Synchronous occurrence of primary cutaneous B‐cell lymphoma and cutaneous Rosai–Dorfman disease in distinct lesions: A unique association

Rosai–Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare subtype of reactive histiocytosis which is seldom associated with Hodgkin's and non‐Hodgkin's lymphomas. To date, the coexistence in the same patient of extra nodal SHML and primary cutaneous B‐cell lymphoma (PCBCL) has been reported in the literature, as metachronous diagnosis in the anatomical area of the original PCBCL or synchronous occurrence in the same lesions. However, no data have been published as for synchronous occurrence of the two pathological entities in distinct anatomical sites. Herein, we report the first ever described synchronous occurrence of PCBCL and SHML, detected in distinct lesions, affecting the same patient. The complete resolution of the patient's PCBCL after rituximab treatment and the concomitant regression of SHML suggest that this clinically benign reactive histiocytic proliferation, potentially triggered by the lymphoma microenvironment itself, may take place not only in the site of the PCBCL lesion, but also in other distant areas not directly affected by the primary cutaneous lymphoma.


| INTRODUCTION
Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare subtype of reactive histiocytosis. 1 More common in young adults, it usually presents with painless lymph node enlargement.Among the reported extra nodal forms, pure cutaneous SHML without nodal disease has been described as the most common subtype. 2 To date, few cases of SHML associated with both Hodgkin and non-Hodgkin lymphomas have been described in the literature, 3 with anecdotical records regarding association with cutaneous lymphomas. 4ong cutaneous lymphomas, approximately one fourth are represented by primary cutaneous B-cell lymphomas (PCBCLs), a group of non-Hodgkin lymphomas originating in and usually confined to the skin. 5Follicle center and marginal zone lymphomas (i.e., PCFCL and PCMZL) are the most common subtypes and usually display an indolent course, while diffuse large B-cell lymphoma leg type (PCDLBCL, LT) is less frequent, yet more aggressive. 5Herein, we report the unique, synchronous occurrence of PCBCL and SHML, detected in distinct lesions, affecting the same patient.

| CASE REPORT
A 72-year-old otherwise healthy man presented to our university clinic complaining of a 6-month history of skin itching and recentonset cutaneous lesions.The physical examination showed several erythematous-violaceous lucent papules, located on his wrists, hands and right thigh.The overall number of lesions was 7, with average diameter of 0.9 cm (range 0.4-1.2cm).The papules did not show any sign of ulceration nor desquamation and appeared to be superficial to the touch, with no evidence of deep infiltration (Figure 1).A 5-mm punch biopsy from a 1.1-cm papule on the wrist (Figure 2 (i.e., generalized skin involvement, with multiple lesions in two noncontiguous body regions). 6The following workup tests (i.e., complete blood count with differential, comprehensive metabolic panel) and contrast CT scan ruled out concomitant extracutaneous involvement.
However, the staging ultrasound displayed an enlarged subcutaneous nodule, sized 12 mm, located at the third distal of the left arm, resembling a suspicious adenopathy.A biopsy of this further lesion was performed, and the specimen (Figure 3) showed a dense and nodular dermal infiltrate (Figure 3A), consisting mainly of lymphocytes and plasma cells, mixed with numerous aggregates of large histiocytes with abundant amphophilic cytoplasm and vesicular nuclei (Figure 3B,C).Immunohistochemical stain was positive for S100 (Figure 4A) and CD68, with signs of emperipolesis (Figure 4B).In addition, reactive lymphoid follicles and areas of fibrosis were seen.No histopathologic nor immunohistochemical features compatible with PCMZL, such as non-epidermotropic dermal infiltrates of small centrocyte-like marginal zone B-cells, were detected in the specimen.
These distinctive histopathologic features led to the diagnosis of cutaneous SHML.The patient's PCMZL was successfully treated with intravenous rituximab 375 mg/m 2 , once weekly for four consecutive weeks, with involution of all cutaneous lesions and regression of the subcutaneous SHML nodule. 7The patient has been followed up for 8 years, with no signs of relapse.

| DISCUSSION
SHML is a rare entity classified among non-malignant histiocytic disorders. 8Defined by its histopathologic features, it frequently mimics a malignant neoplasm, with a variable clinical course ranging from spontaneous regression to, less frequently, progressive lymphadenopathy. 2 To date, the coexistence of PCBCL and SHML in the same patient has been rarely reported in the literature.Gonzalez-Quesada et al described a metachronous occurrence of SHML, 12 years after the diagnosis of a PCMZL in the same anatomical area. 9Moreover, synchronous diagnoses in the same lesions have been described by Machan et al 10 and Garces et al. 11 No data have been published regarding synchronous occurrence (i.e., occurring within 6 months) of the two pathological entities in distinct anatomical sites so far. 12orrection added on 2 February 2023, after first online publication: The preceding sentence was deleted.]Hitherto, the synchronous coexistence of PCBCL and SHML in the same biopsy specimen has been described as an incidental histopathologic finding, with single ) showed uninvolved epidermis overlying a perivascular and periadnexal nodular infiltrate within the dermis (Figure 2A,B), consisting mainly of lymphoplasmacytic infiltrates with monocytoid B-cells (Figure 2C) CD20 + (Figure 2E), bcl-2 + (Figure 2D), bcl-6 À CD10 À , with some follicular structures with germinal centers consisting of bcl-6 + scattered centroblasts collected in small clusters.Reactive T-lymphocytes were revealed.An immunohistochemistry analysis for kappa and lambda light chains was performed and resulted in a monotypic expression of kappa chains (kappa/lamba ratio 9:1).The neoplastic nature of the infiltrate was confirmed by a PCR study for B-cell receptor clonality (FR1-JH, FR2-JH, FR3-JH, codifying locus for heavy chain IgH).A diagnosis of PCMZL was made and, according to International Society for Cutaneous Lymphomas and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer classification, the patient's skin involvement was classified as T3a

F I G U R E 1
Clinical appearance of PCMZL: erythematousviolaceous lucent papules.foci of Rosai-Dorfman disease being detectable in a lymphomatous histopathologic setting.11,13Our case exhibits interesting new evidence.As some authors have suggested, the lymphoma microenvironment may act as a trigger for the MAPK/ERK-induced proliferation of histiocytes and therefore may play an active role in the development of concomitant focal Rosai-Dorfman disease.11WeF I G U R E 2Histopathologic features of PCMZL: (A) (H&E, Â2): Nodular lymphocytic infiltrate with spared epidermis, with perivascular and periadnexal architecture; (B, C) (H&E, Â4 and Â10): Detail of periadnexal lymphocytic infiltrate with monocytoid appearance; (D) (IHC, bcl-2 positive cells); (E) (IHC, CD20 positive cells) F I G U R E 3 Histopathologic features of Rosai-Dorfman disease: (A) (H&E, Â2): Scanning magnification of a dense nodular and well circumscribed dermal infiltrate; (B, C) (H&E, Â10 and Â20): Clusters of epithelioid histiocytes and giant cells with focal emperipolesis admixed with lymphocytes and plasma cells suggest that this clinically benign histiocytic proliferation may take place not only in the site of the PCBCL lesion (i.e., detectable in the same pathology specimen), but also in other distant areas not directly affected by the cutaneous lymphoma.The spontaneous regression of focal Rosai-Dorfman disease seen in our patient supports the evidence that its detection in patients undergoing treatment for cutaneous lymphoma is an incidental histopathologic finding with a clinically benign course. 3,13Further studies, aimed at investigating the relationship between lymphoma microenvironment and the reactive histiocytic proliferations, are needed to fully understand the biopathological mechanisms underlying this first ever described occurrence.ACKNOWLEDGEMENT Open Access Funding provided by Universita degli Studi di Torino within the CRUI-CARE Agreement.