Study of breast cancer incidence in patients of lymphangioleiomyomatosis

Abstract

Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000-2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) ≥ 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32-5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29-9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM.

Keywords: Breast cancer; Incidence; Lymphangioleiomyomatosis; TSC1; TSC2; mTOR.

Fig. 1

Histopathological and immunohistochemical characterization of breast tumors in two LAM patients. a Hematoxylin-eosin (HE) and p63 (patient #1 only) staining results from the corresponding tumors in LAM patients. Arrows mark magnified fields shown in the insets. Three panels are shown for patient #2, which correspond to (i) invasive, (ii) in situ, and (iii) desmoplastic histologies. The p63 marker was used as evidence of a metaplastic carcinoma. b Immunostaining results for ERα and PR in the corresponding breast tumors. Red arrows mark magnified fields shown in the insets and black arrows mark positive cells with a spindle-like phenotype

Fig. 2

Positivity for mTORC1 signaling and metastatic markers in breast tumors of LAM patients. a Results of phospho-Ser235/236-ribosomal protein S6 (pS6) staining in two available breast tumors. Heterogeneity (i.e., positive and negative tumor cells in case #1) and positive cells with a spindle phenotype (case #2, right panels, depicted in insets) can be observed (arrows mark magnified regions). b Results of the analysis of the metastatic markers (FSCN1, ID1, and SOX9) in both cases. Heterogeneity (particularly in case #1) and spindle-like phenotypes (particularly in case #2) can be observed (arrows mark magnified regions)