Abstract

Rosai-Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytosis described by Rosai and Dorfman in 1969. It is a fascinating disease characterized by accumulation of large, pale histiocytes, frequently showing the emperipolesis phenomenon. The variety of pathological aspects and the spectrum of different clinical forms were deeply investigated by Prof. Rosai. Despite recent advancements in the dissection of pathogenetic mechanisms of RDD, with the identification of gene mutations in the MAP kinase pathway, several biological and clinical aspects of this disease remains to be elucidated: this is one of the Prof. Rosai’s legacies.

History of sinus histiocytosis with massive lymphadenopathy and their evolution to Rosai-Dorfman disease

In 1969 Juan Rosai and Ronald Dorfman, at the time both in in the Department of Pathology at the Washington University in St. Louis, published a paper entitled “Sinus Histiocytosis with Massive Lymphoadenopathy” in the journal Archives of Pathology ¹. They described 4 cases of young subjects, presenting with prominent enlargement of lymphnodes, associated with fever and leukocytosis and characterized by extremely dilated subcapsular and medullary sinuses, filled with large histiocytes, with a ovoid, large, pale, vescicular nucleus with a distinct nucleolus, often containing well preserved lymphocytes in their cytoplasm. This latter feature was interpreted as lymphophagocytosis, but the “emperipolesis” phenomenon was also suggested. Absence or paucity of germinal centers, absence of eosinophils, tissue necrosis and granulomas were also part of the morphologic spectrum. These cases were identified in a series of lesions diagnosed as “reticuloendotheliosis” a term encompassing both benign and malignant lesions, including histiocytosis X and other less defined entities. Two of these cases were retrieved from the archive of Barnes Hospital and two were provided by Dorfman from his previous work in South Africa. In their discussion, Rosai and Dorfman also cited other two cases previously published by other Authors with similar morphology and clinical features.

Three years later, Rosai and Dorfman added the description of further 34 cases of the same lesion, reinforcing the specific morphologic and clinical characteristics of this disease ². Most of these cases were received in consultation after their initial report, but they also reviewed already published cases from other Authors, including the four cases described by Destombes in 1965 ³ and the single case described by Lennert with the term of “Lymphadenitis with massive hemophagocytic sinus histiocytosis” ⁴. It is interesting to note that the majority of the initially described cases involved Africans or Afro-Americans from United States or West India, suggesting an unusual infectious process. In this latter report, despite most of the cases had a benign outcome, although with a prolonged clinical course, two cases had a fatal evolution, considered related to SHML. The autoptic reports showed in one case a lymph node diffuse involvement of SHML with a Pseudomonas aeruginosa necrotizing bronchopneumonia as the cause of death, whereas in the other, diffuse amyloidosis was observed, with minimal lymph-node remnants of SHML. Rosai and Dorfman suggested that amyloidosis could be related to the proliferation of plasma cells that was added as an important morphological feature to this disease, along with the possible presence of atypical nuclear features of sinus histiocytes. Two further important observations were described: the possible involvement of other organs and tissues (testes, skin, soft tissue, orbit, eye-lid) and the possible presence of other cell types (plasma cells and red blood cells) in the cytoplasm of histiocytes. In their discussion, Rosai and Dorfman discarded the hypothesis of a malignant hematologic disorder and were also skeptical to relate SHML to the group of “differentiated histiocytosis” that included eosinophilic granuloma, Hand-Schiller-Christian’s disease and Letterer-Siwe’s disease. Their pathogenetic hypothesis was more in favor of an infectious or an immunological abnormal process.

In the following years Rosai established a SHML Registry in which Pathologists all over the world contributed with newly observed cases. Rosai continued to publish new clinical and morphological observations: SHML involving the skin ⁵, the ENT district ⁶ the ophthalmic district ⁷ the bone ⁸, the ultrastructure of SHML ⁹, with neurological disfunctions ¹⁰, cases with fatal course ¹¹, with immunological abnormalities ¹² and again skin ¹³.

In 1990 Rosai published, in two articles with Foucar and Dorfman, a comprehensive description of this disease analyzing the morphological and clinical aspects ¹⁴ as well as an extensive immunophenotypical evaluation ¹⁵ based on the 423 cases collected in the SHML registry.

Rosai’s interest on SHML continued in the following years, describing SHML diagnosis by fine needle aspiration ¹⁶, in rare locations like breast ¹⁷ and intestine ¹⁸, SHML relationship with autoimmune lymphoproliferative disorders ¹⁹ and with IgG4 related disease ²⁰.

The first paper in which the eponym of Rosai-Dorfman disease (RDD) was utilized was published by Diebold et al. in 1976 ²¹, although preceded by Destombes. Destombes described this disease four years before Rosai, in a French journal in 1965. We do not know if Rosai was aware of this paper, probably not; it is more convincing that the fame of Destombes is due to the fact that Rosai in the second paper acknowledged Destombes’ work ³, linking him to this disease. Certainly Destombes described the same entity in his paper, but putting more emphasis on the lipidic features of the histiocytes. It was Rosai’s paper that defined the morphologic clues for the diagnosis of this disease – i.e. the distinctive features of histiocytes with the emperipolesis phenomenon – and allowed the Pathologist community to be able to recognize this disease.

Clinical aspects of RDD

RDD is a specific clinic-pathological entity, deserving a specific group, – R – in the classification of Histiocytosis proposed by the Histiocyte Society (Fig. 1) ²². The first described cases of RDD represent what is now considered the classic form in the scheme proposed by the Histiocyte Society ²²: massive bilateral cervical lymphadenopathy associated with fever and leukocytosis, affecting mainly children and young adults, frequently African and males. Inguinal, mediastinal and axillary lymph node may also be involved, but RDD localization in retroperitoneal nodes is rare. After the identification of the diagnostic morphologic clues, several reports described this disease in almost every organ and tissue, starting from the skin ^23,24. Extranodal involvement is in fact observed in about 40% of cases, usually in older subjects and of different ethnicity, but rarely without lymph-node involvement, with the exception of skin disease. RDD is considered an indolent benign disease, with, in some cases, a spontaneous regression, although a subset of patients may experience an aggressive course, require treatment with systemic therapies.

Cutaneous RDD is in most cases present in a localized form, not associated with systemic or other extracutaneous localizations, affecting older patients, of Caucasian and Asian origin ²⁵ and is classified in the ‘C’ group by the Histiocytic Society ²². RDD has also been observed as associated with neoplastic diseases, including Hodgkin and non-Hodgkin lymphoma, myelodysplastic syndrome, acute leukemia, immunological disorders, some of which linked to germline mutations (SLC29A3 with H syndrome, FAS gene with Autoimmune lymphoproliferative syndrome ALPS) ²⁴. RDD has also been described associated with IgG4 related disease, but it is still controversial if the two diseases are pathogenetically linked ^23,24.

Morphology, immunophenotype and molecular alterations in RDD

The most important diagnostic features of RDD, as delineated in the first paper by Rosai and further supported by immunophenotyping studies, can be summarized in the following points:

1. large, pale histiocytes with large, nucleolated, hypochromatic nuclei (Figs. 2, 3);
2. emperipolesis (Fig. 4);
3. positivity for S100 protein plus histiocytic markers – CD68 and CD163 – and OCT2: negativity for Langerhans cell markers – CD1a and CD207 – (Fig. 5).

None of these features is per se diagnostic of RDD, but all together contribute, in the appropriate clinical setting, to this diagnosis. Emperipolesis, especially in extranodal and skin disease may be subtle or lacking. The cells inside the large histiocytic cytoplasm are lymphocytes, but also plasmacells and red blood cells, may be observed. Usually, the intracytoplasmatic cells are well preserved, but occasionally apoptotic nuclear debris are present. Emperipolesis may also be observed, although rarely, in other histiocytosis, like Erdheim-Chester disease or Juvenile Xanthogranuloma ²⁶. Other pathological features in RDD include the abundance of plasmacells and the presence of fibrosis: plasmacells are admixed with the histiocytic population and are also abundant at the periphery of the histiocytic proliferation; in extranodal site, the presence of fibrosis may also be observed. Foamy histiocytes and Touton cells are not usually abundant, at variance with ECD. Due to the possible association with other neoplastic disorders, a careful examination of the samples is always recommended.

One of the diagnostic clues of RDD is S100 protein immunoreactivity in histiocytes. First described in a single case by Aoyama et al. ²⁷, S100 protein immunoreactivity was confirmed in larger series by Miettinen et al. ²⁸ and Bonetti et al. ²⁹, suggesting a possible relationship of these cells with interdigitating reticulum cells. RDD histiocytes are also positive for generic macrophage markers like CD68, CD163 and CD14, but negative for other dendritic cell markers like CD1a, CD207 and ZBTB46 ³⁰. New positive markers were added to the RDD histiocytic profile only recently, Cyclin D1 ³¹ and OCT2 ³². Histiocytic cells in RDD also frequently express phosphoERK ³³ and p16 ³⁴ (Fig. 6)demonstrating some common pathogenetic aspects with the other Histiocytosis like ECD, JXG and Langerhans cell histiocytosis ^35,36.

PhospoERK expression demonstrates the activation of the MAP kinase pathway. In fact, in an increasing number of RDD cases, gene mutations involving MAPkinase signaling pathway have been discovered in the last few years. The detection of gene mutations in this pathway indicates that RDD is, at least in a significant percentage of cases, a neoplastic disease. The genes most frequently involved are ARAF ³⁷, NRAS, KRAS, MAP2K1 ^33,38,39 and CSF1R ⁴⁰. NRAS mutation was detected in 4 of 7 cases of purely cutaneous RDD, suggesting that this mutation could characterize the cutaneous form ⁴¹ The type of mutations are also usually different from the most frequent mutated gene in other histiocytosis, like LCH and ECD. BRAF V600E mutation is rare in RDD, with very few cases reported till now ⁴ whereas it is the most frequent genetic alteration in the other two histiocytic disorders ³⁶. The presence of somatic mutations, indicating the neoplastic nature of this disease, is in part in contrast with the benign clinical course with spontaneous healing in some case. The possible existence of two forms of RDD, one neoplastic and one reactive, has been suggested.

p16 expression by large pale histiocytes of RDD could be considered as a senescence marker, like what has been demonstrated in ECD and LCH ^35,36,43,44. Activating mutations in the BRAF-MAPK pathway induces a senescence program (oncogene induced senescence, OIS), characterized by a reprogramming of mutated cells with a DNA damage response activation and a senescence-associated secretory phenotype – SASP –, affecting non-mutated bystander cells. This mechanism also explains the composite cellular scenario that we observe at the microscope: a relatively limited number of putative neoplastic cells and a wide array of different cell types representing the majority of cellular population. This aspect is easily appreciated in many cases of LCH, with few CD1a positive cells and many eosinophils and other cell types; in ECD is almost impossible to identify morphologically the mutated histiocytes. In fact, the allele-frequency of BRAF mutation in ECD usually doesn’t exceed 10%, indicating that at least 80% of the cell population is composed of bystander cells; also, utilizing a BRAF mutation specific antibody, due to some cross-reactivity with non-neoplastic macrophages, the identification of the mutated driver histiocytes is still challenging. In RDD mutated cases again, the allele frequency is in the same range: it could be hypothesized that the neoplastic population in RDD is the hallmark, pale, large histiocytes, but we need more precise identification of the mutated cell.

RDD and other histiocytosis

RDD has been reported in association with other forms of histiocytosis, including Langerhans cell histiocytosis ^45,46 and Erdheim-Chester disease ⁴⁷. In some of the reported cases, the two diseases coexisted or manifested during the course of the disease, while in others the proliferating histiocytes showed overlapping clinical, pathological and immunophenotypic features. This aspect indicates again a strict relationship between these entities, sharing a common origin from the myeloid-monocytic lineage and some overlapping mutational event, in particular MAP2KI gene mutation ^47.

RDD: still unexplored aspects

Despite the presence of more than 2000 papers dealing with the clinical and pathological features of RDD, several questions remain to be solved, and surprisingly some peculiar aspects of this disease have not yet been investigated. First of all, what are the biological mechanisms of the emperipolesis phenomenon that characterize RDD and what are the characteristics of the lymphocytes entrapped in the cytoplasm of the histiocytes? What receptors and ligands that are involved in this migration/capture? Certainly most are T lymphocytes, but there are no reports in the literature on their characterization. Additionally, an in depth characterization of the immunoprofile of histiocytes in RDD is still lacking: the most extensive characterization is still that performed in the 1990 Rosai’s paper ¹⁵. This knowledge could serve for the discovery of new specific diagnostic markers and could also open new insight into the origin of these cells and the pathogenesis of RDD. More work is also needed to identify the pathogenetic mechanisms of RDD. What is the cell of origin, at which point of the mielo-monocytic differentiation program the mutation event is able to induce this disease and which are the molecular correlates of the different clinical forms, are part of the biological aspects that need to be investigated.

We are indebted to the extraordinary capacity of Prof. Rosai to identify the unique morphological features characterizing this and other diseases: it is our duty to complete the knowledge of the pathogenesis of this disorder with the support of the technologies that are now available.

Figures and tables

Figure 1.Schematic representation of the different clinical forms of Rosai-Dorfman Disease, proposed by the Histiocyte Society ²².

Figure 2.Lymphnode involved by Rosai-Dorfman disease: (A) Pale and Dark areas in a lymph node (H&E, 40X); (B) Thick and fibrotic capsule in RDD lymph node (H&E, 100X).

Figure 3.Rosai-Dorfman disease: (A) Large, pale histiocytes with large vescicular nuclei with prominent nucleolus (H&E, 600X); (B) Numerous plasma cells admixed with histiocytes in RDD (H&E, 600X).

Figure 4.Different aspects of emperipolesis in Rosai-Dorman disease: (A) Lymphocytes with apoptotic phenomena inside histiocytes (H&E, 600X); (B) Lymphocytes with a clear halo inside a multinucleated histiocytic cell; lymphocytes, plasma cells and red blood cells in a large histiocyte.

Figure 5.Rosai-Dorfman disease: (A) S100 protein immunoreactivity (200X); (B) CD163 (200X); (C) OCT2 (200X).

Figure 6.(A) pERK immunoreactivity in large histiocytes and other cell types in RDD (200X original magnification); (B) p16 immunoreactivity in large histiocytes in RDD (200X).

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