Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Breast Implant-Associated Malignant Lymphoma

  • Laurence de LevalEmail author
  • Dina Milowich
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_4743-1

Synonyms

Definition

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.

Clinical Features

  • Incidence

    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).

  • Age

    The mean age of patients is 50 years.

  • Sex

    All reported cases have occurred in women.

  • Site

    BI-ALCL is by definition a neoplasm arising in the vicinity of a mammary prosthesis.

  • Treatment

    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.

  • 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).

Macroscopy

Most cases present as a periprosthetic effusion (seroma or “in situ” lymphoma) as illustrated in Fig. 1. Figure 1a shows a lymphoid proliferation embedded in fibrinous material at the surface of the periprosthetic capsule; panel 1b shows an area of mild infiltration into the capsule (arrow). Only a minority of cases present as a tumor mass infiltrating into the adjacent breast parenchyma (Fig. 3a), with or without an associated effusion (Clemens et al. 2016). A significant proportion of the patients (around 30%) may present with axillary lymphadenopathy, which is not proven involved by lymphoma in all instances. Lymphomatous involvement of axillary lymph nodes is usually characterized by a low-tumor burden and can feature a sinusoidal, perifollicular, diffuse, or Hodgkin-like pattern, often associated to fibrosis. Lymph node involvement at initial presentation was found to correlate with an inferior overall survival (Ferrufino-Schmidt et al. 2018). Rare cases present with disseminated disease.
Fig. 1

Caspulectomy specimen in a case of BI-ALCL presenting as a seroma, showing a lymphoid proliferation embedded in fibrinous material at the surface of the periprosthetic capsule (A) with mild infiltration into the capsule (B, arrow)

Microscopy

In cases with seroma-associated presentation, tumor cells may be identified in cytological samples from pericapsular effusions or on capsulectomy specimens. The tumor cells are large and pleomorphic, with large nuclei and abundant cytoplasm (Fig. 2). Cells with horseshoe-shaped nuclei and a paranuclear cytoplasmic inclusion (“hallmark cells”) typically encountered in all forms of ALCL are also found in BI-ALCL (Fig. 2, arrows). The neoplastic cells may resemble Hodgkin-like Reed-Sternberg cells. In capsulectomy specimens, the tumor cells are embedded within a proteinaceous and fibrinous meshwork at the surface of the capsule and may show varying degrees of capsular infiltration (Figs. 1b and 2). In the minority of cases characterized by a mass-forming lesion (Fig. 3), the tumor cells infiltrate into the adjacent breast tissue and may be accompanied by a pronounced inflammatory component including prominent eosinophilia; necrosis is frequent and sclerosis is sometimes observed.
Fig. 2

Cytological features of BI-ALCL composed of large pleomorphic cells, including several ≪ hallmark cells ≫, with eccentric horseshoe-shaped nuclei and a prominent paranuclear Golgi region (arrows) (A and B)

Fig. 3

Breast tumorectomy specimen in a case of BI-ALCL presenting as a tumor mass diffusely infiltrating the breast tissue, with focal necrosis (A). Higher power examination shows diffuse cohesive sheets of large pleomorphic lymphoid cells (B)

Immunophenotype

Images A–D on Fig. 4 are from a tumoral BI-ALCL and images E–F from a seroma-associated case. The tumor cells have an immunophenotype similar to that of systemic ALK-negative ALCL: they show strong expression of CD30 with a membrane and paranuclear dot-like pattern of staining (Fig. 4a), incomplete expression of T-cell antigens, and no ALK expression (Fig. 4b). BI-ALCL frequently expresses EMA (Fig. 4c) but is negative for cytokeratins, and features activated cytotoxic immunophenotype (expression of TIA-1, granzyme B (Fig. 4d), and/or perforin (Fig. 4f)). CD45 is expressed in most cases. CD15 is weakly positive in a significant proportion of cases. Regarding T-cell antigens, CD43 is almost constantly expressed, CD4 expression is frequent, and positivity for CD2 and CD3 is more common than for CD5. CD8 expression is unusual, but rare cases may coexpress CD4 and CD8. MUM1 is consistently positive and EBV is consistently negative. Ki67 stains a very high proportion of the nuclei indicating a high proliferation fraction (Fig. 4e).
Fig. 4

Immunohistochemical findings in BI-ALCL: the tumor cells are strongly positive for CD30 with a membrane and paranuclear dot-like pattern (A), negative for ALK (B), positive for EMA (C), and positive for granzyme B indicating an activated cytotoxic profile (D); Ki67 stains a very high proportion of the nuclei indicating a high proliferation fraction (E) and perforin, another marker of activated cytotoxic phenotype, produces fine granular positivity in a subset of the tumor cells (F). Images A-D are from the tumoral BI-ALCL and images E-F from the seroma-associated case

Molecular Features

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).

Differential Diagnosis

  • 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

  1. 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
  2. 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
  3. Letourneau, A., Maerevoet, M., Milowich, D., Dewind, R., Bisig, B., Missiaglia, E., & de Leval, L. (2018, 2018). Dual JAK1 and STAT3 mutations in a breast implant-associated anaplastic large cell lymphoma. Virchow Archiv.  https://doi.org/10.1007/s00428-018-2352-y.CrossRefGoogle Scholar
  4. 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
  5. Rupani, A., et al. (2015). Lymphomas associated with breast implants: A review of the literature. Aesthetic Surgery Journal, 35(5), 533–544.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Institute of Pathology, University Hospital LausanneLausanneSwitzerland