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Non-mammary implant associated anaplastic large cell lymphoma

2020; Elsevier BV; Volume: 53; Issue: 2 Linguagem: Inglês

10.1016/j.pathol.2020.06.022

1465-3931

Mayur Parkhi, Charanpreet Singh, Pankaj Malhotra, Amanjit Bal,

Cancer Diagnosis and Treatment

Anaplastic large cell lymphoma (ALCL) constitutes less than 3% of all non-Hodgkin lymphomas (NHL).1Kim B. Roth C. Chung K.C. et al.Anaplastic large cell lymphoma and breast implants: a systematic review.Plast Reconstr Surg. 2011; 127: 2141-2150Crossref PubMed Scopus (133) Google Scholar Implant associated ALCL was first reported by Keech and Creech2Keech Jr., J.A. Creech B.J. Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant.Plast Reconstr Surg. 1997; 100: 554-555Crossref PubMed Google Scholar in 1997 in a patient with a breast implant. In the last two decades, several case reports and small case series of breast implant associated ALCL (BIA-ALCL) have been reported in the literature and this is now a provisional entity in the current World Health Organization (WHO 2017) classification of hematolymphoid neoplasms.3Swerdlow S.H. Campo E. Harris N.L. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. IARC Press, Lyon2017Google Scholar The currently estimated incidence of BIA-ALCL in the United States is 33 per one million persons with textured breast implants.4Doren E.L. Miranda R.N. Selber J.C. et al.Epidemiology of breast implant-associated anaplastic large cell lymphoma.Plast Reconstr Surg. 2017; 139: 1042-1050Crossref PubMed Scopus (187) Google Scholar The textured implants are associated with a higher risk of disease development as compared to saline implants.5Collett D.J. Rakhorst H. Lennox P. et al.Current risk estimates of breast implant-associated anaplastic large cell lymphoma in textured breast implants.Plast Reconstr Surg. 2019; 143: 30S-40SCrossref PubMed Scopus (97) Google Scholar In 2010, Palraj et al.6Palraj B. Paturi A. Stone R.G. et al.Soft tissue anaplastic large T-cell lymphoma associated with a metallic orthopedic implant: case report and review of the current literature.J Foot Ankle Surg. 2010; 49: 561-564Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar reported ALCL in association with a stainless steel implant for complex right tibia fracture, and recently Mendes et al.7Mendes Jr., J. Mendes Maykeh V.A. Frascino L.F. et al.Gluteal implant-associated anaplastic large cell lymphoma.Plast Reconstr Surg. 2019; 144: 610-613Crossref PubMed Scopus (15) Google Scholar documented ALCL following augmentation gluteoplasty by silicone implant. In the literature, only two cases of non-mammary implant associated extranodal ALCL have been reported. We present a case of a male with a history of oral cavity squamous cell carcinoma for which he underwent marginal mandibulectomy and device implantation (titanium; smooth surface) and developed ALCL 4 years later. To the best of our knowledge, this is the second case of non-silicone prostheses associated ALCL and the third case of implant associated ALCL at the non-mammary site. A 63-year-old man, with well controlled diabetes and hypertension, had a non-healing ulcer over the left buccal mucosa in 2016. On oral examination an ulcero-proliferative growth measuring 3×3 cm was seen in the left buccal mucosa involving the retromolar trigone posteriorly and reaching the gingiva buccal sulcus (cT3N0M0). No cervical lymphadenopathy was noted. The mucosal biopsy revealed squamous cell carcinoma, well differentiated (Fig. 1A). Contrast enhanced computed tomography (CT) scan showed the involvement of buccinator muscle by growth, however there was no evidence of erosion of the underlying mandible or maxilla. The patient underwent wide local excision of the left buccal mucosa with marginal mandibulectomy, upper alveolectomy, left submandibular gland excision, and left modified neck dissection type III. This was followed by free artery-based forearm flap and split thickness skin graft (STSG) for secondary defects. The next day of surgery, a six-hole titanium plate and a six-screw implant was performed as a result of surgical site clot formation (Fig. 1B and C). On pathology examination of the specimen, the depth of invasion was 1 cm (pT2NoMx) and all resected margins and the cervical lymph nodes were free of tumour. He received 30 cycles (60 Gy) of local radiotherapy over the course of one month. Three years later, he developed jaw pain and his metallic implant became exposed in the oral cavity. Magnetic resonance imaging (MRI) was performed with suspicion of recurrence or osteonecrosis and revealed an ill-defined soft tissue mass with mild contrast enhancement at the post-operative site. On further follow-up, the exposed implant was removed by surgery. At this time, the surgeon felt a nodule measuring 1.5×1.0 cm in the upper part of the left cheek along with skin mobilization (Fig. 1D). Excision biopsy of the nodule was carried out. The wide local excision specimen was skin covered and measured 2.0×1.5×1.0 cm. The attached skin was relatively unremarkable. The cut surface revealed an ill-defined grey-white lesion measuring 1.5×1.0×0.6 cm that was firm in consistency and located within the dermis and subcutis but not invading the epidermis. Microscopically, the lesion was composed of predominantly large atypical cells in a dyscohesive growth pattern forming vague nodules in the dermis and subcutis. Tumour cells had large irregular nuclei with prominent nucleoli. The characteristic hallmark cells were also present showing kidney-shaped nuclei and brisk mitosis (Fig. 2A). The background showed mild fibrosis, and chronic inflammation. On immunohistochemistry, leukocyte common antigen (LCA) showed membranous positivity. CD3 and CD20 immunostains were negative but the background reactive T-cells were highlighted by CD3 (Fig. 2C). CD30 showed diffuse strong and uniform immunoreactivity in the large cells in the form of membranous and golgi complex, however ALK immunostain was negative (Fig. 2B,D). MUM1 depicted strong, diffuse, nuclear immunostaining (Fig. 2E). CD38, CD138, S100p, HMB45, pan-cytokeratin and synaptophysin, were all negative. In addition, p63 immunostain showed diffuse nuclear positivity (>90%) in these large cells (Fig. 2F). In situ hybridization for Epstein–Barr virus was negative. Fluorescence in situ hybridization (FISH) did not reveal DUSP22 rearrangement (Fig. 2G). On histopathology, the case was diagnosed as ALCL, ALK-negative with TP63 expression. The probable cause could be non-silicon (titanium) implant associated. The patient has undergone three cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) to date and interim disease assessment is pending. There are only a few cases of lymphoma reported in association with metallic prostheses or osteosynthetic materials, consisting mainly of large B-cell lymphomas and only one case of large T-cell lymphoma, i.e., ALCL.6Palraj B. Paturi A. Stone R.G. et al.Soft tissue anaplastic large T-cell lymphoma associated with a metallic orthopedic implant: case report and review of the current literature.J Foot Ankle Surg. 2010; 49: 561-564Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,8Sanchez-Gonzalez B. Garcia M. Montserrat F. et al.Diffuse large B-cell lymphoma associated with chronic inflammation in metallic implant.J Clin Oncol. 2013; 31: e148-e151Crossref PubMed Scopus (28) Google Scholar The exact pathogenesis behind this association is not yet understood, especially those occurring at non-mammary sites. Presently, orthopaedic implants are typically composed of titanium or cobalt-chromium alloys, stainless steel, titanium, or tantalum, with or without a polyethylene articulating surface.9Kellogg B.C. Hiro M.E. Payne W.G. Implant-associated anaplastic large cell lymphoma: beyond breast prostheses.Ann Plast Surg. 2014; 73: 461-464Crossref PubMed Scopus (19) Google Scholar The index case had undergone titanium implant placement in the mandibular region following surgery for oral squamous cell carcinoma. Non-mammary implant associated ALCL was not documented within the literature until Palraj et al.6Palraj B. Paturi A. Stone R.G. et al.Soft tissue anaplastic large T-cell lymphoma associated with a metallic orthopedic implant: case report and review of the current literature.J Foot Ankle Surg. 2010; 49: 561-564Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar reported the first case in 2010. They described a case of primary extranodal ALCL developing in the setting of joint prosthesis where the immunocompetent elderly patient underwent implantation of stainless steel plate for open reduction internal fixation (ORIF) of a complex tibia fracture and developed ALCL 7 years later at the site of implant. Kellogg et al.9Kellogg B.C. Hiro M.E. Payne W.G. Implant-associated anaplastic large cell lymphoma: beyond breast prostheses.Ann Plast Surg. 2014; 73: 461-464Crossref PubMed Scopus (19) Google Scholar looked retrospectively through the literature and gathered data on association of non-Hodgkin lymphoma or ALCL with mammary and non-mammary (heart valve prostheses, blood vessel prostheses, orthopedic fixation devices, arthroplasty, artificial pacemakers, and indwelling catheters) implants. Their focus was on non-mammary implants showing association with non-Hodgkin lymphoma. On thorough search they found only one case of non-mammary implant associated ALCL which was reported by Palraj et al. as mentioned above. Mendes et al.7Mendes Jr., J. Mendes Maykeh V.A. Frascino L.F. et al.Gluteal implant-associated anaplastic large cell lymphoma.Plast Reconstr Surg. 2019; 144: 610-613Crossref PubMed Scopus (15) Google Scholar described another non-mammary implant associated ALCL in a 63-year-old female after augmentation gluteoplasty with silicone implants. Both the above reported ALK-negative ALCL were morphologically and immunophenotypically similar to BIA-ALCL. The only discordance was with the type of implant used: stainless steel in the joint prosthesis case and silicone implant in the gluteoplasty. All BIA-ALCL patients showed a 'triple negative' genetic profile—negative for ALK, DUSP22 and TP63 rearrangements—and were characterised by mutational and gene expression profiles consistent with aberrant activation of the JAK/STAT pathway.3Swerdlow S.H. Campo E. Harris N.L. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. IARC Press, Lyon2017Google Scholar The present case was negative for ALK immunoexpression and DUSP22 rearrangement but showed diffuse p63 immunoreactivity. The latter positivity on immunohistochemistry is considered a screening test which needs further confirmation by FISH for TP63 rearrangement (not done in our case). The previous two reported cases were not investigated for DUSP22 or TP63 rearrangements. The pathogenesis for mammary or non-mammary prostheses associated ALCL is yet unknown and needs to be explored. There are many hypotheses considered like chronic inflammation as the potential etiological agent in view of the ability of implants to promote T-cell infiltration and immune response.10Hu H. Jacombs A. Vickery K. et al.Chronic biofilm infection in breast implants is associated with an increased T-cell lymphocytic infiltrate: implications for breast implant-associated lymphoma.Plast Reconstr Surg. 2015; 135: 319-329Crossref PubMed Scopus (152) Google Scholar Other possibilities considered include high expression of interleukin-2 and interleukin-6 receptors; strong activation of signal transducer and activator of transcription 3 (STAT3) signaling, likely causing autocrine production of IL-6; chronic bacterial antigen stimulation and sustained T-cell production; and high levels of IL-13 and IgE as part of the ALCL microenvironment causing chronic allergic reaction.11Marra A. Viale G. Pileri S.A. et al.Breast implant-associated anaplastic large cell lymphoma: a comprehensive review.Cancer Treat Rev. 2020; 84: 101963Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Palraj et al.6Palraj B. Paturi A. Stone R.G. et al.Soft tissue anaplastic large T-cell lymphoma associated with a metallic orthopedic implant: case report and review of the current literature.J Foot Ankle Surg. 2010; 49: 561-564Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar suggested chronic inflammatory reaction to a particular antigenic stimulus (the implant) that evolved to lymphoma through clonal transformation and/or genetic mutation of a particular subset of lymphocytes, while Mendes et al.7Mendes Jr., J. Mendes Maykeh V.A. Frascino L.F. et al.Gluteal implant-associated anaplastic large cell lymphoma.Plast Reconstr Surg. 2019; 144: 610-613Crossref PubMed Scopus (15) Google Scholar considered the role of implant surface in ALCL genesis (textured are more prone to lymphoma genesis than smooth). The role of chronic inflammation rather than implant surface can be considered more in our case. In implant associated lymphomas, prothesis explantation and complete excision of any residual mass are the recommended approaches. Systemic chemotherapy is generally recommended for patients with locally advanced and disseminated diseases, mainly using treatment protocols routinely adopted for systemic ALCLs (e.g., CHOP, CHOEP, etc.). Limited data are available regarding the treatment of non-mammary implant associated ALCL. The first documented joint prosthesis associated ALCL patient was lost to follow-up while no adjuvant chemotherapy was considered in gluteal implant associated ALCL, however the patient was disease free. Our patient has received chemotherapy (CHOP regime) and was doing well at last follow-up. In conclusion, oncologists and pathologists should be more observant in patients who undergo silicone or non-silicone device implantation as these surgical procedures will continue to rise in various non-neoplastic and neoplastic lesions. Though the morphology and immunophenotyping of mammary and non-mammary implant associated ALCL is similar to ALK-negative ALCL, such cases need to be further investigated for DUSP22 or TP63 rearrangements as the latter carries dismal prognosis. The exact biological relationship between the implant device and ALCL needs to be addressed and explored at the molecular level. The authors state that there are no conflicts of interest to disclose.