Reverse koebnerization of primary cutaneous follicle center lymphoma following skin biopsy

IntroductionPrimary cutaneous follicle center lymphoma (PCFCL) is the most common form of cutaneous B-cell lymphoma and makes up 55% to 60% of all primary cutaneous B-cell lymphomas.1Vitiello P. Sica A. Ronchi A. Caccavale S. Franco R. Argenziano G. Primary cutaneous B-cell lymphomas: an update.Front Oncol. 2020; 10: 651Crossref PubMed Scopus (25) Google Scholar The prognosis for PCFCL is excellent, and the 5-year survival rate is >95%. However, recurrences can be common, and therefore, safe and effective treatments that can be repeated are desirable.1Vitiello P. Sica A. Ronchi A. Caccavale S. Franco R. Argenziano G. Primary cutaneous B-cell lymphomas: an update.Front Oncol. 2020; 10: 651Crossref PubMed Scopus (25) Google Scholar Patients commonly present with grouped pink papulonodules, with the scalp and forehead as favored locations.1Vitiello P. Sica A. Ronchi A. Caccavale S. Franco R. Argenziano G. Primary cutaneous B-cell lymphomas: an update.Front Oncol. 2020; 10: 651Crossref PubMed Scopus (25) Google Scholar The limited number of patients with PCFCL makes it difficult to study its pathogenesis, which remains largely unknown. A minority of primary cutaneous B-cell lymphoma cases originating in Austria and Scotland have been associated with endemic Borrelia species infection.2Goodlad J.R. Davidson M.M. Hollowood K. et al.Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland.Am J Surg Pathol. 2000; 24: 1279-1285Crossref PubMed Scopus (202) Google ScholarKoebnerization, and reverse koebnerization, are 2 phenomena that are also poorly understood.3AlHargan A. AlKhawajah M. AlAjlan M. AlHumidi A. AlTuwaijri R. Reverse Koebner phenomenon induced by the Mantoux test in erythrodermic psoriasis: a case report and literature review.JAAD Case Rep. 2018; 4: 586-589Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar The Koebner phenomenon describes the appearance of new lesions on previously unaffected sites following local trauma, and has been reported in various dermatological conditions, including lichen planus, psoriasis, and vitiligo.3AlHargan A. AlKhawajah M. AlAjlan M. AlHumidi A. AlTuwaijri R. Reverse Koebner phenomenon induced by the Mantoux test in erythrodermic psoriasis: a case report and literature review.JAAD Case Rep. 2018; 4: 586-589Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Reverse koebnerization, however, is a significantly rarer event that describes the improvement or resolution of lesions locally following trauma.3AlHargan A. AlKhawajah M. AlAjlan M. AlHumidi A. AlTuwaijri R. Reverse Koebner phenomenon induced by the Mantoux test in erythrodermic psoriasis: a case report and literature review.JAAD Case Rep. 2018; 4: 586-589Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This report describes 3 instances of the reverse Koebner phenomenon in 2 individuals with PCFCL, induced by punch biopsies.Case reportA 59-year-old man presented with a 5-month history of multiple asymptomatic, violaceous nodules and telangiectasia on the right frontal aspect of the scalp (Fig 1). He described 2 months of intermittent non-drenching night sweats, but denied fevers, chills, or weight loss. He was otherwise healthy and not on any medication. Four years previously, he had a 4-mm asymptomatic nodule at the same site. A skin biopsy then showed an atypical CD20+ B-cell proliferation and rare CD68+ histiocytes. One month following the biopsy, the nodule resolved spontaneously. His skin disease had been in remission for 4 years. When he presented again with new lesions at the same site, a punch biopsy demonstrated a nodular, deep dermal lymphocytic proliferation with a significant population of larger, atypical cells but no tingible body macrophages nor evidence of polarization. The CD4:CD8 ratio was within normal limits. Immunohistochemical staining showed CD10+, CD20+, CD21+, BCL2+, BCL6+, and MUM1− B lymphocytes. Ki67 was ∼40%. Because of the presence of rare CD68+ histiocytes and BCL2+ B cells, pseudolymphoma was also considered. However, the predominant lymphocytic infiltrate, alongside the absence of eosinophils, plasma cells, or tingible body macrophages, favored a diagnosis of PCFCL. Although PCFCL is classically associated with negativity for BCL2, BCL2+ PCFCLs are possible and have not been found to have any worse prognosis.4Pileri A. Agostinelli C. Bertuzzi C. et al.BCL-2 expression in primary cutaneous follicle center B-cell lymphoma and its prognostic role.Front Oncol. 2020; 10: 662Crossref PubMed Scopus (3) Google Scholar Furthermore, although BCL2+ often implies secondary cutaneous follicle center lymphoma, cases of BCL2+ PCFCL are not uncommon either.5Kim B.K. Surti U. Pandya A. Cohen J. Rabkin M.S. Swerdlow S.H. Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas.Am J Surg Pathol. 2005; 29: 69-82Crossref PubMed Scopus (83) Google Scholar Physical examination revealed no cervical, axillary, or inguinal lymphadenopathy nor hepatomegaly. His complete blood count, lactate dehydrogenase, creatinine, liver transaminases, flow cytometry, urinalysis, and computed tomography (CT) scan of his head, neck, chest, abdomen, and pelvis were unremarkable. At 1-month follow-up, all cutaneous nodules had resolved again following biopsy (Fig 2). He was referred to hematology and it was verified that his lymphoma was skin-limited.Fig 2Resolution of nodules. Photograph taken 4 weeks following punch biopsy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The second case is a 77-year-old man presenting with a 2-year history of a 2-cm pale, violaceous plaque with telangiectasia on the left frontal aspect of the scalp, which reportedly developed after an insect bite (Fig 3). It improved with topical steroids but never resolved. He has a history of type 2 diabetes, gastroesophageal reflux, hypothyroidism, migraines, and deep vein thrombosis following orthopedic surgery. His medications included levothyroxine, pantoprazole, empagliflozin, warfarin, metformin, and gabapentin. He had no other cutaneous lesions, weight loss, or systemic complaints, but reported non-drenching night sweats 2-3 times per week. A punch biopsy revealed a dense lymphocytic infiltrate throughout the dermis, separated from the epidermis by a grenz zone. The infiltrate predominantly involved centrocytes admixed with some centroblasts with irregularly shaped lymphoid follicles. The CD4:CD8 ratio was within normal limits. Immunohistochemical stains revealed CD20+, CD79a+, BCL2+, BCL6+, variable CD23+, CD5−, CD10−, CD30−, CD56−, cyclin D1− and MUM1− B lymphocytes. Ki67 was ∼10%. A diagnosis of pseudolymphoma was considered, given the history of possible arthropod assault. However, the biopsy showed a predominantly lymphocytic infiltrate, and lacked eosinophils, plasma cells, or tingible body macrophages. When he returned for suture removal after 2 weeks, the plaque had resolved (Fig 4). He was referred to hematology for further work-up. A staging CT revealed 3 small lymph nodes (size, 1.2-1.4 cm) in the paratracheal and hilar region that were perceived to be inflammatory, and a follow-up CT scan will be done after 3 months. He is monitored by hematology with the diagnosis of PCFCL.Fig 3A 2-cm violaceous plaque with telangiectasia on the left frontal aspect of the scalp that had been present for 2 years, reportedly developing after an insect bite.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 4Resolution of plaque following punch biopsy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)DiscussionAlthough reverse koebnerization in PCFCL has not been formally reported in the dermatology literature, it appears to be a phenomenon clinically recognized by clinicians from both dermatology and hematology disciplines (Dr C. Faught, MD, Hematologist, email communication, April 18, 2020). Reverse koebnerization, although rare, has been reported in dermatologic conditions such as granuloma annulare, leukocytoclastic vasculitis, and bullous pemphigoid, which can be induced by a skin biopsy, tattooing, or tight clothing.6Chen C.A. Mikailov A. Faulkner-Jones B. Wu P.A. Leukocytoclastic vasculitis sparing a tattoo with halo effect.JAAD Case Rep. 2015; 1: 269-271Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 7Mohapatra L. Samal K. Mohanty P. Dash S. Reverse Koebner phenomenon in bullous pemphigoid - a case report.Indian Dermatol Online J. 2019; 10: 692-694Crossref PubMed Google Scholar, 8Naveen K.N. Pai V.V. Athanikar S.B. Gupta G. Parshwanath H.A. Remote reverse Koebner phenomenon in generalized granuloma annulare.Indian Dermatol Online J. 2014; 5: 219-221Crossref PubMed Google Scholar The infrequent and diversified nature of this phenomenon causes difficulties in elucidating a plausible mechanism.The current hypothesis suggests that alteration of the immunologic microenvironment at the site of trauma is an important factor in this phenomenon.6Chen C.A. Mikailov A. Faulkner-Jones B. Wu P.A. Leukocytoclastic vasculitis sparing a tattoo with halo effect.JAAD Case Rep. 2015; 1: 269-271Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar For reverse koebnerization in leukocytoclastic vasculitis and bullous pemphigoid, it has been hypothesized that trauma prevented immune complexes from depositing in adequate concentrations within the area of trauma, leading to the resolution of lesions.7Mohapatra L. Samal K. Mohanty P. Dash S. Reverse Koebner phenomenon in bullous pemphigoid - a case report.Indian Dermatol Online J. 2019; 10: 692-694Crossref PubMed Google Scholar,9Yadav S. De D. Kanwar A.J. Reverse Koebner phenomenon in leukocytoclastic vasculitis.Indian J Dermatol. 2011; 56: 598-599Crossref PubMed Scopus (15) Google ScholarThe recurrence of PCFCL in our first case in the same anatomical site aligns with the concept of locus minoris resistentiae, describing a body site that is more susceptible to the onset of disease than the rest of the body due to a localized immune dysregulation.10Ruocco V. Ruocco E. Piccolo V. Brunetti G. Guerrera L.P. Wolf R. The immunocompromised district in dermatology: a unifying pathogenic view of the regional immune dysregulation.Clin Dermatol. 2014; 32: 569-576Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Skin biopsies in both cases likely triggered local inflammatory responses to clear the malignant lymphocytes, which is similar to the reverse koebnerization seen in granuloma annulare.9Yadav S. De D. Kanwar A.J. Reverse Koebner phenomenon in leukocytoclastic vasculitis.Indian J Dermatol. 2011; 56: 598-599Crossref PubMed Scopus (15) Google ScholarReverse koebnerization is a rare phenomenon, which seems to result from changes in the local immunological microenvironment. More research is needed to gain a deeper understanding of the underlying physiological process. Knowledge of reverse koebnerization is clinically useful, as skin biopsy may become an inadvertent therapeutic option for local skin disease in PCFCL, as has been observed in granuloma annulare.8Naveen K.N. Pai V.V. Athanikar S.B. Gupta G. Parshwanath H.A. Remote reverse Koebner phenomenon in generalized granuloma annulare.Indian Dermatol Online J. 2014; 5: 219-221Crossref PubMed Google Scholar Recurrence and “retreatment” with biopsy may be needed. Years of remission, as experienced by our patient, would likely be considered an acceptable response. IntroductionPrimary cutaneous follicle center lymphoma (PCFCL) is the most common form of cutaneous B-cell lymphoma and makes up 55% to 60% of all primary cutaneous B-cell lymphomas.1Vitiello P. Sica A. Ronchi A. Caccavale S. Franco R. Argenziano G. Primary cutaneous B-cell lymphomas: an update.Front Oncol. 2020; 10: 651Crossref PubMed Scopus (25) Google Scholar The prognosis for PCFCL is excellent, and the 5-year survival rate is >95%. However, recurrences can be common, and therefore, safe and effective treatments that can be repeated are desirable.1Vitiello P. Sica A. Ronchi A. Caccavale S. Franco R. Argenziano G. Primary cutaneous B-cell lymphomas: an update.Front Oncol. 2020; 10: 651Crossref PubMed Scopus (25) Google Scholar Patients commonly present with grouped pink papulonodules, with the scalp and forehead as favored locations.1Vitiello P. Sica A. Ronchi A. Caccavale S. Franco R. Argenziano G. Primary cutaneous B-cell lymphomas: an update.Front Oncol. 2020; 10: 651Crossref PubMed Scopus (25) Google Scholar The limited number of patients with PCFCL makes it difficult to study its pathogenesis, which remains largely unknown. A minority of primary cutaneous B-cell lymphoma cases originating in Austria and Scotland have been associated with endemic Borrelia species infection.2Goodlad J.R. Davidson M.M. Hollowood K. et al.Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland.Am J Surg Pathol. 2000; 24: 1279-1285Crossref PubMed Scopus (202) Google ScholarKoebnerization, and reverse koebnerization, are 2 phenomena that are also poorly understood.3AlHargan A. AlKhawajah M. AlAjlan M. AlHumidi A. AlTuwaijri R. Reverse Koebner phenomenon induced by the Mantoux test in erythrodermic psoriasis: a case report and literature review.JAAD Case Rep. 2018; 4: 586-589Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar The Koebner phenomenon describes the appearance of new lesions on previously unaffected sites following local trauma, and has been reported in various dermatological conditions, including lichen planus, psoriasis, and vitiligo.3AlHargan A. AlKhawajah M. AlAjlan M. AlHumidi A. AlTuwaijri R. Reverse Koebner phenomenon induced by the Mantoux test in erythrodermic psoriasis: a case report and literature review.JAAD Case Rep. 2018; 4: 586-589Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Reverse koebnerization, however, is a significantly rarer event that describes the improvement or resolution of lesions locally following trauma.3AlHargan A. AlKhawajah M. AlAjlan M. AlHumidi A. AlTuwaijri R. Reverse Koebner phenomenon induced by the Mantoux test in erythrodermic psoriasis: a case report and literature review.JAAD Case Rep. 2018; 4: 586-589Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This report describes 3 instances of the reverse Koebner phenomenon in 2 individuals with PCFCL, induced by punch biopsies.