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research-article2016
IJSXXX10.1177/1066896916632587International Journal of Surgical PathologyRyan et al
Case Reports
Classical Hodgkin Lymphoma Arising Adjacent to a Breast Implant
International Journal of Surgical Pathology 1–8 © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896916632587 ijs.sagepub.com
Ciara Ryan, MB, MRCSI, FRCPath1, Yasser Ged, MB1, Fiona Quinn, PhD1, Jan Walker, BSc1, John Kennedy, MB, FRCPI1, Charles Gillham, MB, MRCP, FRCR1, Stefania Pittaluga, MD, PhD2, Ronan McDermott, MB, MRCPI, FRCR, FFRRCSI1, Elisabeth Vandenberghe, MB, PhD, MRCPI, MRCPath1, Cliona Grant, MB, MRCPI1, and Richard Flavin, MD, PhD, FRCPath1
Abstract Breast implant–associated lymphoma has recently gained wide recognition. Anaplastic large cell lymphoma (ALCL) is the most frequently diagnosed subtype in this setting but the spectrum is broadening. A 66-year-old woman developed swelling and itch around her saline implant 6 years after its insertion. Imaging revealed a fluid collection surrounding the implant with an adjacent mass. Microscopy showed sclerotic tissue punctuated by discrete cellular nodules comprising small lymphocytes, eosinophils and interspersed large atypical Hodgkin Reed-Sternberg (HRS)-like cells. The HRS-like cells stained positively for CD30 and CD15 by immunohistochemistry. Small T-lymphocytes formed rosettes around HRS-like cells. Appearances were consistent with classical Hodgkin lymphoma (HL). Multiplex polymerase chain reaction demonstrated no clonal rearrangements of immunoglobulin or T-cell receptor genes, however, a t(14;18)(q32;q21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was present. Staging positron emission tomography–computed tomography scan revealed FDG-avid masses in the right axilla and pelvis. Subsequent pathological examination identified low-grade follicular lymphoma (FL) with a t(14;18) translocation at these sites. To our knowledge, this is the first case of HL arising adjacent to a breast implant. An awareness of this diagnosis is important as classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens. It is also important in the differential diagnosis for implant-associated ALCL as both contain large atypical CD30-positive cells highlighting the need for full immunohistochemical and molecular workup in such cases. This case also adds to the large body of literature regarding the association between HL and FL. Keywords breast, lymphoma, breast implant, Hodgkin lymphoma, follicular lymphoma
Introduction Malignant lymphoma occurring in the setting of breast implants has gained much recognition in recent years. Implant-associated anaplastic large cell lymphoma (iALCL), while remaining rarely reported, is now becoming a more widely accepted entity.1-12 Other lymphoma subtypes associated with breast implants are exceedingly rare and reported mainly as case reports. The spectrum is expanding and includes cutaneous T-cell lymphoma,13,14 extranodal follicular lymphoma,15 primary cutaneous follicle center lymphoma,16 large B-cell lymphoma,17 lymphoplasmacytic lymphoma,18 and extranodal NK/T-cell lymphoma, nasal type.19 Despite this diversity of subtype, the common denominator is that these are all cases of nonHodgkin lymphoma (NHL). We report the first case of Hodgkin lymphoma (HL) associated with a breast implant.
It is well documented that, despite their lost B-cell phenotype, the cells of origin for HL are mature B-cells.20,21 Within published literature it has been noted that NHL and HL occur in the same patient more often than expected by chance.22 Our case of HL, as well as its novel proximity to a breast implant, occurs synchronously with a low-grade follicular lymphoma with both harboring the same translocation. It therefore further adds to the literature regarding the complex relationship between HL and NHL. 1
St James’s Hospital, Dublin, Ireland National Institute of Health/National Cancer Institute, Bethesda, MD, USA 2
Corresponding Author: Ciara Ryan, Department of Histopathology, St James’s Hospital, Dublin 8, Ireland. Email: [email protected]
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Figure 1. Ultrasound left breast demonstrating relationship between breast implant, seroma and adjacent mass which, on biopsy, was classical Hodgkin lymphoma (star, breast implant; arrow, seroma fluid surrounding implant; cross, mass containing classical Hodgkin lymphoma).
Clinical Summary A 66-year-old woman presented with persistent swelling and itch around a left breast saline implant. Six years prior to this she was diagnosed with stage IA invasive ductal carcinoma of the left breast and was treated with a wide local excision. Three years later she had a local recurrence with metastatic disease in axillary lymph nodes and underwent a left mastectomy and left axillary node clearance with immediate reconstruction. She declined adjuvant chemotherapy and radiotherapy and was started on an aromatase inhibitor. Her background history also included colon carcinoma in 1998. Radiological investigations demonstrated fluid surrounding her left breast implant with an ill-defined irregular hypoechoic mass in the 3 o’clock position, adjacent to the fluid around the implant, measuring 2.5 × 2 cm (Figure 1). Features were highly concerning for locally recurrent breast carcinoma. Fluid surrounding the implant was aspirated and subsequent core needle biopsy and wire-guided excision of the mass were performed. Post-operative staging positron emission tomography– computed tomography scan revealed a 3.9 × 1.5 cm mass along the inferolateral aspect of the left breast implant with faint FDG (18F-fluorodeoxyglucose) activity, a mildly FDG avid 1.6 × 1.4 cm right axillary lymph node and an 8.6 × 5.3 × 6.3 cm FDG avid soft tissue pelvic mass. Follow-up magnetic resonance imaging of pelvis showed a complex left adnexal mass.
Figure 2. Fluid surrounding breast implant aspirated for cytological evaluation. Specimen contained large malignant cells with a mixed inflammatory background.
She underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, left pelvic lymphadenectomy, and excisional biopsy of the right axillary lymph node (contralateral to the breast mass).
Pathological Findings Cytological examination of periprosthetic fluid showed that large malignant cells had exfoliated into the periprosthetic space (Figure 2) and tissue sampling was recommended for further assessment. Core needle biopsy from the left breast mass comprised fibrotic tissue with interspersed large atypical cells within a mixed inflammatory background composed of small lymphocytes, eosinophils and neutrophils with scattered foci of necrosis. Immunohistochemical studies revealed that these large cells stained positively for CD30. They were negative for pan-cytokeratins AE1AE3 and KerMNF excluding carcinoma. Immunohistochemical staining for CD20, CD3, CD2, CD5, CD7, CD8, CD68, and Alk1 was also negative in the large atypical cells. Morphology and immunophenotype raised the possibility of a CD30positive lymphoproliferative disorder however, further subtyping by immunohistochemistry and molecular analysis was precluded by the limited tissue acquired by core needle biopsy, which prompted excision of the mass. Microscopy from the excisional biopsy revealed predominantly sclerotic tissue, along with some skeletal muscle and fat, punctuated by discrete cellular nodules comprising mostly small lymphocytes with occasional eosinophils and scattered rare large atypical Hodgkin Reed-Sternberg (HRS)-like cells, including mononuclear and mummified variants (Figure 3a and b). Occasional
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Figure 3. (a) Excisional biopsy of left breast comprising predominantly sclerotic tissue, punctuated by discrete cellular nodules. (b) Cellular nodules were composed of mostly small lymphocytes with occasional eosinophils and scattered large atypical Hodgkin Reed-Sternberg (HRS)-like cells including mononuclear (shown here) and mummified variants. (c, d). Immunohistochemical studies for CD30 (c) and CD15 (d) revealed positive staining in these large HRS-like cells.
granulomata were also present. Similar to the core needle biopsy, these HRS-like cells stained positively for CD30 by immunohistochemistry (Figure 3c). They were also positive for CD15 (Figure 3d) and showed focal weak PAX5 and MUM1 staining. They were negative for CD20, CD68, CD5, CD7, CD8, Alk1, and EBER. CD2 and CD3 stained small T-lymphocytes, which formed rosettes surrounding some HRS-like cells. Morphological appearance, in combination with this immunoprofile, was consistent with classical HL. Multiplex PCR demonstrated the presence of a weak t(14;18)(q32;q21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene. No clonal rearrangements of either immunoglobulin or T-cell receptor genes were demonstrated. The unusual presence of this t(14;18) translocation prompted further studies to investigate the possibility of a background follicular lymphoma (FL). Immunohistochemical studies for CD10, Bcl-2, and Bcl-6 showed no evidence of a background FL. This was
supported by fluorescence in situ hybridization (FISH), which failed to detect a t(14;18) translocation or bcl-2 gene rearrangement. There were no remaining large HRS cells present in the formalin-fixed paraffin-embedded block for this study (Figure 4), therefore the presence of t(14;18) translocation in HRS could not be proven; however, similarly, the presence of a systemic FL with localization in the breast within the background HL microenvironment was not supported. The left ovarian tumor, excised 1 month later, was composed of cytologically atypical cells with a high mitotic index (up to 30/10 high power field) and tumor necrosis consistent with a high-grade sarcoma. By immunohistochemistry, tumor cells were strongly and diffusely positive for smooth muscle actin, calretinin and CD34 with focal desmin staining. Findings were most consistent with a high-grade leiomyosarcoma. A separately submitted internal iliac adhesion comprised a similar population consistent with metastatic leiomyosarcoma.
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International Journal of Surgical Pathology blocks and was analyzed by a series of multiplex PCR assays, which tested for immunoglobulin gene rearrangements, T-cell receptor gene rearrangements and the BCL2-JH t(14;18) translocation. Immunoglobulin gene rearrangement analysis was performed by PCR using BioMed primers and probes and PCR products visualized using GeneScan. FISH analysis was performed on sections from FFPE blocks using Abbott Vysis probe sets.
Management and Follow-up
Figure 4. Fluorescence in situ hybridization (FISH) failed to detect a t(14;18) translocation; however, there were no remaining large Hodgkin Reed-Sternberg (HRS) cells present in the formalin-fixed paraffin-embedded block for this study.
Pelvic lymph nodes, received as a staging component of this surgical procedure, contained one node with monomorphic follicles comprising predominantly cleaved centrocytes with occasional admixed centroblasts (less than 5 per high power field) (Figure 5a). Cells within the follicles showed strong staining for CD20, CD10, Bcl6, and Bcl2 (Figure 5b and c). Less than 10% of cells stained positively with MIB1. Features were consistent with a low-grade FL. There was no evidence of classical HL in this lymph node. Molecular genetic analysis detected the t(14;18)(q32;q21) BCL2-JH translocation at the major breakpoint region of the BCL2 gene by polymerase chain reaction (PCR), confirming this diagnosis. The pathologically enlarged right axillary lymph node—contralateral to the left breast mass—was excised at the same time as pelvic surgery and morphologically and immunophenotypically showed involvement by a low-grade FL with no involvement by classical HL. The diagnosis of FL was supported by molecular genetic studies, which demonstrated the presence of clonal immunoglobulin heavy chain (VFR1-J and VFR2-J) and light chain kappa (V-J) gene rearrangements by PCR, indicating the presence of a monoclonal B-cell population. Similar to the breast lesion and pelvic lymph node, the t(14;18) (q32;q21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was detected by multiplex PCR in this axillary lymph node.
Methods and Materials Immunohistochemical studies were performed on sections from formalin-fixed, paraffin-embedded (FFPE) tissue using standard protocols. DNA was extracted from FFPE
The patient received adjuvant pelvic radiotherapy (50.4G y/28 fractions) for her high-grade ovarian leiomyosarcoma. She had stage 3 FL with involvement of lymph nodes above and below the diaphragm and stage 1E HL with involvement of a single extranodal site. In terms of managing her lymphomas, following multidisciplinary review and careful discussion with the patient, a watch and wait policy was adopted. Surveillance computed tomography scan of the thorax, abdomen and pelvis and breast mammography performed 6 months after surgery showed stable disease.
Discussion Primary breast lymphoma is defined as a primary lesion within the breast, with or without regional nodal involvement, but no other extramammary sites of involvement.23 The breast is an unusual site for extranodal lymphoma— lymphoma comprises less than 0.5% of all breast malignancies and breast represents the primary site in approximately 2% of extranodal lymphomas. The vast majority of primary breast lymphomas are B-cell lymphomas, of which, diffuse large B-cell lymphomas are the most common. Other, less frequent, histologic subtypes include extra-nodal marginal zone lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma), Burkitt lymphoma, follicular lymphoma and B-lymphoblastic lymphoma. Primary T-cell lymphomas of the breast (in patients without breast implants) are extremely rare, typically described as case reports and comprise peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma (ALCL), and precursor T-lymphoblastic lymphoma.24,25 Primary HL of the breast is exceedingly rare. Primary HL of the breast was first described by Kuckens in 1928.26 Subsequently, Wood and Coltman27 described 8 cases of HL confined to the breast in 1973. This was followed in 2000 when Pillemer and Harris28 reported a case of HL involving only the right breast and bilateral axillary lymph nodes. In 2010, Hoimes et al29 described a case of stage IV disease with localizing findings of breast nodule and swelling, ipsilateral axillary and supraclavicular adenopathy and a previously identified
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Figure 5. (a) Pelvic lymph node excision showed effaced lymph node architecture with replacement by monomorphic follicles comprising predominantly cleaved centrocytes. (b, c) Cells within the follicles showed strong staining for Bcl2 (b) and CD20 (c) consistent with a low-grade follicular lymphoma.
prominent intramammary node present for at least 2 years before the diagnosis of HL—all of which strongly support breast as the primary site. To date, there has been no description of primary HL occurring around a breast implant. Malignant lymphoma occurring in the setting of breast implants has gained increased recognition in recent years. Despite large epidemiological studies providing little evidence for an increased risk of lymphoma in women who have received breast implants, published case reports and case series have prompted interest in a causal link between them.3-5 The pathogenesis of breast implant–associated lymphomas is largely unknown, most likely due to their rarity. It is speculated that, via prolonged microscopic leaks of silicone or saline, there is stimulation of the immune system leading to activation of lymphocytes, driving clonal expansion and development of malignant lymphoma.17,30
First described in 1997 by Keech et al,31 implant-associated anaplastic large cell lymphoma (iALCL) is now a well-known, yet rarely reported, entity. It most commonly presents as a periprosthetic fluid collection and less frequently as a solid tumor mass. There is a marked variability in time from implant to lymphoma presentation; implants appear to be either cosmetic or reconstructive and are both saline and silicone. Morphologically, neoplastic cells are large, with abundant cytoplasm and pleomorphic nuclei. They stain positively for CD30 but are mostly negative for Alk1. Molecular genetic studies, where reported, show clonal T-cell receptor gene rearrangements.8-10 While iALCL is the most widely documented lymphoma in patients who have had breast implants other lymphomas have been reported, mainly as case reports. Duvic et al,13 in 1995, described three cases of cutaneous T-cell lymphoma in association with silicone implants. In the same year, Cook et al15 published a case of extranodal
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follicular lymphoma presenting as capsular contractures and a palpable nodule within soft tissue adjacent to a silicone implant. Similarly, in 2014, Jones et al16 reported a case of primary cutaneous follicle center lymphoma arising adjacent to a silicone implant. Also in 2014, Smith et al17 described a large B-cell lymphoma arising in a breast implant capsule. Kraemer et al,18 in 2004, highlighted a case of lymphoplasmacytic lymphoma in a patient with bilateral leaking silicone implants. The rare Epstein-Barr virus (EBV)-driven extra-nodal NK/T-cell lymphoma, nasal type, was described in 2012 by Aladily et al19 in a woman with bilateral saline implants who developed pain in her right breast. The diagnosis was supported by the demonstration of EBV-encoded RNA in neoplastic cells by in situ hybridization and a monoclonal T-cell receptor gene rearrangement by PCR and added to the expanding spectrum of lymphomas known to be associated with breast implants.19 All cases in our literature review are, therefore, examples of NHL. To our knowledge, our case is unique as the first description of HL adjacent to a breast implant. Similar to iALCL, our case of HL presented as a periprosthetic effusion/seroma which contained malignant cells on cytology. An awareness of the possibility of HL arising within fluid and tissue surrounding breast implants is important as it may prompt future diagnoses of this entity. Classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens and periprosthetic fluids, particularly in the absence of a clinical history. Knowledge of the potential for HL to occur adjacent to the site of a breast implant may stimulate a search for HRS cells and further investigation using immunohistochemistry if there is any suspicion of malignancy. On core needle biopsy there was a suspicion of a CD30-positive lymphoproliferative disorder, however, tissue was limited for further investigation. Our case highlights the need to complete full immunohistochemical panels for HL and NHL, as well as ancillary molecular studies, to comprehensively subtype implant-associated lymphomas because the presence of large atypical CD30-positive cells may be a diagnostic pitfall leading to a misdiagnosis of iALCL if the reporting pathologist is unaware of the possibility of HL in this setting. Although our primary aim is to highlight the novel diagnosis of HL associated with a breast implant, a further point of interest in this case is the presence of the t(14;18) (q32;q21) BCL2-JH translocation in FFPE tissue from the breast excision specimen containing HL in the absence of an obvious follicular lymphoma in the HL microenvironment. A diagnosis of FL in the pelvic and axillary lymph nodes was made just 1 month after the diagnosis of HL. The FL also harbored the t(14;18)(q32;q21) BCL2-JH translocation involving the major breakpoint region of the
bcl2 gene. The possibility of systemic FL at the site of the breast implant was refuted by FISH which failed to demonstrate a t(14;18) translocation or bcl2 gene rearrangement in the absence of HRS cells in the FFPE block analyzed. Although infrequent, HL and NHL can occur as composite lymphomas (occurring in the same anatomic site) and as sequential or simultaneous lymphomas (occurring at separate sites) and this appears to occur more often than expected by chance alone.22 Over the past 20 years, several studies have indicated that HRS cells most likely derive from germinal centre B-cells. It is recognized that both HL and FL can develop in parallel from a common premalignant precursor with the 2 distinct phenotypes resulting from different transforming events.21 The vast majority of NHLs associated with classical HL are of B-cell origin and are most commonly of FL subtype. Several studies—Bräuninger et al,32 Küppers et al,33 and Marafioti et al34—have supported a common clonal origin of both HL and FL by demonstrating identical clonal immunoglobulin variable region gene rearrangements in HRS cells and FL cells single cell PCR-amplification. Nakamura et al35 and Yoshida et al36 demonstrated common t(14;18)(q32;q21) BCL2-JH translocations via single cell PCR amplification and chromogenic and fluorescence in situ hybridization, respectively. Our case of simultaneous HL and FL, demonstrated the t(14;18)(q32;21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene in both lymphomas. Although there were insufficient large HRS cells remaining in FFPE blocks to demonstrate a t(14;18) (q32;q21) BCL2-JH translocation in these cells, the absence of an obvious FL on hematoxylin and eosin, immunohistochemical analysis, and FISH raises the possibility that the translocation was in fact in these HRS cells. This case may, thus, add to the literature already describing 2 very different lymphoma subtypes with similar molecular characteristics. The presence of synchronous HL and FL in this patient and the detection of the IgH/BCL2 translocation by PCR in the breast tissue suggests that the HL developed as a progression of the underlying follicular lymphoma. This finding weakens the suggestion that the HL may have an etiological link with the breast implant and therefore most likely represents a coincidental finding.
Conclusion This case is the first described case of HL arising in the context of a breast implant. Our description of this novel finding, particularly given the inflammatory milieu in HL, aims to prevent the dismissal of a mixed inflammatory morphology as merely reactive when reporting capsulectomy specimens or masses adjacent to implants.
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Ryan et al Although previously well documented, our case incidentally also increases the body of literature surrounding the association between HL and FL occurring as composite, synchronous or sequential lymphomas. It further supports the theory of a common clonal origin for HL and FL when occurring in the same patient. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Miranda RN, Aladily TN, Prince HM, et al. Breast implantassociated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol. 2014;32:114-120. 2. Thompson PA, Prince HM. Breast implant-associated anaplastic large cell lymphoma: a systematic review of the literature and mini-meta analysis. Curr Hematol Malig Rep. 2013;8:196-210. 3. Largent J, Oefelein M, Kaplan HM, Okerson T, Boyle P. Risk of lymphoma in women with breast implants: analysis of clinical studies. Eur J Cancer Prev. 2012;21:274-280. 4. Lipworth L, Tarone RE, McLaughlin JK. Breast implants and lymphoma risk: a review of the epidemiologic evidence through 2008. Plast Reconstr Surg. 2009;123:790-793. 5. Vase MØ, Friis S, Bautz A, Bendix K, Sørensen HT, d’Amore F. Breast implants and anaplastic large-cell lymphoma: a Danish population-based cohort study. Cancer Epidemiol Biomarkers Prev. 2013;22:2126-2129. 6. Xu J, Wei S. Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity. Arch Pathol Lab Med. 2014;138:842-846. 7. Lazzeri D, Agostini T, Bocci G, et al. ALK-1-negative anaplastic large cell lymphoma associated with breast implants: a new clinical entity. Clin Breast Cancer. 2011;11:283-296. 8. Hart AM, Lechowicz MJ, Peters KK, Holden J, Carlson GW. Breast implant–associated anaplastic large cell lymphoma: report of 2 cases and review of the literature. Aesthet Surg J. 2014;34:884-894. 9. Brody GS, Deapen D, Taylor CR, et al. Anaplastic large cell lymphoma (ALCL) occurring in women with breast implants: analysis of 173 cases. Plast Reconstr Surg. 2015;135:695-705. 10. Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim B. Breast implant–associated anaplastic large cell lymphoma: a systematic review. Plast Reconstr Surg. 2015;135:713-720. 11. Taylor CR, Siddiqi IN, Brody GS. Anaplastic large cell lymphoma occurring in association with breast implants: review of pathologic and immunohistochemical features in 103 cases. Appl Immunohistochem Mol Morphol. 2013;21:13-20.
12. Chai SM, Kavangh S, Ooi SS, et al. Anaplastic large-cell lymphoma associated with breast implants: a unique entity within the spectrum of peri-implant effusions. Diagn Cytopathol. 2014;42:929-938. 13. Duvic M, Moore D, Menter A, Vonderheid EC. Cutaneous T-cell lymphoma in association with silicone breast implants. J Am Acad Dermatol. 1995;32:939-942. 14. Sendagorta E, Ledo A. Sézary syndrome in association with silicone breast implant. J Am Acad Dermatol. 1995;33: 1060-1061. 15. Cook PD, Osborne BM, Connor RL. Follicular lymphoma adjacent to foreign body granulomatous inflammation and fibrosis surrounding silicone breast prosthesis. Am J SurgPathol. 1995;19:712-717. 16. Jones JC, Chokshi S, Pistenmaa D. Primary cutaneous follicle center lymphoma arising adjacent to silicone breast implant. Clin Breast Cancer. 2014;14:e65-e67. 17. Smith BK, Gray SS. Large B-cell lymphoma occur ring in a breast implant capsule. Plast Reconstr Surg. 2014;134:e670-e671. 18. Kraemer DM, Tony HP, Gattenlöhner S, Müller JG. Lymphoplasmacytic lymphoma in a patient with leaking silicone implant. Haematologica. 2004;89:ELT01. 19. Aladily TN, Nathwani BN, Miranda RN, et al. Extranodal NK/T-cell lymphoma, nasal type, arising in association with saline breast implant: expanding the spectrum of breast implant–associated lymphomas. Am J Surg Pathol. 2012;36:1729-1734. 20. Küppers R. Molecular biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2009:491-496. 21. Küppers R, Dührsen U, Hansmann ML. Pathogenesis, diagnosis and treatment of composite lymphoma. Lancet Oncol. 2014;15:e435-e446. 22. Jaffe ES, Zarate-Osorno A, Medeiros LJ. The interrelationship of Hodgkin’s disease and non-Hodgkin’s lymphomas— lessons learned from composite and sequential malignancies. Semin Diagn Pathol. 1992;9:297-303. 23. Cheah CY, Campbell BA, Seymour JF. Primary breast lymphoma. Cancer Treat Rev. 2014;40:900-908. 24. Modi Y, Thomas D, Shaaban H, Layne T, Guron G. Nodular sclerosing Hodgkin’s lymphoma with breast involvement: case report and review of the literature. J Nat Sci Biol Med. 2014;5:467-469. 25. Gualco G, Chioato L, Harrington WJ Jr, Weiss LM, Bacchi CE. Primary and secondary T-cell lymphomas of the breast: clinico-pathologic features of 11 cases. Appl Immunohistochem Mol Morphol. 2009;17:301-306. 26. Kuckens H. Localised breast lymhogranuloma as a form of mammary tumour. Beitr Path Anat. 1928;80:135. 27. Wood NL, Coltman CA. Localized primary extranodal Hodgkin’s disease. Ann Intern Med. 1973;78:113-118. 28. Pillemer EA, Harris NL. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 16-2000. A 53-year-old woman with swelling of the right breast and bilateral lymphadenopathy. N Engl J Med. 2000;342:1590-1597. 29. Hoimes CJ, Selbst MK, Shafi NQ, Rose MG, Rosado MF. Hodgkin’s lymphoma of the breast. J Clin Oncol. 2010;10;28:e11-e13.
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30. Farkash EA, Ferry JA, Harris NL, et al. Rare lymphoid malignancies of the breast: a report of two cases illustrating potential diagnostic pitfalls. J Hematop. 2009;20;2:237-244. 31. Keech JA Jr, Creech BJ. Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant. Plast Reconstr Surg. 1997;100:554-555. 32. Bräuninger A, Hansmann ML, Strickler JG, et al. Identification of common germinal-center B-cell precursors in two patients with both Hodgkin’s disease and non-Hodgkin’s lymphoma. N Engl J Med. 1999;340:1239-1247. 33. Küppers R, Sousa AB, Hansmann ML, Strickler JG, Rajewsky K, Hansmann ML. Common germinal-center B-cell origin of the malignant cells in two composite lymphomas, involving classical Hodgkin’s disease and
either follicular lymphoma or B-CLL. Mol Med. 2001;7: 285-292. 34. Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Huhn D, Stein H. Classical Hodgkin’s disease and follicular lymphoma originating from the same germinal center B cell. J Clin Oncol. 1999;17:3804-3809. 35. Nakamura N, Ohshima K, Abe M, Osamura Y. Demonstration of chimeric DNA of bcl-2 and immunoglobulin heavy chain in follicular lymphoma and subsequent Hodgkin lymphoma from the same patient. J Clin Exp Hematop. 2007;47:9-13. 36. Yoshida M, Ichikawa A, Miyoshi H, et al. High frequency of t(14;18) in Hodgkin’s lymphoma associated with follicular lymphoma. Pathol Int. 2012;62:518-524.
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research-article2016
IJSXXX10.1177/1066896916632587International Journal of Surgical PathologyRyan et al
Case Reports
Classical Hodgkin Lymphoma Arising Adjacent to a Breast Implant
International Journal of Surgical Pathology 1–8 © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896916632587 ijs.sagepub.com
Ciara Ryan, MB, MRCSI, FRCPath1, Yasser Ged, MB1, Fiona Quinn, PhD1, Jan Walker, BSc1, John Kennedy, MB, FRCPI1, Charles Gillham, MB, MRCP, FRCR1, Stefania Pittaluga, MD, PhD2, Ronan McDermott, MB, MRCPI, FRCR, FFRRCSI1, Elisabeth Vandenberghe, MB, PhD, MRCPI, MRCPath1, Cliona Grant, MB, MRCPI1, and Richard Flavin, MD, PhD, FRCPath1
Abstract Breast implant–associated lymphoma has recently gained wide recognition. Anaplastic large cell lymphoma (ALCL) is the most frequently diagnosed subtype in this setting but the spectrum is broadening. A 66-year-old woman developed swelling and itch around her saline implant 6 years after its insertion. Imaging revealed a fluid collection surrounding the implant with an adjacent mass. Microscopy showed sclerotic tissue punctuated by discrete cellular nodules comprising small lymphocytes, eosinophils and interspersed large atypical Hodgkin Reed-Sternberg (HRS)-like cells. The HRS-like cells stained positively for CD30 and CD15 by immunohistochemistry. Small T-lymphocytes formed rosettes around HRS-like cells. Appearances were consistent with classical Hodgkin lymphoma (HL). Multiplex polymerase chain reaction demonstrated no clonal rearrangements of immunoglobulin or T-cell receptor genes, however, a t(14;18)(q32;q21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was present. Staging positron emission tomography–computed tomography scan revealed FDG-avid masses in the right axilla and pelvis. Subsequent pathological examination identified low-grade follicular lymphoma (FL) with a t(14;18) translocation at these sites. To our knowledge, this is the first case of HL arising adjacent to a breast implant. An awareness of this diagnosis is important as classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens. It is also important in the differential diagnosis for implant-associated ALCL as both contain large atypical CD30-positive cells highlighting the need for full immunohistochemical and molecular workup in such cases. This case also adds to the large body of literature regarding the association between HL and FL. Keywords breast, lymphoma, breast implant, Hodgkin lymphoma, follicular lymphoma
Introduction Malignant lymphoma occurring in the setting of breast implants has gained much recognition in recent years. Implant-associated anaplastic large cell lymphoma (iALCL), while remaining rarely reported, is now becoming a more widely accepted entity.1-12 Other lymphoma subtypes associated with breast implants are exceedingly rare and reported mainly as case reports. The spectrum is expanding and includes cutaneous T-cell lymphoma,13,14 extranodal follicular lymphoma,15 primary cutaneous follicle center lymphoma,16 large B-cell lymphoma,17 lymphoplasmacytic lymphoma,18 and extranodal NK/T-cell lymphoma, nasal type.19 Despite this diversity of subtype, the common denominator is that these are all cases of nonHodgkin lymphoma (NHL). We report the first case of Hodgkin lymphoma (HL) associated with a breast implant.
It is well documented that, despite their lost B-cell phenotype, the cells of origin for HL are mature B-cells.20,21 Within published literature it has been noted that NHL and HL occur in the same patient more often than expected by chance.22 Our case of HL, as well as its novel proximity to a breast implant, occurs synchronously with a low-grade follicular lymphoma with both harboring the same translocation. It therefore further adds to the literature regarding the complex relationship between HL and NHL. 1
St James’s Hospital, Dublin, Ireland National Institute of Health/National Cancer Institute, Bethesda, MD, USA 2
Corresponding Author: Ciara Ryan, Department of Histopathology, St James’s Hospital, Dublin 8, Ireland. Email: [email protected]
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Figure 1. Ultrasound left breast demonstrating relationship between breast implant, seroma and adjacent mass which, on biopsy, was classical Hodgkin lymphoma (star, breast implant; arrow, seroma fluid surrounding implant; cross, mass containing classical Hodgkin lymphoma).
Clinical Summary A 66-year-old woman presented with persistent swelling and itch around a left breast saline implant. Six years prior to this she was diagnosed with stage IA invasive ductal carcinoma of the left breast and was treated with a wide local excision. Three years later she had a local recurrence with metastatic disease in axillary lymph nodes and underwent a left mastectomy and left axillary node clearance with immediate reconstruction. She declined adjuvant chemotherapy and radiotherapy and was started on an aromatase inhibitor. Her background history also included colon carcinoma in 1998. Radiological investigations demonstrated fluid surrounding her left breast implant with an ill-defined irregular hypoechoic mass in the 3 o’clock position, adjacent to the fluid around the implant, measuring 2.5 × 2 cm (Figure 1). Features were highly concerning for locally recurrent breast carcinoma. Fluid surrounding the implant was aspirated and subsequent core needle biopsy and wire-guided excision of the mass were performed. Post-operative staging positron emission tomography– computed tomography scan revealed a 3.9 × 1.5 cm mass along the inferolateral aspect of the left breast implant with faint FDG (18F-fluorodeoxyglucose) activity, a mildly FDG avid 1.6 × 1.4 cm right axillary lymph node and an 8.6 × 5.3 × 6.3 cm FDG avid soft tissue pelvic mass. Follow-up magnetic resonance imaging of pelvis showed a complex left adnexal mass.
Figure 2. Fluid surrounding breast implant aspirated for cytological evaluation. Specimen contained large malignant cells with a mixed inflammatory background.
She underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, left pelvic lymphadenectomy, and excisional biopsy of the right axillary lymph node (contralateral to the breast mass).
Pathological Findings Cytological examination of periprosthetic fluid showed that large malignant cells had exfoliated into the periprosthetic space (Figure 2) and tissue sampling was recommended for further assessment. Core needle biopsy from the left breast mass comprised fibrotic tissue with interspersed large atypical cells within a mixed inflammatory background composed of small lymphocytes, eosinophils and neutrophils with scattered foci of necrosis. Immunohistochemical studies revealed that these large cells stained positively for CD30. They were negative for pan-cytokeratins AE1AE3 and KerMNF excluding carcinoma. Immunohistochemical staining for CD20, CD3, CD2, CD5, CD7, CD8, CD68, and Alk1 was also negative in the large atypical cells. Morphology and immunophenotype raised the possibility of a CD30positive lymphoproliferative disorder however, further subtyping by immunohistochemistry and molecular analysis was precluded by the limited tissue acquired by core needle biopsy, which prompted excision of the mass. Microscopy from the excisional biopsy revealed predominantly sclerotic tissue, along with some skeletal muscle and fat, punctuated by discrete cellular nodules comprising mostly small lymphocytes with occasional eosinophils and scattered rare large atypical Hodgkin Reed-Sternberg (HRS)-like cells, including mononuclear and mummified variants (Figure 3a and b). Occasional
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Figure 3. (a) Excisional biopsy of left breast comprising predominantly sclerotic tissue, punctuated by discrete cellular nodules. (b) Cellular nodules were composed of mostly small lymphocytes with occasional eosinophils and scattered large atypical Hodgkin Reed-Sternberg (HRS)-like cells including mononuclear (shown here) and mummified variants. (c, d). Immunohistochemical studies for CD30 (c) and CD15 (d) revealed positive staining in these large HRS-like cells.
granulomata were also present. Similar to the core needle biopsy, these HRS-like cells stained positively for CD30 by immunohistochemistry (Figure 3c). They were also positive for CD15 (Figure 3d) and showed focal weak PAX5 and MUM1 staining. They were negative for CD20, CD68, CD5, CD7, CD8, Alk1, and EBER. CD2 and CD3 stained small T-lymphocytes, which formed rosettes surrounding some HRS-like cells. Morphological appearance, in combination with this immunoprofile, was consistent with classical HL. Multiplex PCR demonstrated the presence of a weak t(14;18)(q32;q21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene. No clonal rearrangements of either immunoglobulin or T-cell receptor genes were demonstrated. The unusual presence of this t(14;18) translocation prompted further studies to investigate the possibility of a background follicular lymphoma (FL). Immunohistochemical studies for CD10, Bcl-2, and Bcl-6 showed no evidence of a background FL. This was
supported by fluorescence in situ hybridization (FISH), which failed to detect a t(14;18) translocation or bcl-2 gene rearrangement. There were no remaining large HRS cells present in the formalin-fixed paraffin-embedded block for this study (Figure 4), therefore the presence of t(14;18) translocation in HRS could not be proven; however, similarly, the presence of a systemic FL with localization in the breast within the background HL microenvironment was not supported. The left ovarian tumor, excised 1 month later, was composed of cytologically atypical cells with a high mitotic index (up to 30/10 high power field) and tumor necrosis consistent with a high-grade sarcoma. By immunohistochemistry, tumor cells were strongly and diffusely positive for smooth muscle actin, calretinin and CD34 with focal desmin staining. Findings were most consistent with a high-grade leiomyosarcoma. A separately submitted internal iliac adhesion comprised a similar population consistent with metastatic leiomyosarcoma.
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International Journal of Surgical Pathology blocks and was analyzed by a series of multiplex PCR assays, which tested for immunoglobulin gene rearrangements, T-cell receptor gene rearrangements and the BCL2-JH t(14;18) translocation. Immunoglobulin gene rearrangement analysis was performed by PCR using BioMed primers and probes and PCR products visualized using GeneScan. FISH analysis was performed on sections from FFPE blocks using Abbott Vysis probe sets.
Management and Follow-up
Figure 4. Fluorescence in situ hybridization (FISH) failed to detect a t(14;18) translocation; however, there were no remaining large Hodgkin Reed-Sternberg (HRS) cells present in the formalin-fixed paraffin-embedded block for this study.
Pelvic lymph nodes, received as a staging component of this surgical procedure, contained one node with monomorphic follicles comprising predominantly cleaved centrocytes with occasional admixed centroblasts (less than 5 per high power field) (Figure 5a). Cells within the follicles showed strong staining for CD20, CD10, Bcl6, and Bcl2 (Figure 5b and c). Less than 10% of cells stained positively with MIB1. Features were consistent with a low-grade FL. There was no evidence of classical HL in this lymph node. Molecular genetic analysis detected the t(14;18)(q32;q21) BCL2-JH translocation at the major breakpoint region of the BCL2 gene by polymerase chain reaction (PCR), confirming this diagnosis. The pathologically enlarged right axillary lymph node—contralateral to the left breast mass—was excised at the same time as pelvic surgery and morphologically and immunophenotypically showed involvement by a low-grade FL with no involvement by classical HL. The diagnosis of FL was supported by molecular genetic studies, which demonstrated the presence of clonal immunoglobulin heavy chain (VFR1-J and VFR2-J) and light chain kappa (V-J) gene rearrangements by PCR, indicating the presence of a monoclonal B-cell population. Similar to the breast lesion and pelvic lymph node, the t(14;18) (q32;q21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was detected by multiplex PCR in this axillary lymph node.
Methods and Materials Immunohistochemical studies were performed on sections from formalin-fixed, paraffin-embedded (FFPE) tissue using standard protocols. DNA was extracted from FFPE
The patient received adjuvant pelvic radiotherapy (50.4G y/28 fractions) for her high-grade ovarian leiomyosarcoma. She had stage 3 FL with involvement of lymph nodes above and below the diaphragm and stage 1E HL with involvement of a single extranodal site. In terms of managing her lymphomas, following multidisciplinary review and careful discussion with the patient, a watch and wait policy was adopted. Surveillance computed tomography scan of the thorax, abdomen and pelvis and breast mammography performed 6 months after surgery showed stable disease.
Discussion Primary breast lymphoma is defined as a primary lesion within the breast, with or without regional nodal involvement, but no other extramammary sites of involvement.23 The breast is an unusual site for extranodal lymphoma— lymphoma comprises less than 0.5% of all breast malignancies and breast represents the primary site in approximately 2% of extranodal lymphomas. The vast majority of primary breast lymphomas are B-cell lymphomas, of which, diffuse large B-cell lymphomas are the most common. Other, less frequent, histologic subtypes include extra-nodal marginal zone lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma), Burkitt lymphoma, follicular lymphoma and B-lymphoblastic lymphoma. Primary T-cell lymphomas of the breast (in patients without breast implants) are extremely rare, typically described as case reports and comprise peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma (ALCL), and precursor T-lymphoblastic lymphoma.24,25 Primary HL of the breast is exceedingly rare. Primary HL of the breast was first described by Kuckens in 1928.26 Subsequently, Wood and Coltman27 described 8 cases of HL confined to the breast in 1973. This was followed in 2000 when Pillemer and Harris28 reported a case of HL involving only the right breast and bilateral axillary lymph nodes. In 2010, Hoimes et al29 described a case of stage IV disease with localizing findings of breast nodule and swelling, ipsilateral axillary and supraclavicular adenopathy and a previously identified
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Figure 5. (a) Pelvic lymph node excision showed effaced lymph node architecture with replacement by monomorphic follicles comprising predominantly cleaved centrocytes. (b, c) Cells within the follicles showed strong staining for Bcl2 (b) and CD20 (c) consistent with a low-grade follicular lymphoma.
prominent intramammary node present for at least 2 years before the diagnosis of HL—all of which strongly support breast as the primary site. To date, there has been no description of primary HL occurring around a breast implant. Malignant lymphoma occurring in the setting of breast implants has gained increased recognition in recent years. Despite large epidemiological studies providing little evidence for an increased risk of lymphoma in women who have received breast implants, published case reports and case series have prompted interest in a causal link between them.3-5 The pathogenesis of breast implant–associated lymphomas is largely unknown, most likely due to their rarity. It is speculated that, via prolonged microscopic leaks of silicone or saline, there is stimulation of the immune system leading to activation of lymphocytes, driving clonal expansion and development of malignant lymphoma.17,30
First described in 1997 by Keech et al,31 implant-associated anaplastic large cell lymphoma (iALCL) is now a well-known, yet rarely reported, entity. It most commonly presents as a periprosthetic fluid collection and less frequently as a solid tumor mass. There is a marked variability in time from implant to lymphoma presentation; implants appear to be either cosmetic or reconstructive and are both saline and silicone. Morphologically, neoplastic cells are large, with abundant cytoplasm and pleomorphic nuclei. They stain positively for CD30 but are mostly negative for Alk1. Molecular genetic studies, where reported, show clonal T-cell receptor gene rearrangements.8-10 While iALCL is the most widely documented lymphoma in patients who have had breast implants other lymphomas have been reported, mainly as case reports. Duvic et al,13 in 1995, described three cases of cutaneous T-cell lymphoma in association with silicone implants. In the same year, Cook et al15 published a case of extranodal
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follicular lymphoma presenting as capsular contractures and a palpable nodule within soft tissue adjacent to a silicone implant. Similarly, in 2014, Jones et al16 reported a case of primary cutaneous follicle center lymphoma arising adjacent to a silicone implant. Also in 2014, Smith et al17 described a large B-cell lymphoma arising in a breast implant capsule. Kraemer et al,18 in 2004, highlighted a case of lymphoplasmacytic lymphoma in a patient with bilateral leaking silicone implants. The rare Epstein-Barr virus (EBV)-driven extra-nodal NK/T-cell lymphoma, nasal type, was described in 2012 by Aladily et al19 in a woman with bilateral saline implants who developed pain in her right breast. The diagnosis was supported by the demonstration of EBV-encoded RNA in neoplastic cells by in situ hybridization and a monoclonal T-cell receptor gene rearrangement by PCR and added to the expanding spectrum of lymphomas known to be associated with breast implants.19 All cases in our literature review are, therefore, examples of NHL. To our knowledge, our case is unique as the first description of HL adjacent to a breast implant. Similar to iALCL, our case of HL presented as a periprosthetic effusion/seroma which contained malignant cells on cytology. An awareness of the possibility of HL arising within fluid and tissue surrounding breast implants is important as it may prompt future diagnoses of this entity. Classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens and periprosthetic fluids, particularly in the absence of a clinical history. Knowledge of the potential for HL to occur adjacent to the site of a breast implant may stimulate a search for HRS cells and further investigation using immunohistochemistry if there is any suspicion of malignancy. On core needle biopsy there was a suspicion of a CD30-positive lymphoproliferative disorder, however, tissue was limited for further investigation. Our case highlights the need to complete full immunohistochemical panels for HL and NHL, as well as ancillary molecular studies, to comprehensively subtype implant-associated lymphomas because the presence of large atypical CD30-positive cells may be a diagnostic pitfall leading to a misdiagnosis of iALCL if the reporting pathologist is unaware of the possibility of HL in this setting. Although our primary aim is to highlight the novel diagnosis of HL associated with a breast implant, a further point of interest in this case is the presence of the t(14;18) (q32;q21) BCL2-JH translocation in FFPE tissue from the breast excision specimen containing HL in the absence of an obvious follicular lymphoma in the HL microenvironment. A diagnosis of FL in the pelvic and axillary lymph nodes was made just 1 month after the diagnosis of HL. The FL also harbored the t(14;18)(q32;q21) BCL2-JH translocation involving the major breakpoint region of the
bcl2 gene. The possibility of systemic FL at the site of the breast implant was refuted by FISH which failed to demonstrate a t(14;18) translocation or bcl2 gene rearrangement in the absence of HRS cells in the FFPE block analyzed. Although infrequent, HL and NHL can occur as composite lymphomas (occurring in the same anatomic site) and as sequential or simultaneous lymphomas (occurring at separate sites) and this appears to occur more often than expected by chance alone.22 Over the past 20 years, several studies have indicated that HRS cells most likely derive from germinal centre B-cells. It is recognized that both HL and FL can develop in parallel from a common premalignant precursor with the 2 distinct phenotypes resulting from different transforming events.21 The vast majority of NHLs associated with classical HL are of B-cell origin and are most commonly of FL subtype. Several studies—Bräuninger et al,32 Küppers et al,33 and Marafioti et al34—have supported a common clonal origin of both HL and FL by demonstrating identical clonal immunoglobulin variable region gene rearrangements in HRS cells and FL cells single cell PCR-amplification. Nakamura et al35 and Yoshida et al36 demonstrated common t(14;18)(q32;q21) BCL2-JH translocations via single cell PCR amplification and chromogenic and fluorescence in situ hybridization, respectively. Our case of simultaneous HL and FL, demonstrated the t(14;18)(q32;21) BCL2-JH translocation involving the major breakpoint region of the bcl2 gene in both lymphomas. Although there were insufficient large HRS cells remaining in FFPE blocks to demonstrate a t(14;18) (q32;q21) BCL2-JH translocation in these cells, the absence of an obvious FL on hematoxylin and eosin, immunohistochemical analysis, and FISH raises the possibility that the translocation was in fact in these HRS cells. This case may, thus, add to the literature already describing 2 very different lymphoma subtypes with similar molecular characteristics. The presence of synchronous HL and FL in this patient and the detection of the IgH/BCL2 translocation by PCR in the breast tissue suggests that the HL developed as a progression of the underlying follicular lymphoma. This finding weakens the suggestion that the HL may have an etiological link with the breast implant and therefore most likely represents a coincidental finding.
Conclusion This case is the first described case of HL arising in the context of a breast implant. Our description of this novel finding, particularly given the inflammatory milieu in HL, aims to prevent the dismissal of a mixed inflammatory morphology as merely reactive when reporting capsulectomy specimens or masses adjacent to implants.
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Ryan et al Although previously well documented, our case incidentally also increases the body of literature surrounding the association between HL and FL occurring as composite, synchronous or sequential lymphomas. It further supports the theory of a common clonal origin for HL and FL when occurring in the same patient. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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