling is recommended for high grade ACC or for tumors in which there is a component of a second type of invasive carcinoma [3]. Systemic therapy is given for patients with lymph node metastasis [3].

Conclusions
In summary, solid variant of adenoid cystic carcinoma with basaloid features is an unusual tumor composed of solid nests of basaloid appearing cells with moderate to marked nuclear atypia, rare intercalated ducts and deposition of basement membrane material [3].

Key Points
  • Recognition of solid ACC as special type of carcinoma with a more favorable prognosis

  • Identification of pseudolumens with basement membrane material as well as true glandular lumens will aid in diagnosis

  • C-Kit and CK7 may be helpful adjuncts to diagnosis

Key Words
Breast, carcinoma, adenoid cystic carcinoma, basal-like

References
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  2. Shin SJ, DeLellis RA, Ying L, Rosen PP. Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol 2000;24(9):1231-8.

  3. Shin SJ, Rosen PP. Solid variant of mammary adenoid cystic carcinoma with basaloid features: a study of nine cases. Am J Surg Pathol 2002;26(4):413-20.

  4. Rosen PP. Breast Pathology. Lippincott Williams & Wilkins 2009.

  5. Trendell-Smith NJ, Peston D, Shousha S. Adenoid cystic carcinoma of the breast: a tumour commonly devoid of oestrogen receptors and related proteins. Histopathology 1999;35(3):241-8.

  6. Azoulay S, Lae M, Freneaux P, Merle S, Al Ghuzlan A, Chnecker C, et al. KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. Mod Pathol 2005;18(12):1623-31.

  7. Mastropasqua MG, Maiorano E, Pruneri G, Orvieto E, Mazzarol G, Vento AR, et al. Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. Mod Pathol 2005;18(10):1277-82.

  8. Crisi GM, Marconi SA, Makari-Judson G, Goulart RA. Expression of c-kit in adenoid cystic carcinoma of the breast. Am J Clin Pathol 2005;124(5):733-9.

  9. Ro JY, Silva EG, Gallager HS. Adenoid cystic carcinoma of the breast. Hum Pathol 1987;18(12):1276-81.

  10. Kleer CG, Oberman HA. Adenoid cystic carcinoma of the breast: value of histologic grading and proliferative activity. Am J Surg Pathol 1998;22(5):569-75.

  11. Arpino G, Clark GM, Mohsin S, Bardou VJ, Elledge RM. Adenoid cystic carcinoma of the breast: molecular markers, treatment, and clinical outcome. Cancer 2002;94(8):2119-27.

  12. Khalifeh IM, Albarracin C, Diaz LK, Symmans FW, Edgerton ME, Hwang RF, et al. Clinical, Histopathologic, and Immunohistochemical Features of Microglandular Adenosis and Transition Into In Situ and Invasive Carcinoma. Am J Surg Pathol 2008.

  13. Acs G, Simpson JF, Bleiweiss IJ, Hugh J, Reynolds C, Olson S, et al. Microglandular adenosis with transition into adenoid cystic carcinoma of the breast. Am J Surg Pathol 2003;27(8):1052-60.

  14. Albores-Saavedra J, Heard SC, McLaren B, Kamino H, Witkiewicz AK. Cylindroma (dermal analog tumor) of the breast: a comparison with cylindroma of the skin and adenoid cystic carcinoma of the breast. Am J Clin Pathol 2005;123(6):866-73.

  15. Da Silva L, Buck L, Simpson PT, Reid L, McCallum N, Madigan BJ, et al. Molecular and morphological analysis of adenoid cystic carcinoma of the breast with synchronous tubular adenosis. Virchows Arch 2009;454(1):107-14.

  16. Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, et al. Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol 2008;216(2):141-50.