Diagnosis and Discussion - Case 1110

FINAL DIAGNOSIS

Florid lobular carcinoma in situ, nuclear grade 2, with calcifications and focal comedonecrosis.

 

DISCUSSION

Lobular carcinoma in situ (LCIS) is a nonobligate precursor of invasive breast carcinoma with a 7-10-fold increased risk of invasive carcinoma in the ipsilateral and contralateral breasts. Management ranges from active surveillance to excision depending on the histopathologic findings. The latter is especially true in cases of pleomorphic and florid LCIS (FLCIS).

 

Classic LCIS shows distension of more than 50% of the terminal ductal lobular unit acini with non-polarizing, small, bland, and loosely cohesive cells with eccentric nuclei and infrequent intracytoplasmic vacuoles. This contrasts with atypical lobular hyperplasia lesions, where less than 50% of the acini are involved or the acini are not distended relative to other acini in the specimen. On the other hand, in ductal lesions, like atypical ductal hyperplasia and ductal carcinoma in situ, the neoplastic cells are cohesive, devoid of intracytoplasmic vacuoles, and polarize around lumens with occasional comedonecrosis in higher grade lesions.

 

FLCIS is a rare and aggressive variant of LCIS. They have prominent expansile ductal distention with solid pattern of neoplastic cells proliferation. They can mimic ductal carcinoma in situ in histology and radiology. Cases with accompanying necrosis are frequently associated with invasive lobular carcinoma (ILC), which is why they are usually surgically excised.

 

Immunohistochemical staining is helpful in reaching the correct diagnosis, as the management of LCIS differs from ductal carcinoma in situ. ER and PR hormone receptors are positive and Her2/neu is negative. Mucin stains are positive in cells with intracytoplasmic vacuoles. Both benign and cancerous ductal epithelium have normal membranous expression of cell adhesion markers such as E-cadherin and p120 catenin. The internal domain of E-cadherin interacts with p120 and other catenin complex proteins (Figure 1). In the presence of E-cadherin, p120 catenin production is inhibited (negative feedback) and there is a loss of the other catenin complex proteins. The lack of membranous cell adhesion molecules expression and the consequent upregulation of cytoplasmic p120 catenin expression is characteristic of LCIS and ILC, giving rise to their round dyscohesive morphology. It is important to keep in mind that in a minority of cases E-cadherin can still be expressed in the presence of a CDH1 mutation, therefore it is important to assess other catenin complex proteins expression in cases where the morphology is strongly suggestive of a lobular lesion.

 

 

Figure 1. E-cadherin-regulated signaling pathways in breast cancer

 

Luo, G., Huang, D., Tao, R. & Chen, J. (2016). The role of E-cadherin - 160C/A polymorphism in breast cancer. Open Life Sciences, 11(1), 110-115. https://doi.org/10.1515/biol-2016-0015

 

LCIS and ILC have a similar molecular profile. The most common mutation is the biallelic inactivation of the tumor suppressor CDH1 (E-cadherin gene) at 16q22.1. The first CDH1 allele inactivation is mostly due to frameshift mutations leading to a non-functional protein while the second allele inactivation is due to hypermethylation (muting of the gene) or loss of heterozygosity. Patients with germline CDH1 mutation have 40-50% risk of ILC by age of 80, in addition to their increased risk of hereditary diffuse gastric cancer. Other less common recurrent mutations include PIK3CA and CBFB mutations. Aggressive LCIS variants, such as FLCIS, were found to have additional variants, like ERBB2, ERBB3 and CCND1, and have more genetic instability.

 

REFERENCES

  1. Dabbs, D.J., Geyer, F.C. and Reis-Filho, J.S. (2012) “Lobular Carcinoma in situ and atypical lobular hyperplasia,” in Breast pathology. Philadelphia, PA: Elsevier/Saunders, pp. 380–392.
  2. Dupont, W.D. and Page, D.L. (1985) “Risk factors for breast cancer in women with proliferative breast disease,” New England Journal of Medicine, 312(3), pp. 146–151. Available at: https://doi.org/10.1056/nejm198501173120303.
  3. The American Cancer Society medical and editorial content team (no date) Non-cancerous breast conditions - American Cancer Society. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/5034.00.pdf.
  4. Vasef, M.A. and Auerbach, A. (2020) “Lobular carcinoma,” in Molecular oncology. 2nd edn. Amsterdam: Elsevier, pp. 676–679.
  5. Shamir, E.R. et al. (2019) “Pleomorphic and florid lobular carcinoma in situ variants of the breast,” American Journal of Surgical Pathology, 43(3), pp. 399–408. Available at: https://doi.org/10.1097/pas.0000000000001191.
  6. Schnitt, S.J. and Collins, L.C. (2018) Biopsy interpretation of the breast. Philadelphia: Wolters Kluwer.
  7. Foschini, M.P. et al. (2019) “Pre-operative management of pleomorphic and florid lobular carcinoma in situ of the breast: Report of a large multi-institutional series and review of the literature,” European Journal of Surgical Oncology, 45(12), pp. 2279–2286. Available at: https://doi.org/10.1016/j.ejso.2019.07.011.
  8. Singh, K., Sung, C.J. and Quddus, M.R. (2020) “Descriptive study comparing outcomes of classic and nonclassic lobular carcinoma in situ (florid and pleomorphic) initially diagnosed on core needle biopsy,” The Breast Journal, 26(12), pp. 2350–2356. Available at: https://doi.org/10.1111/tbj.14085
  9. Harrison, B.T. et al. (2020) “Genomic profiling of pleomorphic and florid lobular carcinoma in situ reveals highly recurrent ERBB2 and Errb3 alterations,” Modern Pathology, 33(7), pp. 1287–1297. Available at: https://doi.org/10.1038/s41379-020-0459-6.