This case of orbital, extranodal RDD with features reminiscent of IgG4-RD presented a diagnostic dilemma that highlights the subtleties in diagnosing either disease in an atypical location and supports the potential existence of an overlap syndrome.
The differential diagnosis before surgical debulking was broad. One possibility was inflammatory myofibroblastic tumor (IMT), which tends to occur in children and can present as a well-defined soft tissue mass (as initially seen in our patient) [5, 6]. Although uncommon, orbital IMT has been reported in both children and adults; its clinical features (unilaterality, proptosis, diplopia, periocular swelling, and others) are often similar to our patient’s [5, 7, 8]. Ocular adnexal lymphoma was also on the differential, as patients can present with exophthalmia, orbital mass, reduced visual acuity, and diplopia [9]. Orbital meningioma, Graves’ orbitopathy, and idiopathic orbital inflammation, although less likely, were also considered [10, 11].
Histopathological analysis following the initial surgical debulking of the lesion’s orbital portion revealed several key features, described above and shown in Fig. 3a-f, that met consensus criteria (delineated by Deshpande et al. in 2012) for tissue diagnosis of IgG4-RD [12]. Also supporting this diagnosis was the presence of myofibroblasts and dense regions of IgG4-immunopositive plasma cells. IgG4-RD typically presents as a systemic fibro-inflammatory process accompanied by multifocal tumor-like lesions [12]. Although type 1 autoimmune pancreatitis is the archetypal manifestation, the head and neck region is the second most commonly affected area [13, 14]. The first systematic review of head and neck IgG4-RD found that the orbit was the most frequently affected site [15, 16]. Interestingly, an additional systematic review of pediatric IgG4-RD found that primary orbital disease was the most common manifestation in children [17, 18]. Orbital IgG4-RD in adults usually involves the lacrimal gland; however, in children, the surrounding orbital soft tissues, musculature, and trigeminal nerve branches are more typically involved (as seen in our patient) [15, 18]. First-line IgG4-RD treatment is typically 2–4 weeks of steroids (usually prednisone) followed by a gradual taper [19]. In the rare case that steroids fail to control disease, rituximab is considered second-line treatment [20]. A systematic review of treatment outcomes in 95 patients with orbital IgG4-RD suggested that rituximab is the most efficacious non-steroidal immunosuppressive agent, with a success rate greater than 90% [21]. The failure of our patient’s lesion to respond to both steroids and rituximab, while possible in IgG4-RD, is extremely unusual and questioned the validity of this initial diagnosis.
Histopathological analysis following the second debulking surgery shifted our diagnosis towards RDD. RDD is an inflammatory syndrome characterized by uncontrolled histiocytic proliferation [22]. It is rare, with an incidence in the United States of approximately 100 cases annually [23]. While extranodal RDD is identified in approximately 43% of cases, ophthalmic presentations have been reported in only 11% [22]. Facial cutaneous RDD is even rarer, and interestingly, most facial cutaneous RDD manifestations (including those seen in the periorbital soft tissues) present as isolated lesions [24]. Age at presentation is skewed towards younger individuals (such as our patient), with a mean age at diagnosis of approximately 21 years [22]. Males and/or those of African descent are disproportionately affected [23]. RDD treatment varies by affected site, ranging from observation alone in simple lymphadenopathy or asymptomatic cutaneous RDD to steroids for more symptomatic, progressive, or multifocal disease—although steroid efficacy is not well-established [23].
The biopsy specimens obtained from the second surgical debulking were most notable for having numerous “RDD cells”: large, S-100-positive histiocytes with “watery-clear” or “foamy” cytoplasm and a hypochromatic nucleus with a conspicuous nucleolus (Fig. 3k) [25]. Emperipolesis, another canonical feature of RDD, was also observed (Fig. 3k) [23]. Emperipolesis is less conspicuous in cutaneous manifestations of RDD; in equivocal inflammatory facial lesions, larger excisional biopsy specimens seem necessary to better ensure comprehensive analysis of such features [24]. Some features of IgG4-RD, such as an elevated plasma cell IgG4/IgG expression ratio, were still present; however, in this specimen, the ratio did not strictly meet IgG4-RD diagnostic criteria, and both storiform fibrosis and obliterative phlebitis were absent as well. Local recurrence of RDD following surgical resection—particularly in orbital disease, as in this case—is not uncommon [26,27,28]. Ultimately, local disease progression despite steroid and rituximab treatment, the need for extensive surgical debulking to achieve disease stabilization, new histopathological findings, and a clinical picture consistent with RDD converged onto a final unifying diagnosis of extranodal RDD, notably with focal atypical features reminiscent of IgG4-RD.
Interestingly, a report published by Bertero et al. described a similar case of an orbito-temporal mass ultimately diagnosed as “Rosai-Dorfman meningeal disease with IgG4-related disease histological features”; just as in our case, initial histopathological analysis of was suggestive of IgG4-RD, while further samples exhibited features pathognomonic for RDD [29]. The histologic overlap between IgG4-RD and RDD in both of these cases may indicate a common pathogenesis underlying at least a subset of these two inflammatory processes. Kuo et al. first proposed a potential relationship between IgG4-RD and RDD based on shared histological and molecular features across 12 cutaneous RDD cases [30]. In addition to the presence of pathognomonic “RDD cells,” all 12 cases demonstrated abundant IgG4-positive plasma cells and various degrees of stromal fibrosis. Furthermore, three cases in this series met strict consensus criteria for plasma cell expression of IgG4 for IgG4-RD established by Deshpande et al. [12], with an IgG4/IgG ratio greater than 0.4 [30]. Fayne et al. provide another cases series also suggesting that, especially in primary cutaneous manifestations of RDD, there exists a potential subgroup with an abundance of plasma cells and inconsistent RDD features throughout the lesion (particularly emperipolesis) [31]. In a larger series of 26 RDD samples, which included both nodal and extranodal cases, Zhang et al. found that 30.8% of cases displayed an IgG4/IgG ratio that met consensus criteria for IgG4-RD [32]. Additionally, they demonstrated that IgG4 plasma cell burden and regulatory T-cell (T-reg) infiltration were positively correlated with the degree of lesional sclerosis, particularly in recurrent or persistent disease [32]. T-regs produce interleukin-10 (IL-10) and transforming growth factor-β (TGF-β); the former induces IgG4 class switching, and the latter induces collagen production and fibrosis—both critical phenomena in IgG4-RD pathogenesis [33]. The variable presence of T-regs and subsequent IgG4 expression in RDD, particularly in extranodal progressive disease (as seen in our patient), suggests either that RDD and IgG4-RD may coexist across a single pathological spectrum, or that RDD may demonstrate characteristics of IgG4-RD during specific phases of disease progression as a consequence of T-reg influence on associated inflammation.
Another key observation from Zhang et al. was that adult RDD cases harbored more sclerosis than pediatric cases [32]. Two additional series replicated this association of older age at presentation with increased sclerosis and IgG4-RD features [34, 35]. In a series of 32 nodal and extranodal specimens reviewed by Liu et al., three demonstrated an IgG4/IgG ratio greater than 0.4—all from older adolescents or adult patients [34]. Menon et al., who reviewed the largest RDD series to date of 70 samples for features of IgG4-RD, also found that 12 cases met consensus criteria for IgG4 expression; the median age at presentation of these 12 cases and the median age at presentation of all IgG4-positive cases in the series (55 and 54 years, respectively) were both significantly higher than that for IgG4-negative cases, at 27 years [35]. Menon et al. also identified a significant male predominance among the highest IgG4-expressing cases [35]. Presentation of cutaneous RDD with features of IgG4-RD in an older adolescent male fits with the limited clinical and histopathological data on this potential overlap syndrome. The seemingly temporal nature of the presentation of RDD with IgG4-RD features is furthermore suggestive of a spectrum disorder, with pathogenesis potentially varying according to age of onset in addition to the likely varied contribution of T-regs. Identification of RDD cases that lean towards IgG4-RD may also have critical implications for treatment. Most RDD cases undergo spontaneous remission [36], but a handful of reports on refractory cases—in particular, those with IgG4 immunopositivity—have noted unusual steroid-responsiveness [32, 37]. Since IgG4-RD and related syndromes are known to respond dramatically to steroid treatment [38], further investigation into IgG4’s role as a potential biomarker for steroid-responsiveness in RDD is warranted, although this phenomenon was not immediately apparent after a short course of steroids in this patient’s case.
The diagnostic dilemma highlighted by this case is critically hypothesis-generating with respect to the nature of adult extranodal RDD and its potential relationship with IgG4-RD. Informative histopathological evidence was not obtainable without substantial surgical tissue sampling. Furthermore, the patient’s lesion appeared to display not only regional differences in plasma cell and histiocyte expression, but also a clinical response to treatment not clearly consistent with any previously reported RDD-related or IgG4-RD–related entity. Previous series have identified examples of RDD with features of IgG4-RD, especially in young adults with progressive, refractory disease. Further investigation into whether RDD and IgG4-RD may exist across a shared pathological spectrum due to similar molecular pathogenesis, likely dependent on T-regs, is necessary to improve our understanding and optimize our management of these rare and challenging systemic diseases.
