Breast Implant-Associated Malignant Lymphoma
Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a very rare form of T-cell lymphoma that arises in association with various kinds of breast implants. In the recently revised WHO classification of hematological malignancies, BI-ALCL is introduced as a new provisional disease entity, distinct from the other types of ALCLs already recognized (Oishi 2018). While the morphological and immunophenotypical features of BI-ALCL are indistinguishable from those of systemic ALK-negative ALCL, the specificity of the newly described entity is its clinical presentation in association with and the vicinity of a breast implant.
A nationwide study based on the pathology registry in the Netherlands established that BI are associated with a markedly increased risk (400 times) of developing ALCL, but the absolute risk remains very small, estimated to one case for every 50,000 women with BI by the age of 50 years, one per 12,000 by the age of 70, and one per 7,000 by the age of 75. The mean interval between implant insertion and lymphoma diagnosis is 10–13 years in different studies, but wide variations (1–32 years) are observed. There is no clear-cut association with the type of implant (silicone, saline, textured or not).
The mean age of patients is 50 years.
All reported cases have occurred in women.
BI-ALCL is by definition a neoplasm arising in the vicinity of a mammary prosthesis.
Surgical management with complete surgical resection (total capsulectomy and implant removal) is essential to achieve optimal event-free survival in patients with BI-ALCL. In cases restricted to the seroma cavity, the addition of chemotherapy does not appear to affect outcome.
While most patients have excellent outcome, several studies have highlighted an association between the clinical pattern and disease aggressiveness, i.e., most cases presenting as a seroma appear to be cured with surgery alone and infrequently experience recurrences, while the presence of a solid tumor mass is an adverse prognostic factor. Clemens MW et al. conducted a clinical follow-up study of 87 patients (median follow-up time 45 months): the overall survival rate was 93% at 3 years and 89% at 5 years, respectively. Patients with lymphoma confined to the fibrous periprosthetic capsule had a better outcome than those with lymphoma spread beyond the capsule, and patients who underwent complete surgical excision (total capsulectomy and breast implant removal) had a better overall survival than those who received partial excision, chemotherapy, or radiation therapy only. A detailed longitudinal analysis of patients who died of BI-ALCL showed locoregional dissemination of the disease to the breast, locoregional lymph nodes, chest wall, and mediastinum but no systemic dissemination typical of other lymphomas. It was therefore suggested to use a staging system for BI-ALCL similar in its principles to those applied to solid tumors (Clemens et al. 2016).
T-cell receptor genes are rearranged in most cases.
Limited information is available on the genetic lesions underlying the development and progression of BI-ALCL and its molecular pathogenesis. Conventional cytogenetics and/or sequencing analyses have been reported in a small number of cell lines established from BI-ALCL or from primary lymphoma specimens.
Three IL2-dependent TLBR (T-cell breast lymphoma) cell lines established from seroma-associated BI-ALCL had clonally abnormal complex karyotypes with a modal number of 47 chromosomes in one cell line (TLBR-1) and a hypertriploid pattern in TLBR-2 and TLBR-3. Functional studies on these three cell lines showed evidence of STAT3 activation, while pharmacological inhibition of STAT3 inhibition induced in vitro cell death.
Seven cases of BI-ALCL were successfully analyzed by whole exome or targeted next-generation sequencing using a large panel of 465 cancer-associated genes, and of these only four showed somatic variants (reviewed in Letourneau et al. 2018). The STAT3 S614R variant was detected by whole exome sequencing or targeted sequencing in two cases (including the primary tumor from which TLBR-1 cell line was derived), as the sole abnormality in the latter and in combination with pathogenic mutations in TP53 and SOCS1 in the other case. One somatic variant was detected in the other two cases, affecting JAK1 (G1097 V) or DNMT3A (W176X). In one case of BI-ALCL which presented as a solid tumor mass and recurred as an in situ capsular lesion, dual gain-of-function mutations in JAK1 and STAT3 were identified in both specimens, suggesting pathogenetic mechanisms overlapping with those of systemic ALK-negative ALCLs (Letourneau et al. 2018) However, rearrangements of the IRF4/DUSP22 locus at 6p25 and of TP63 (frequently observed in systemic or primary cutaneous ALCL) have not been found in any of the cases tested so far (Oishi et al. 2018).
Primary breast implant-associated ALCL is cytologically and by immunophenotype indistinguishable from systemic ALK-negative ALCL. Although rarely, systemic ALCL in patients with breast implants may manifest in the breast with a presentation mimicking BI-ALCL. Likewise, primary cutaneous ALCL involving the breast in women harboring breast implants may grow near the breast implant, and in that situation the origin of the neoplasm may be questioned. Staging and clinical history are therefore critical to establish the correct diagnosis.
Other types of lymphomas have been reported to occur in association with breast implants: mycosis fungoides/Sézary syndrome, extranodal NK/T-cell lymphoma, nasal type, and different types of B-cell lymphomas (diffuse large B-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, marginal zone B-cell lymphoma). These lymphomas differ from BI-ALCL both by their morphology and immunophenotype.
Hodgkin lymphoma is an entity with significant overlapping morphological and immunophenotypical features with BI-ALCL. The Hodgkin/Reed-Sternberg cells of Hodgkin lymphoma are typically scarce in a prominent inflammatory background, coexpress CD30 and CD15, and have a B-cell genotype with expression of a markedly attenuated B-cell immunophenotype. They are usually negative for T-cell antigens. Although Hodgkin lymphoma very rarely occurs in extranodal localizations, an exceptional case of Hodgkin lymphoma arising adjacent to a breast implant has been reported in a woman who had a history of follicular lymphoma, and the Hodgkin lymphoma was shown to represent transformation from the preexisting follicular lymphoma.
Chronic inflammatory lesions associated to a breast implant may contain occasional CD30+ activated lymphoid cells and must be distinguished from BI-ALCL.
References and Further Reading
- Clemens, M. W., Medeiros, L. J., Butler, C. E., Hunt, K. K., Fanale, M. A., Horwitz, S., Weisenburger, D. D., Liu, J., Morgan, E. A., Kanagal-Shamanna, R., Parkash, V., Ning, J., Sohani, A. R., Ferry, J. A., Mehta-Shah, N., Dogan, A., Liu, H., Thormann, N., Di Napoli, A., Lade, S., Piccolini, J., Reyes, R., Williams, T., McCarthy, C. M., Hanson, S. E., Nastoupil, L. J., Gaur, R., Oki, Y., Young, K. H., & Miranda, R. N. (2016). Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma. Journal of Clinical Oncology, 34(2), 160–168.CrossRefGoogle Scholar
- Ferrufino-Schmidt, M. C., Medeiros, L. J., Liu, H., Clemens, M. W., Hunt, K. K., Laurent, C., Lofts, J., Amin, M. B., Ming Chai, S., Morine, A., Di Napoli, A., Dogan, A., Parkash, V., Bhagat, G., Tritz, D., Quesada, A. E., Pina-Oviedo, S., Hu, Q., Garcia-Gomez, F. J., Jose Borrero, J., Horna, P., Thakral, B., Narbaitz, M., Hughes, R. C., 3rd, Yang, L. J., Fromm, J. R., Wu, D., Zhang, D., Sohani, A. R., Hunt, J., Vadlamani, I. U., Morgan, E. A., Ferry, J. A., Szigeti, R., C Tardio, J., Granados, R., Dertinger, S., Offner, F. A., Pircher, A., Hosry, J., Young, K. H., & Miranda, R. N. (2018). Clinicopathologic features and prognostic impact of lymph node involvement in patients with breast implant-associated anaplastic large cell lymphoma. The American Journal of Surgical Pathology, 42(3), 203–305.CrossRefGoogle Scholar
- Oishi, N., Brody, G. S., Ketterling, R. P., Viswanatha, D. S., He, R., Dasari, S., Mai, M., Benson, H. K., Sattler, C. A., Boddicker, R. L., McPhail, E. D., Bennani, N. N., Harless, C. A., Singh, K., Clemens, M. W., Medeiros, L. J., Miranda, R. N., & Feldman, A. L. (2018). Genetic subtyping of breast implant-associated anaplastic large cell lymphoma. Blood, 132(5), 544–547.CrossRefGoogle Scholar