Lymphomatoid papulosis associated with Hodgkin lymphoma: two case reports and a short review of literature

Dear Editors, Lymphomatoid papulosis (LyP) is a rare lymphoproliferative disorder, characterized by the development of self-regressing crops of papular, papulo-necrotic and/or nodular erythematous skin lesions with histologic features of a cutaneous CD30+ T-cell lymphoma. LyP shows an estimated world-wide incidence of 1.2 – 1.9 cases per million and has an excellent prognosis, with a 5-year disease-specific survival rate close to 100%. However, in 20% – 50% of cases, LyP may be associated with another type of cutaneous or systemic lymphoma, most commonly mycosis fungoides (MF), primary cutaneous anaplastic large-cell lymphoma (pcALCL), and more rarely Hodgkin lymphoma (HL).1, 2 In this paper, we report two cases of HL-associated LyP along with a brief literature review. A 54-year-old woman with classic HL diagnosed in 2019 at stage IIIB, refractory to several lines of therapy including brentuximab and ruxolitinib, progressed to stage IVs (skeletal) in 2023. Therefore, the patient was switched to pembrolizumab 200 mg every 3 weeks, and subsequently developed firm erythematous and asymptomatic skin papules and patches located on the scalp (Figure 1a, b), neck, left axilla, and groin. Treatment was discontinued, and she underwent skin biopsy; however, in the following weeks, spontaneous resolution of the lesions was observed. Histological examination documented a mixed pleomorphic lymphohistiocytic infiltrate with foci of necrosis, featuring large atypical CD30+ T-cells with positive TCR clonality. The histological and clinical picture was consistent with LyP (Figure 2). Other differential diagnoses, such as other CD30+ lymphomas, drug adverse reactions, pityriasis lichenoides, and the rare cutaneous localization of HL, were excluded after a double independent histopathological evaluation (conducted in Trieste and Bologna, the latter being a referral center for cutaneous lymphomas). Due to the worsening of her overall condition, the patient was placed under palliative care, but was lost to follow-up after returning to her home country. A 69-year-old man presented with plaques on the forehead and trunk (Figure 1c–e), including a persistent crusted lesion of the left scapular region (Figure 1e–f). The patient reported a history of stage IIB HL diagnosed in 2009, which relapsed in 2018, but subsequently went into remission (previous treatments were polychemotherapy, radiotherapy, nivolumab, brentuximab, and autologous stem cell transplant). After crust removal, dermoscopic evaluation of the scapular lesion revealed a pinkish area with polymorphous vessels, shiny white streaks, and erosion with the "sticky fiber sign" (Figure 1g). The lesion was excised, and histology was compatible with primary CD30+ T lymphoproliferative disorder of the skin, interpreted as LyP. Other differential diagnoses, such as other cutaneous or systemic lymphomas and pityriasis lichenoides, were excluded after independent histopathological evaluations in Trieste and Bologna. In the following months, the lesions showed a waxing and waning course and were treated with cycles of topical corticosteroids. The hematologic follow-up remained unchanged, as the HL was still in remission. A search of PubMed and Science.gov databases was conducted to gather information on the association between LyP and HL, using the terms "lymphomatoid papulosis" and "Hodgkin lymphoma". Only articles published in English from 1980 onwards have been selected. Additional relevant papers were identified by manually checking the references of the included literature. A total of 202 articles were initially screened. After assessing relevance and excluding duplicates, 30 papers were collected (Table 1). B HL (n = 3); A HL (n = 1) B HL (n = 1); A HL (n = 1) Concomitant MF; HL and MF in remission for 1 year, then HL recurrence and MF with large cell transformation Including also the two original cases reported in this paper, data comprised 49 patients (23 males, 9 females, sex not reported in 17 cases). Taking into account the available data, the mean age of onset was 47.3 years (standard deviation [SD] 17.4, range 18–79) for LyP, while it was 52.7 years (SD 14.8, range 22–79) for HL. In most cases, LyP preceded HL (27 on 43 with available information; 62.8%), after a mean of 13.4 years (SD 10.9, range 2–36). LyP followed HL in 14/43 cases (32.6%), after a mean of 5.6 years (SD 5.7, range 1–16), including our two patients. The conditions were concomitant in 2/43 cases (4.6%). Interestingly, nine patients died (2 for unrelated causes), and in most patients LyP persisted with a waxing and waning course, even after HL remission. Data is summarized in Table 1. In a multicentric Dutch cohort study, an associated hematological malignancy (HM) was found in 15.5% (78/504) of the LyP patients, including MF (39.7%), pcALCL (37.2%), and more rarely HL (2.6%).1, 2 Hodgkin lymphoma associated-LyP was confirmed to be an uncommon finding by other two retrospective studies (3.5% and 7%, respectively), with HL more often following LyP diagnosis.2, 3 The biological association between LyP and MF or pcALCL could be explained by the hypothesis that a single neoplastic clone of lymphocytes can clinically manifest as a concomitance of multiple types of lymphoma, including LyP.4 Furthermore, MF, LyP, and pcALCL neoplastic cells share markers such as CD30, and analyzing TCR gene rearrangement, different studies found a clonal relationship between LyP and some associated HMs, suggesting that both disorders could arise from a common lymphoid progenitor of T-cell lineage.5 However, regarding the association between LyP and HL, a plausible explanation remains controversial, because HL appears to derive from B-cell lineage, while LyP is a T-cell lymphoma. Nonetheless, the immune system abnormalities associated with HL itself or its treatment could contribute to the incidence of a subsequent LyP.6 In conclusion, in this paper we report two cases of LyP associated with HL. Although rare, the epidemiology supports this association; however, an etiopathogenetic explanation remains controversial. Future research should focus on potentially shared genetic and environmental factors, immune dysregulation, and T-cell and B-cell cross-talk to elucidate the precise pathways leading to these co-occurring lymphomas. None.