Coexistence of Rosai-Dorfman disease and Hodgkin’s lymphoma in a patient with cervical lymphadenopathy

Abstract

A man in his 40s, with no tobacco or alcohol habit, was referred to the otorhinolaryngology department presenting with a 2-month history of enlarged left cervical lymphadenopathy with no other signs or symptoms. The ear, nose and throat examination showed no abnormalities apart from the described lymphadenopathy. An ultrasound scan suggested these nodes to be part of either an inflammatory or a malignant process. Subsequent positron emission tomography-CT proved those lymph nodes to be metabolically active, as well as others within the thorax. Cervicotomy was performed and the histopathological analysis showed dilated sinuses and histiocytes with emperipolesis. Suspecting Rosai-Dorfman disease (RDD), high-dose steroid therapy was started; but given no improvement was observed, a second cervicotomy was performed, with the histopathological diagnosis of the latter of Hodgkin’s lymphoma. The present article aims to emphasise the need to exclude haematological disorders whenever RDD histology is observed, given their possible coexistence, and a worse outcome and clinical and histopathological semblance.

Background

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is an uncommon disorder histopathologically characterised by extensive lymph node sinus expansion with a diffuse infiltrate of histiocytes. Haematolymphoid cells may be observed engulfed within a vacuole or floating freely in the cytoplasm of the histiocytes, being this histological finding known as emperipolesis, which is characteristic but not specific of RDD.

RDD is classified into five different categories: familial, classic (nodal), extranodal, neoplasia-associated and immune disease-associated subtypes. Classic RDD presented as bilateral cervical nodes, most common in young males. In a high proportion of extranodal subtype, skin, upper respiratory tract, bones or retro-orbital tissue are also involved.

The aetiology remains unknown. Studies have associated RDD with viral infections such as herpes viruses, Epstein-Barr virus, cytomegalovirus and HIV, although a clear link has not been proven.¹ Nevertheless, as the rest of histiocytic disorders, it usually responds to systemic steroid therapy.

Classically, RDD cells were considered to be polyclonal, reactive and non-neoplastic.¹ However, in nearly half of the cases, RDD cells show NRAS, KRAS, ARAF and MAP2K1 mutations, which suggests the possibility of a haematolymphoid neoplastic process.²

In addition, emperipolesis is not an exclusive finding of RDD; it can be evidenced in other malignant conditions such as haematolymphoid diseases (Hodgkin’s and non-Hodgkin’s lymphoma, acute and chronic myeloid leukaemia, myeloproliferative disorders, myelodysplastic syndrome) and non-haematological malignancies (multiple myeloma, neuroblastoma, rhabdomyosarcoma),³ which must be present in our differential diagnosis. Moreover, RDD coexisting, even on the same lymph node, with haematological diseases such as lymphoma has been previously reported in literature.^{4 5}

Case presentation

A man in his 40s was referred from the haematology department to the ear, nose and throat (ENT) department for a lymph node cervicotomy. The patient, who had no smoking or drinking habits and no prior medical conditions, presented with a 2-month history of enlarged left cervical lymphadenopathy, which had increased in size over time despite antibiotic and anti-inflammatory treatment. He did not present with weight loss, recurrent fever, night sweats or any other symptoms.

Physical examination showed multiple rounded lymph nodes, the largest with a size of up to 3 cm, firm and mobile, on the inferior third left sternocleidomastoid muscle. He did not present with any other lymphadenopathy nor hepatosplenomegaly, and the otorhinolaryngology examination was unremarkable.

Blood test showed no abnormalities and serological tests were negative, whereas the ultrasound scan displayed multiple enlarged lymph nodes with increased vascularity on the left side of the neck, suggesting either inflammatory or malignant process. In addition, positron emission tomography (PET)-CT scan (figure 1) proved those lymph nodes to be metabolically active, as well as others in the supraclavicular, mediastinal, paratracheal and subcarinal areas.

Figure 1.

Positron emission tomography-CT scan showing the hypermetabolic lymphadenopathy described: (A) hypermetabolic lymph nodes on the inferior third of the left sternocleidomastoid muscle (arrow), (B) paratracheal, subcarinal and cervical hypermetabolic nodes (arrows), and (C) supraclavicular adenopathy (arrow).

Surgical excision of one of the palpable lymph nodes on the neck was performed, and the histopathological analysis showed dilated sinuses with histiocytes (CD4+, CD68+, OCT2+, S100+, CD1a−) engulfing small lymphocytes (emperipolesis), a hallmark but not pathognomonic feature of RDD (figure 2). CD20, BCL6 and CD23 immunohistochemistry was positive but not BCL2 nor EBER.

Figure 2.

Histopathological findings of Rosai-Dorfman disease: (A) histiocytes positive for CD4 immunohistochemical staining; (B, C) lymph node with dilated sinuses with a population of histiocytes presenting large, round or oval nucleus and extensive and eosinophilic cytoplasm showing emperipolesis of intact lymphocytes inside.

High-dose steroid therapy was started after suspecting RDD; but after 4 weeks of treatment, the lymph nodes did not present any remission whatsoever, making it necessary to exclude a primary malignant disorder coexisting with RDD histology, which led to a second cervicotomy of another cervical lymph node, being the histopathological diagnosis of the latter of Hodgkin’s lymphoma, a mixed cellularity type.

Differential diagnosis

Cervical masses are a common report in otorhinolaryngology outpatient practice, given that in most cases, they occur as a result of diseases within the head and neck area. The four major causes are: congenital, inflammatory, infectious and neoplastic. In adults, neoplasms (mainly head and neck tumours) comprise most of the cases of masses that are persistent and resistant to non-steroidal anti-inflammatory drug treatment, especially in males with tobacco and alcohol habits. These are usually painless, firm (stony-hard consistency), adhered and larger than 1 cm masses. Full ENT examination must be performed in these patients as well as imaging tests and histopathological analysis are required. The characteristics of the masses (rounded, mobile) in our patient, the lack of ENT-related symptoms, as well as the otherwise normal ENT examination and PET-CT not showing any primary tumour, made us consider other possibilities.

Mononucleosis-type syndromes, tuberculosis and autoinflammatory syndromes are also common causes of chronically enlarged cervical nodes. Serologies and specific blood tests are needed to rule out these conditions. Serological tests were normal and no granulomas were observed in the biopsy specimen in our patient.

Histiocytosis is a rare cause of lymphadenopathy. Histiocytosis comprises several different syndromes, such as Langerhans cell histiocytosis, Erdheim-Chester disease or Rosai-Dorfman-Destombes disease, for instance. Clinical manifestations are similar for all histiocytosis, being the histological findings usually required to distinguish each of them. RDD histopathology is classically characterised by emperipolesis; however, this sign is not pathognomonic, as it may be observed in other conditions, such as haematolymphoid and non-haematolymphoid neoplasms. RDD immunohistochemistry is positive for CD68, CD163, OCT2, S100 and cyclin D1/BCL1 and negative for CD1a. Both histological and immunohistochemistry features of RDD were observed in this patient, which led to the possible diagnosis of RDD.

Haematological malignancies are also frequently presented as persistent lymphadenopathy within the neck, as well as in other lymph node areas. They are usually soft and painless masses. Hepatosplenomegaly and the so-called B symptoms (fever, drenching night sweats and loss of more than 10% of body weight for over 6 months) may also be present. Full body images, as well as blood tests, histopathological and immunohistochemistry analyses, are usually performed in these cases. Excision of a node, instead of fine core needle biopsy, is usually preferred in these cases in order to obtain adequate tissue for pathological study. Histopathological and immunohistochemistry analyses usually show Hodgkin and Reed-Sternberg cells and positive CD15, CD30, EBER and BCL2 immunohistochemistry. The first node resected in our patient did not show these characteristics and the patient did not report B symptoms whatsoever.

Outcome and follow-up

After the diagnosis of Hodgkin’s lymphoma stage IIA (two or more lymph nodes above the diaphragm without B symptoms), our patient began chemotherapy and ABVD regimen, and has already completed two cycles with complete metabolic response (Deauville score 3) on PET-CT scan. He has been followed up at the haematology outpatient clinic for 5 months since the diagnosis and is asymptomatic, has general well-being and performs his daily life activities.

Discussion

SHML, also known as RDD, is a benign condition. It was first described by Rosai and Dorfman in 1969 and since then, many more cases are available in literature, with a prevalence of 1:200 000 and an estimated 100 new cases per year in the USA.¹ RDD is more common in males and in individuals of African descent, whereas cutaneous RDD is more common in female Asians.

Neoplasia-associated RDD has been rarely described in literature in patients with haematological diseases. Neoplasms associated with RDD include lymphomas, leukaemias, malignant histiocytoses, Langerhans cell histiocytosis and Erdheim-Chester disease.⁶ Some studies suggest a frequency of neoplasia-associated RDD of around 10%,⁷ whereas there are no large-scale studies that specify the frequency of lymphoma associated with RDD up to date. The two most common types of lymphomas associated with RDD are follicular lymphoma and nodular lymphocyte-predominant Hodgkin’s lymphoma.⁸ As described in literature, both diseases may have a synchronous⁹ or metachronous occurrence¹⁰ and may involve different anatomical sites. However, in some patients, small foci of RDD and histopathological features of lymphoma can be found involving even the same biopsy specimen.¹¹ The detection of RDD histological characteristics in patients affected by lymphoma does not modify therapeutic decisions and patients should receive first-line treatment for lymphoma. Therefore, diagnosis of RDD alone must be established after excluding primary malignant disorders in which RDD histology (histiocytes with emperipolesis) may represent a reactive process or a neoplasia-associated disease. Some authors suggest that more than 10% of a biopsy specimen should demonstrate RDD features in order to constitute RDD as a neoplasia-associated entity rather than a reactive process.¹

As Garces et al describe, the pathophysiology of RDD coexisting with lymphoma has not been clarified. Nevertheless, these authors propose the hypothesis of a MAPK/ERK cascade dysregulation to correlate both diseases. The MAPK/ERK cascade dysregulation can be found in haematological diseases as well as in nearly half of RDD cases, and is supposed to be induced either by gene mutations or as a result of the influence of growth factors, cytokines and chemokines produced by the associated lymphoma.¹¹ Activated ERK induces CCND1 transcription, which encodes for cyclin D1, a molecule that has multiple functions in both physiological and pathological states. In physiological states, it allows a cell to undergo from G1 to S phase, as part of a cell cycle. In pathological states, cyclin D1 upregulation leading to cell cycle hyperactivity is a major oncogenic mechanism for many ERK-driven neoplasms. In some studies, moderate to strong expression of cyclin D1 has been found in nearly 90% of RDD cases.³

It is not yet known whether the presence of RDD histology in patients affected by haematological malignancies affects the prognosis of these patients. More studies are required to elucidate the implications of the MAPK/ERK pathway dysregulation in patients showing histological features of RDD.

Learning points.

• Rosai-Dorfman disease (RDD) is a rare histiocytic disease usually presented as bilateral cervical lymphadenopathy in children and young adults. RDD features include dilated lymph node sinuses with histiocytes showing emperipolesis.

• Emperipolesis is a hallmark of RDD but it can be found in other diseases.

• RDD may be found in association with tumours, mainly lymphomas.

• Diagnosis of RDD alone must be established after excluding primary malignant disorders.

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