Malignant fibroadenoma with CHEK2 mutation: a novel case

      Sir,
      A 34-year-old fit and well lady presented to her general practitioner complaining of a palpable left breast lump at the 12 o'clock region for 2 years. An ultrasound was requested and showed a 23 mm oval, hypoechoic lesion with minor vascularity. The differential diagnoses included a fibroadenoma and a phyllodes tumour.
      She subsequently proceeded to have an ultrasound guided core biopsy which showed a benign fibroepithelial lesion consistent with a fibroadenoma. However, there were features of focal ductal hyperplasia with intracytoplasmic mucin and squamoid differentiation. These features were considered unusual and an excisional biopsy was suggested in view of the findings.
      She was referred to a specialist breast surgeon for follow up. Further clinical history revealed a maternal great grandmother with breast cancer. The patient opted for an excisional biopsy. The histopathology of the excision showed a complex fibroadenoma with areas of low grade ductal carcinoma in situ (DCIS) (Fig. 1A,B) and a focal area of early G2 invasive ductal carcinoma (IDC) (Fig. 1C) of non-special type confirmed with immunohistochemistry (Fig. 2). Hormonal receptors were ER positive, PR positive and HER2 negative. Given that there was early IDC minimally clear of the resection margins, the patient proceeded to have a sentinel lymph node biopsy and re-excision, both of which show no evidence of malignancy. Interestingly, despite the fibroadenoma showing extensive epithelial proliferation with in situ carcinoma and invasive carcinoma, the adjacent breast parenchyma was non-proliferative.
      Fig. 1
      Fig. 1H&E. (A) Benign fibroadenoma on the right transitioning to DCIS (arrow) on the left. (B) Widespread low grade DCIS. (C) DCIS and the invasive component (arrow).
      Fig. 2
      Fig. 2Immunohistochemistry staining with CK5/6 showing loss of myoepithelial cells.
      The case was discussed at the multidisciplinary meeting, which recommended tamoxifen, radiotherapy and genetic testing due to her young age. The genetic testing panel included BRCA1, BRCA2, TP53, STK11, PTEN, CHEK2, PALB2 and ATM genes. The result identified a germline mutation in checkpoint kinase 2 (CHEK2) 1100delC. The patient subsequently opted for bilateral prophylactic mastectomies which were negative for malignancy.
      Fibroadenoma is one of the most common benign breast tumours. The reported incidence of carcinoma arising within a fibroadenoma is rare and ranges from 0.0125% to 0.3% with a peak age range of 42–44 years old which is approximately 20 years later than the peak age of a usual fibroadenoma.
      • Pick P.W.
      • Iossifides I.A.
      Occurrence of breast carcinoma within a fibroadenoma. A Review.
      Malignancies occurring in fibroadenomas are usually carcinoma in situ and very rarely invasive carcinomas.
      • Greenberg R.
      • Skornick Y.
      • Kaplan O.
      Management of breast fibroadenomas.
      It is postulated that carcinoma involving a fibroadenoma may arise from the adjacent breast tissue and infiltrate the fibroadenoma or arise within the fibroadenoma as well as the adjacent breast tissue. The presence of fibroadenoma or even complex fibroadenoma in itself is not considered an independent risk factor for breast cancer.
      • Nassar A.
      • Visscher D.W.
      • Degnim A.C.
      • Frank R.D.
      • Vierkant R.A.
      • Frost M.
      Complex fibroadenoma and breast cancer risk: a mayo clinic benign breast disease cohort study.
      Only a small proportion of fibroadenomas are ever sampled or excised, with the majority of cases followed up conservatively.
      Of the small quantity of cases sampled, the reported rates of preoperative malignancies diagnosed (via cytology or core biopsy) are very rare.
      • Psarianos T.
      • Kench J.G.
      • Ung O.A.
      • Bilous A.M.
      Breast carcinoma in a fibroadenoma: diagnosis by fine needle aspiration cytology.
      ,
      • Yano Y.
      • Ueno E.
      • Kamma H.
      • et al.
      Non-invasive lobular carcinoma within a fibroadenoma, a preoperative diagnosed case.
      This is due to the heterogeneity of the lesion and extensive sampling is necessary because the areas of interest can be very focal.
      Studies have demonstrated that benign breast diseases (BBD) in fibroadenomas do not lead to an increased risk of malignancy when compared to BBD in general breast tissue.
      • Nassar A.
      • Visscher D.W.
      • Degnim A.C.
      • Frank R.D.
      • Vierkant R.A.
      • Frost M.
      Complex fibroadenoma and breast cancer risk: a mayo clinic benign breast disease cohort study.
      To date no known histological features on core biopsies have been shown to be associated with increased risk of malignancy in fibroadenomas.
      Reported clinico-radiological risk factors warranting an excision biopsy in fibroadenomas include symptomatic lesions, newly appearing or enlarging mass, immobile or poorly circumscribed mass, presence of microcalcifications, age >35 years, size >2.5 cm and atypical biopsy features.
      • Hubbard J.L.
      • Cagle K.
      • Davis J.W.
      • Kaups K.L.
      • Kodama M.
      Criteria for excision of suspected fibroadenomas of the breast.
      ,
      • Baker K.S.
      • Monsees B.S.
      • Diaz N.M.
      • Destouet J.M.
      • McDivitt R.W.
      Carcinoma within fibroadenomas: mammographic features.
      Our case showed BBD on the core biopsy and there was family history of breast cancer two generations prior. Nevertheless, no studies have shown an association between family history of breast cancer and fibroadenoma with malignancy.
      The rarity of the lesion precludes systematic assessment and hence there are no management guidelines established. Most authors agree that fibroadenomas with carcinoma behave like breast cancer of the same stage and should be managed similarly. However, the prognosis is reported to be more favourable than conventional types of breast carcinoma, which raises the question on the need for radiation therapy in completely excised lesions.
      • Abe H.
      • Hanasawa K.
      • Naitoh H.
      • Endo Y.
      • Tani T.
      • Kushima R.
      Invasive ductal carcinoma within a fibroadenoma of the breast.
      In recent times, molecular studies have assisted in the understanding of familial breast cancer arising in non-BRCA1/BRCA2 patients. One of the genes that have been implicated is the CHEK2 gene. The significance of changes in the CHEK2 gene is not well understood. Based on current information, it is indicated that the gene is a risk modifier for developing breast cancer.
      Studies have shown that individuals with a CHEK2 gene fault have increased risk (20–25%) for developing breast cancer in general and cases with a previous diagnosis have an even greater risk (30–40%) to represent with further breast cancer in their lifetime.
      • Schmidt M.K.
      • Hogervorst F.
      • van Hien R.
      • et al.
      Age- and tumor subtype-specific breast cancer risk estimates for CHEK2∗1100delC carriers.
      ,
      • Cybulski C.
      • Wokołorczyk D.
      • Jakubowska A.
      • et al.
      Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.
      This increase in cancer risk is also dependent on personal and family history. Other studies have suggested that CHEK2 carriers also show an increased risk of cancer in the colon, prostate, thyroid and ovary.
      • Apostolou P.
      • Papasotiriou I.
      Current perspectives on CHEK2 mutations in breast cancer.
      CHEK2 is a tumour suppressor gene that encodes for serine/threonine kinase and plays a major role in the regulation of the cell cycle, apoptosis and DNA repair. Early studies suggest CHEK2 may have prognostic implications, showing that the use of chemotherapy in combination with CHEK2 inhibitors has beneficial effects by sensitising tumour cells to the drugs.
      • Cybulski C.
      • Lubiński J.
      • Wokołorczyk D.
      • et al.
      Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.
      One study has shown that there is significantly increased frequency of germline mutations in DCIS under the age of 40. These findings are consistent with our patient's demographics, and similarly in line with the reported peak age of fibroadenoma with malignancy in the literature.
      None of the cases of fibroadenoma with malignancy reported in the literature mention molecular findings. It is unknown how many of these cases are associated with germline mutations. Further studies are required to assess this subgroup of patients.
      To the authors' knowledge, we report the first case of CHEK2 mutation present in a fibroadenoma with in situ and invasive malignancy. This case illustrates the importance of molecular testing in unusual breast cancers. The identification of germline mutations such as CHEK2 has current and future merit in management and prognostic implications involving the patient and family members.

      Conflicts of interest and sources of funding

      The authors state that there are no conflicts of interest to disclose.

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