Case 12 -

Adenoid Cystic Carcinoma of Breast, Solid/Basaloid Subtype Dr. Christopher Elston

Clinical History A female aged 73 years was referred to the Breast Clinic with a three-week history of a lump in the right breast. Clinical examination and mammography revealed a mass lesion, suspicious of malignancy in the upper inner quadrant. Following needle core biopsy a right mastectomy and axillary dissection were carried out. The section is from the lesion. Case 12 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Macroscopic appearances A simple mastectomy specimen weighing 866 gm. In the upper inner quadrant 35 mm from the nipple there is a moderately defined firm mass lesion measuring 13 mm in maximum diameter. Microscopic appearances The section, which is representative of the whole lesion, shows a well-circumscribed tumour composed of islands of dark staining ovoid to spindle shaped epithelial cells with little cytoplasm. The islands are surrounded by a thin eosinophilic membrane. Occasional glandular lumina containing eosinophilic secretions are present but the epithelial structures are mainly solid. There is moderate nuclear pleomorphism but mitotic figures are scanty. No in situ component is seen. Focal areas of fibrosis are noted centrally. Vascular invasion is absent. Differential diagnosis The two distinguishing histological features of this tumour are the 'basaloid' appearance of the epithelial cells and the presence of a stromal eosinophilic membrane around tumour cell islands. This morphological pattern is similar to that seen in the solid type of adenoid cystic tumours (ACC) of salivary gland but must also be distinguished from small cell carcinoma, primary or metastatic and ductal carcinoma of no special type (ductal/NST). The presence of cystic spaces raises the possibility of invasive cribriform carcinoma but the typical 'punched-out' glandular pattern is lacking. Whilst these distinctions are difficult to make with certainty on the morphological appearances alone the correct diagnosis may be achieved with ease by means of immunohistology. In ACC the eosinophilic membrane is composed of basement lamina and this can be confirmed by immunostaining with laminin and collagen 1V which also decorate secretions in pseudo-cystic spaces; this feature is lacking in ductal/NST and small cell carcinomas. The tumour cells are uniformly positive with cytokeratins (eg, MNF 116, AE1/AE3 and CK7); they are usually of two types, basaloid and luminal which can be demonstrated by positive immunoreactivity with CK 14, CK5/6 and E-cadherin respectively. Assessment of hormone receptor status may also be helpful; oestrogen receptor (ER) and progesterone receptor (PR) are virtually always absent in ACC compared with 80% positivity in other epithelial breast tumours. It has recently been suggested that c-kit, a transmembrane tyrosine kinase receptor protein (cd117) is positive in most cases of ACC of salivary glands and that the same pattern is also present in over 90% of cases in the breast. P63, a gene involved in embryonal development and cell differentiation and which is expressed in the basal and myoepithelial components of breast epithelium is also expressed in a high percentage of breast ACC (>80%). In contrast, c-kit and p63 are negative in most other breast carcinomas although p63 may be expressed in the 'basal' subtype of ductal/NST carcinomas. In view of this a panel of immunohistochemical markers was applied to the present case; the results are shown in Table 1 below. Table 1. Pattern of Immunoreactivity. Antibody Result Laminin + Collagen IV + CK 5/6 focally + CK 14 focally + CK 7 + c-kit focally + p63 + Smooth muscle myosin (SMM) basal cells + Smooth muscle actin (SMA) basal cells + E-cadherin + HER 2 - ER - PR - These immunostaining characteristics are confirmatory of the histological diagnosis of adenoid cystic carcinoma (ACC) of the breast, solid/basaloid subtype. Discussion Adenoid cystic carcinoma is a rare special type, accounting for 0.1 – 1% of all malignant epithelial tumours of the breast. Morphologically this subset of breast carcinoma is indistinguishable from ACC arising in other sites, particularly salivary gland. The constituent neoplastic cells are of two types, luminal and basal/myoepithelial, arranged in a wide spectrum of histological patterns, all of which may be present in the same tumour. Three basic morphological subtypes are recognised, tubular-trabecular, cribriform and solid. The relative proportions of each pattern have been used in salivary ACC to produce a grading system and this can also be applied to the breast, as follows: Grade I – glandular/cystic, no solid areas Grade II – glandular/cystic with solid areas constituting <30% Grade III – solid component >30% of the mass As shown above, immunohistochemistry is helpful in confirming the diagnosis of ACC. The basal cells are positive for CK5/6, CK14 and, usually focally, for myoepithelial markers such as SMM, SMA, calponin and p63, although the latter, perhaps surprisingly, may be negative in basaloid cases. The luminal cells are usually positive for CK7. C-kit has emerged as the most useful antibody, being positive in over 90% of cases, although interestingly the exceptions seem to be of the solid/basaloid subtype, which was not the case here. The polarity of the different cell types may also be demonstrated by immunostaining; basaloid cells usually express laminin, fibronectin and collagen IV, whereas luminal cells express proteins related to cell polarisation and epithelial differentiation such as E-cadherin and B-catenin. Overall ACC of the breast carries an excellent prognosis with a low rate of axillary node involvement (<10%). Local recurrence is uncommon and probably related to inadequate resection. Only rare examples of distant metastasis have been recorded and long-term survival is close to 100%. It has been suggested that the solid subtype (grade III), especially the basaloid variant, is more aggressive with a greater propensity to develop lymph node and distant metastasis but the number of cases reported is very small. A search of the recent world literature found a total of 15 cases of solid/basaloid ACC with appropriate follow-up. Axillary node metastases were found in six (40%, one micrometastatic) and distant metastases in two (13%). There was only one death (7%). These data should be interpreted with care (some are based on single case reports) and need confirmation from larger studies, but they do indicate that the solid/basaloid may be more likely to develop lymph node metastases and have a slightly worse prognosis than the tubular/trabecular and cribriform sub-types. Nevertheless, it is worth emphasising that the reported long-term survival for this type is still in excess of 90%. Follow up The tumour was shown to have the following histopathological characteristics: Tumour size – 13 mm Type – adenoid cystic carcinoma Grade – 2 Lymph node stage – 1 (0/8) Vascular invasion – none Nottingham Prognostic (NPI) – 3.26 (Good Prognostic Group [GPG], 92% 10- year survival chance) The NPI was based on data from common types of invasive breast carcinoma rather than rare subtypes such as adenoid cystic carcinoma and the predicted long-term survival for the GPG of 92% is a slight underestimate for ACC overall; as noted above the true figure is close to 100%. However, this figure may not be inappropriate for the solid sub-type. The patient was not given adjuvant systemic therapy for her breast tumour. However, a complication in the present case was the finding of follicular lymphoma in axillary lymph nodes. Further investigation revealed bone marrow and splenic involvement by lymphoma – stage IV disease. She was therefore treated with chlorambucil, nizatidine and prednisolone for her lymphoma. She remains well and tumour free after four years follow-up. Final diagnosis Adenoid cystic carcinoma of breast, solid/basaloid subtype References Crisi GM, Marconi SA, Makari-Judson G, Goulart RA. Expression of c-kit in adenoid cystic carcinoma of the breast. Amer J Clin Pathol 2005; 124: 733-739. Fukuoka K, Hirokawa M, Shimizu M et al. Basaloid type adenoid cystic carcinoma of the breast. APMIS 1999; 107: 762-766. Mastropasqua MG, Maiorano E, Pruneri G 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: 1277-1282. Pia-Foschini M, Reis-Filho JS, Lakhani SR. Salivary gland-like tumours of the breast: surgical and molecular pathology. J Clin Pathol 2003; 56: 497-506. Ro JY, Silva EG, Gallager HS. Adenoid cystic carcinoma of the breast. Hum Pathol 1987; 18: 1276-1281. Shin SJ, Rosen PP. Solid variant of mammary adenoid cystic carcinoma with basaloid features. Amer J Surg Pathol