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CC BY 4.0 · Indian J Med Paediatr Oncol
DOI: 10.1055/s-0044-1795162
Case Report with Review of Literature

Persistent Generalized Lymphadenopathy: A Diagnostic Conundrum—Case Report and Review of Literature

Mahin Mundra 
1   Department of Pediatrics, VMMC & Safdarjung Hospital, New Delhi, India
,
Vaishnavi Sreenivasan 
1   Department of Pediatrics, VMMC & Safdarjung Hospital, New Delhi, India
,
Nisha Swami
1   Department of Pediatrics, VMMC & Safdarjung Hospital, New Delhi, India
,
Kawaldeep Kaur
1   Department of Pediatrics, VMMC & Safdarjung Hospital, New Delhi, India
,
Bhavika Rishi 
2   National Institute of Pathology, Indian Council of Medical Research (ICMR), New Delhi, India
,
Aroonima Misra 
2   National Institute of Pathology, Indian Council of Medical Research (ICMR), New Delhi, India
,
Sumit Mehndiratta 
1   Department of Pediatrics, VMMC & Safdarjung Hospital, New Delhi, India
,
Amitabh Singh 
1   Department of Pediatrics, VMMC & Safdarjung Hospital, New Delhi, India
› Author Affiliations

Funding None.
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Abstract

Generalized lymphadenopathy is a nonspecific sign with heterogenous etiology including infective, inflammatory, and malignant causes. We present the case of a child who presented with generalized lymphadenopathy, involving the cervical, axillary, mediastinal, and inguinal groups, along with recurring fever, tonsillar enlargement, and parotid swelling for 2 years. She had coexisting undernutrition and hepatosplenomegaly on examination. After ruling out common infective causes like tuberculosis, autoimmune and neoplastic conditions were considered. The diagnosis was made by histopathology of the axillary node biopsy, which revealed characteristic features of Rosai–Dorfman disease (RDD). She was started on oral steroids but was lost to follow-up after 6 months. We report this case to emphasize that RDD, a subtype of non-Langerhans histiocytosis, should be considered as a differential in young patients with persistent generalized lymphadenopathy.


 

Keywords

histiocytosis - emperipolesis - lymphadenopathy - steroids

Introduction

Rosai–Dorfman disease (RDD) is a rare subtype of non-Langerhans cell histiocytosis (LCH) that was initially described by Destombes in 1965 and later by Rosai and Dorfman in 1969. Originally, it was called sinus histiocytosis with massive lymphadenopathy (SHML).[1] Presentations include nodal and extranodal disease in sites such as skin, nasal cavity, bone, soft tissue, and central nervous system (CNS). On histopathology, RDD is characterized by histiocytes demonstrating emperipolesis. These histiocytes are S100 and CD163 positive but CD1a negative on immunohistochemistry. However, the pathognomonic histiocytes are often obscured on biopsy. The accompanying infiltrates and fibrosis are mistaken for nonspecific chronic inflammation, thus requiring multiple biopsies to establish the diagnosis.[2]


 

Case Report

A 3-year-old girl presented to our tertiary care outpatient department with a history of fever and multiple swellings in the neck, axillary, and groin regions for a duration of 2 years and having worsened in the preceding 6 months. The patient also had a history of noisy breathing. The fever was characterized as intermittent, moderate grade, with no rashes or chills. Her birth and family histories were unremarkable. During multiple outpatient hospital visits over the 2 years, she had been treated symptomatically with oral antibiotics with no improvement.

On examination, the child was alert, active, playful, and interested in the surroundings. She had generalized lymphadenopathy—involving cervical, axillary, inguinal groups—the lymph nodes were large, measuring greater than 5 cm, discrete, firm, nonmatted, and bilaterally enlarged. She also had grade 3 tonsillar hypertrophy and enlarged parotid glands. Anthropometry revealed moderate wasting and severe stunting with a short trunk (upper-to-lower segment ratio of 1.12:1). She had wrist widening and frontal bossing, suggestive of rickets. Systemic findings were substantial for hepatosplenomegaly although respiratory, cardiovascular, and neurological examinations were noncontributory. There was no hearing or visual abnormality.

Basic bloodwork showed moderate anemia with few target cells, normal leucocyte and platelet counts, and a mildly raised erythrocyte sedimentation rate (ESR). Serum vitamin D levels were found to be low (8 ng/mL) and she was started on therapeutic doses of vitamin D. We proceeded to investigate for the cause of generalized lymphadenopathy. Infective workup was negative. Ultrasonography found mild ileocecal thickening and enlarged mesenteric and inguinal nodes in the abdomen with bilateral bulky parotid glands with intraparotid nodes in the neck. Contrast computed tomography (CT) imaging of the chest and neck showed enlarged cervical lymph nodes and tonsils with posterior nasopharyngeal obliteration, centrilobular nodules in the lungs with a tree-in-bud appearance, as well as enlarged paratracheal and para-aortic nodes. Fine needle aspiration cytology of the largest cervical node was noncontributory, showing only nonspecific reactive hyperplasia. Bone marrow examination was unremarkable. The child was started on antitubercular therapy based on radiological findings and her long history of fever. Even after 4 months of antitubercular therapy while on outpatient basis follow-up, the child showed no improvement in her condition with increasing size of the neck nodes and parotid glands, and persistent fever. Autoimmune workup was done in parallel, with results as follows: antinuclear antibodies (ANA)—strongly positive (4 + , nucleus speckled); rheumatoid factor—positive; anti-U1snRNP—positive (3 + ). The workup performed for the child is depicted in [Table 1]. Biopsy was performed on the cervical and axillary lymph nodes and sent for histopathological examination. The cervical tissue only showed chronic sialadenitis and follicular hyperplasia, but the axillary biopsy confirmed the diagnosis. Classical features of RDD—prominent sinus histiocytosis with emperipolesis—were observed ([Fig. 1]). Immunohistochemistry—showing S100 positivity and CD1a negativity—supported the diagnosis. The child was started on oral prednisolone at 2 mg/kg/d and showed good clinical improvement initially with slight decrease in the size of the cervical nodes. Written informed consent was obtained from the parents for publication of the clinical details of the child for the case report. After 6 months of starting steroid treatment, the child was lost to outpatient follow-up. Upon further inquiry, it was found that she had succumbed to the disease.

Table 1

Workup performed for the index case

Sl. no.

Test

Value and interpretation

Normal range

1

Hemoglobin (g/dL)

9.7—moderate anemia

 > 11

2

Total leukocyte counts (cells/L)

6.9 × 109—normal

5.0–14.5 × 109

3

Platelet counts (cells/L)

25 × 109—normal

25–35 × 109

4

Peripheral blood smear

Normal with no atypical cells

–

5

Erythrocyte sedimentation rate (mm/h)

32—elevated

0–25

6

Viral markers (hepatitis B and C and HIV)

Negative

–

7

EBV and CMV DNA PCR (blood)

Negative

–

8

CBNAAT and AFB smear of gastric aspirate

Negative

–

9

Serum vitamin D levels (ng/mL)

6—deficiency

 > 20

10

Skeletal survey

Generalized osteopenia

–

11

Fundus examination, echocardiogram

Normal

–

12

Serum amylase levels (U/L)

192—elevated

0–80

13

Fine needle aspiration cytology of cervical node

Reactive hyperplasia

–

14

Ultrasonography of abdomen

Multiple discrete enlarged mesenteric and inguinal lymph nodes—few of them necrotic—largest 1.8 cm with ileocecal junction thickening

–

15

Ultrasonography of the neck

Multiple enlarged non-necrotic cervical nodes with bilateral bulky parotid glands and enlarged intraparotid lymph nodes

–

16

Serum immunoglobulin profile

–

Serum immunoglobulin A

63—normal

27–195

Serum immunoglobulin G

1,814—mildly elevated

500–1,400

Serum immunoglobulin M

178—normal

24–210

17

Autoimmune profile

–

ANA

Strongly positive (4 + )

RA factor

Positive

Anti-U1snRNP

Positive (3 + )

Anti-Ro and anti-La antibodies

Negative

18

Contrast-enhanced CT of the abdomen and neck

Soft tissue attenuation in the posterior nasopharynx with enlarged para-aortic and paratracheal nodes and multiple centrilobular nodules in the lungs

–

19

Histopathological biopsy of the cervical and axillary nodes

Cervical node: reactive lymphoid hyperplasia with chronic sialadenitis

Axillary node: prominent sinus histiocytosis with emperipolesis (S100 positive, CD1a negative)

–

Abbreviations: AFB, acid-fast bacilli smear; ANA, antinuclear antibody; CBNAAT, cartridge-based nucleic acid amplification test; CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein–Barr virus; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; RF, rheumatoid factor.


Zoom
Fig. 1 The arrow demonstrates a large histiocyte with small lymphocytes in the cytoplasm (emperipolesis). Histopathological image of the axillary lymph node biopsy of the child with Rosai–Dorfman disease (hematoxylin and eosin): 400× magnification. Histiocytic infiltration (as marked with arrow) with large eosinophilic cytoplasm and pale vesicular nuclei engulfing small lymphocytes (emperipolesis).

 

Discussion

Persistent generalized lymphadenopathy is a nonspecific sign often considered to be of infective or malignant etiology. Children are often subjected to multiple courses of antibiotics and antitubercular therapy before an alternative diagnosis is considered. We attempt to highlight the possibility of RDD as an unusual cause of such a common presentation.

Rosai and Dorfman, in 1969, described a condition called SHML in four young patients with fever, lymphadenopathy, and leukocytosis—with a common feature of lesions termed as “reticuloendotheliosis.”[1] Prominent lymph nodes with large histiocytes that contained intact lymphocytes within their cytoplasm was noted—a phenomenon termed as emperipolesis as early as 1925 by Lewis.[3] The eponym “Destombes–Rosai–Dorfman syndrome” was first used in 1976 by Diebold et al, which widely publicized this disease.[4] The extranodal involvement of other organs and tissues such as the skin, orbits, soft tissue, bone, liver, kidney, respiratory tract, and CNS, as well as proliferation of other cell lines such as plasma cells, was described by Foucar et al in an extensive evaluation of 423 cases.[5] Eisen et al published the classical immunophenotyping findings seen in SHML cells: reactivity for S100 protein and histiocytic markers (CD68 and CD163) and negativity for Langerhans cell markers (CD1a and CD207).[6]

Classical and extranodal RDD have been classified into the “R” group of histiocytoses, while cutaneous RDD features in the “C” group.[7] Classical sporadic RDD presents as massive, bilateral painless cervical lymphadenopathy with constitutional symptoms of fever and night sweats. Other lymph node groups may also be involved less commonly such as retroperitoneal nodes.[1] Extranodal involvement has been described in approximately 40% cases, rarely in isolation, including skeletal, CNS, and visceral organ involvement.[8] The involvement of the kidney, liver, heart, and lower respiratory tract portends a poor prognosis. In general, prognosis has been found to correlate both with the number of nodal groups and with the number of extranodal systems involved.[5] Rare involvement of the bone marrow with cytopenias in pediatric RDD has been described with a fatal outcome.[9]

Our child had extranodal involvement of pulmonary nodules and bilateral parotid enlargement with ultrasonography showing intraparotid lymph nodes as diffusely scattered hypoechoic solid lesions. There was no xerostomia. Scintigraphy could not be performed at our center. Similar presentation with salivary gland involvement (with or without nodal involvement) has been reported in six cases of pediatric RDD until 2014.[10] Whether such a presentation is a manifestation of intrasalivary nodes or extranodal disease is poorly understood.[5]

Infective triggers have been linked to RDD such as Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human immunodeficiency virus (HIV), but never proven as etiological agents.[11] Our patient tested negative for these viral serologies. Our child had positive autoantibodies with high titers of ANA and anti-U1-RNP but did not fulfil the criteria for mixed connective tissue disorder or systemic Lupus erythematosus (SLE). We could not find any reports of such an association with RDD. It is possible that there was an autoimmune association in our case and that on follow-up other supportive clinical manifestations might have been noted. Histiocytic proliferation akin to SHML has been seen in patients with rare inherited autoimmune lymphoproliferative syndrome (ALPS) with S100+ histiocytes and emperipolesis. Hence, it has been suggested that RDD may be an attenuated form of ALPS with self-limited nodal features and examination of peripheral blood for double negative T cells must be performed in evaluation.[12] The autoimmune association extends to monogenic RAS-associated autoimmune leukoproliferative disease with a gain-of-function KRAS mutation explaining the coexistence of SLE and RDD in a child.[13] Autoimmune hemolytic anemia has also been described with extranodal RDD.[14]

In a report of four cases by Lu et al, lymphoma and RDD were identified in the same biopsy specimen, but it was deemed an incidental reactive finding as there was no evidence of SHML elsewhere.[15] Hence, the recommendation is that greater than 10% of a specimen should demonstrate RDD morphology to constitute neoplasia-associated RDD as a distinct entity.[16] Coexistence of LCH with cutaneous and nodal RDD has also been described, suggesting that the two might be part of a broad clinicopathological spectrum with a common precursor.[17] RDD often contains immunoglobulin G4+ (IgG4 + ) plasma cells, complicating the differentiation from hyper-IgG4 syndrome. Hence, it has been recommended that IgG4 + -plasma-cell infiltration be looked for in all suspected cases of RDD.[18]

Diagnosis is based on the clinical features, histological picture of large histiocytes with emperipolesis, and supportive immunophenotyping mentioned earlier. Emperipolesis is not restricted to RDD and is also seen in LCH, lymphoma, and rhinoscleroma. S100/CD68+ and CD1a immunohistochemical profile is necessary to prove RDD.[16] Our case was diagnosed based on classical histopathology and immunochemistry in a child with nodal and extranodal (parotid gland and pulmonary) involvement.

Studies show that a notable number of cases harbor MAPK signaling pathway gene mutations, suggesting that RDD is a form of clonal neoplasia. Commonly involved genes are NRAS, KRAS, and MAP2K1. BRAF V600E mutation, commonly seen in LCH, is rare in RDD.[11]

A treatment algorithm has been proposed by Abla et al.[16] Asymptomatic patients with cutaneous RDD or those with uncomplicated lymphadenopathy may be candidates for observation, as 20 to 50% of such patients go into spontaneous remissions. Steroids are the mainstay of treatment and often response is achieved at 1.5 to 2 mg/kg/d of prednisolone followed by gradual tapering to a minimum. Dexamethasone has been used successfully in hilar adenopathy and CNS RDD. Chemotherapeutic agents are opted for in steroid-refractory cases. Cladribine, methotrexate, vincristine, and 6-MP (singly or in combination with steroids) have been used in adults with disseminated or refractory RDD. Often multifocal extranodal disease does not respond to steroids alone. The use of thalidomide and lenalidomide have also been described in refractory RDD cases. Rituximab has been used for immune-related RDD. Targeted therapies such as MEK inhibitors are underway.

Radiotherapy has been beneficial in alleviation of local symptoms such as in refractory airway obstruction, and debilitating soft tissue and orbital bone disease. Surgery (apart from biopsy) is warranted only for debulking (spinal compression or airway compromise) or excision of cutaneous lesions.[16] RDD is known to have remissions and exacerbations over several years. Spontaneous complete remission is seen in up to 50% of untreated nodal/cutaneous RDD.[19] Prognosis is found to be worse with extranodal involvement and mortality increases with the number of visceral organs involved.[5]

The strength of our case lies in its potential to bring this uncommon cause of generalized lymphadenopathy to the attention of practicing physicians. Histopathology and immunohistochemistry can help confirm such a diagnosis and prevent a child from being subjected to repeated antibiotic courses and unnecessary antitubercular therapy. Hence, we would like to highlight the need to be open to all diagnoses and to consider excision or core needle biopsy of the involved node at the earliest in the disease course of generalized lymphadenopathy. Our child had high titers of autoantibodies; hence, the limitation of our study is that we were unable to explore the association between combined RDD and positivity for anti-U1-RNP antibodies on follow-up. We were also unable to follow up for steroid refractoriness as RDD is known to have remissions and exacerbations over years.


 

Conclusion

Classical sporadic RDD presents with constitutional symptoms and massive bilateral painless cervical lymphadenopathy. Biopsy and immunohistochemistry help in making a timely diagnosis of RDD and prevent unnecessary antibiotic exposure. Involvement of multiple nodal and extranodal sites together contributes to a poor prognosis. It is important to consider alternate diagnoses at the earliest in a difficult case of generalized lymphadenopathy.


 

 

Conflict of Interest

None declared.

Patient's Consent

Informed consent was obtained from the parents of the child for publication of the clinical data.


Authors' Contributions

M.M., V.S., N.S., and K.K. managed the patient, reviewed the literature, and drafted the manuscript. B.R., A.M., A.S., and S.M. managed the patient, reviewed the manuscript, and critically revised the manuscript. All the authors contributed to reviewing the literature, drafting the manuscript, and approving the final version of the manuscript. A.S. shall act as the guarantor and corresponding author of the article.



Address for correspondence

Dr. Amitabh Singh, MD
Department of Pediatrics
VMMC & Safdarjung Hospital
Ansari Nagar, New Delhi 110029
India   

Publication History

Article published online:
30 December 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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Zoom
Fig. 1 The arrow demonstrates a large histiocyte with small lymphocytes in the cytoplasm (emperipolesis). Histopathological image of the axillary lymph node biopsy of the child with Rosai–Dorfman disease (hematoxylin and eosin): 400× magnification. Histiocytic infiltration (as marked with arrow) with large eosinophilic cytoplasm and pale vesicular nuclei engulfing small lymphocytes (emperipolesis).