Keywords
Rosai-Dorfman disease - histiocytic disorder - intramedullary spinal cord masses
Introduction
Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy,
is an uncommon benign histiocytic proliferative disorder which was named after J.
Rosai and R. F. Dorfman in 1969.[1]
[2] However, an extensive search of the literature done by Gaitonde revealed that it
was first reported by Destombes in 1965.[3]
[4] Although RDD has been reported in all age groups, it most frequently presents in
children and young adults, with a slight male predominance,[5] and it is mainly observed in individuals of African and European descent rather
than in Asian populations.[6] It is generally characterized by bilateral, painless, massive cervical lymphadenopathy.
In around 30% of cases, extranodal involvement can be found, including the skin, orbit,
upper respiratory tract, and bones.[7] Central nervous system (CNS) involvement has been described but is uncommon and
is often intracranial. It usually manifests as dural-based masses, and intraparenchymal
involvement is less common. Intramedullary spinal cord involvement is rare.[8] We present an extremely rare case of isolated intramedullary spinal RDD. To our
knowledge, there are only a handful of cases described in children, and this is the
first case described in an infant.
Case Report
An 18-month-old previously healthy girl presented with forward head tilt, progressive
cervical kyphosis, and difficulty in walking with frequent falling. She had no history
of preceding trauma or infection and no constitutional symptoms. Family history was
significant for breast cancer in her paternal grandmother and CNS tumors in the paternal
side. Physical examination revealed a well appearing child with no skin rashes, abnormal
pigmentation, or palpable lymphadenopathy. Her cardiac, respiratory, and abdominal
examinations were normal. Neurologically, she had left lower limb weakness Grade 2/5,
with Brisk reflexes, normal upper limbs and right lower limb examination, and no cranial
nerve affection. Her laboratory investigations showed white blood cells 8.6 × 103/µL, hemoglobin 13.3 g/dL, platelets 277 × 103/µL, erythrocyte sedimentation rate 10 mm/hr, immunoglobulin A 85 mg/dL, immunoglobulin
M 167 mg/dL, and immunoglobulin G 731 mg/dL.
Cervical magnetic resonance imaging (MRI) was done before referral to our institution
revealing an oval, well-defined, intramedullary soft tissue lesion exerting fusiform
cord expansion extending from C6 to D3 level surrounded by proximal and distal cord
edema. The lesion displays relatively intermediate signal on T1, as well as on T2
and short tau inversion recovery-weighted images and shows homogenous avid post-contrast
enhancement on T1 post-contrast images ([Figs. 1]–[3]). The lesion displayed no calcifications, necrosis, or cystic changes. The top differential
diagnoses postulated were intramedullary astrocytoma, ependymoma, and ganglioglioma.
Surgical intervention was done for trial of mass excision, but only open biopsy was
performed. Histopathological examination revealed polymorphic population formed of
lymphocytes, excess eosinophils, together with histiocytic aggregates having vesicular
nuclei and eosinophilic cytoplasm. However, there was no evidence of emperipolesis.
Moderate vascularity was also seen. Immunohistochemical staining was positive for
protein S100 and CD68 and negative for CD1a, GFAP, and CD34. This picture was suggestive
of RDD. However, further immunohistochemical and molecular analysis to confirm the
diagnosis was not done due to logistical issues.
The patient was started on steroid treatment to decrease spinal cord edema with minimal
improvement. One month later, a repeat cervical MRI was done showing similar findings
with decreased spinal cord edema.
Fig. 1 Sagittal T1-weighted image showing intermediate intensity spinal cord fusiform swelling
extending from C6 to D3 level.
Fig. 2 Sagittal T1-weighted post-contrast image showing avid homogenous enhancement of a
well-defined intramedullary oval lesion with better delineation of its extent.
Fig. 3 Sagittal T2-weighted image showing the isointense intramedullary spinal cord lesion
with increased signal intensity in the proximal and distal cord denoting spinal cord
edema.
Discussion
Classical sporadic RDD typically involves lymph nodes.[2]
[9] Extranodal disease is apparent in approximately 40% of all cases, and most commonly
involves the skin, retro-orbital tissue, nasal cavity, bone, and soft tissue.[10] RDD of the nervous system has been reported in less than 5% of all cases, most of
which were in the brain. Involvement of the spine has been described in only 20% of
those with CNS involvement, with the vast majority of cases being related to the Dura.[11] A retrospective analysis showed that 210 cases of CNS involvement were reported
ever since the description of the disease, of which only 24 were isolated spinal RDD.
Most cases of isolated spinal RDD were extramedullary dural-based lesions; only two
cases were intramedullary.[8] Moreover, in children, isolated intramedullary spinal RDD is extremely rare and
has only been reported twice in two 12 years old children, making our case the first
reported in an infant.[7]
[12]
The diagnosis of RDD cannot depend on imaging as there are no pathognomonic features.[1] CNS RDD usually presents with dural-based lesions; and that along with their homogenous
enhancement on post-contrast T1-weighted images leads to their frequent misdiagnosis
as meningiomas. On T1-weighted images, RDD usually appears as a single or multiple
well-defined lesions with isointense or hyperintense signal that shows distinct and
homogenous contrast enhancement.[13] On T2-weighted images, RDD usually displays isointense signal, yet lesions with
hypo- and hyperintense signal have been reported.[1]
[13] Heterogeneous hypointense signal on T2-weighted images has been reported for numerous
cases and has been proposed to be used as a differentiating point between RDD and
meningiomas, which are commonly iso- or hyperintense on T2-weighted images. Calcifications
are rarely seen in RDD.[5]
RDD is a disease of nonmalignant histiocytes that infiltrate lymph nodes or extranodal
tissues. Definitive diagnosis can only be made by histological analysis of the affected
tissues. The association between emperipolesis, which is the nondestructive phagocytosis
of lymphocytes or erythrocytes, and a typical immunohistochemical pattern characterized
by positivity for S-100 protein and CD68 antigen and negativity for CD1a antigen is
diagnostic for RDD.[14] In cases where emperipolesis is not described, preventing the confirmatory diagnosis
of RDD, Langerhans cell histiocytosis (LCH) is included in the differential diagnosis
as it is also positive for S-100 protein. However, LCH is often also positive for
the CD1a antigen.[15] Further immunohistochemical and molecular analysis can be used to add strength to
the diagnosis, such as the detection of BRAF mutations, which are seen in almost two-thirds of LCH cases and rarely seen in RDD.[16] Our case showed the typical immunohistochemical characteristics; however, emperipolesis
was not an evident feature and further immunohistochemical and molecular analysis
was not done due to logistical issues.
Laboratory abnormalities are nonspecific with elevated erythrocyte sedimentation rate
and leukocytosis, high ferritin, hypergammaglobulinemia, and autoimmune hemolytic
anemia.[17]
The etiology of RDD is unknown and it is considered an idiopathic histiocytosis. Links
to human herpes virus, parvovirus B19, and Epstein–Barr virus have been made, but
none have been confirmed so far.[18] Clonal nature of some RDD patients has been proven, specifically those that show
KRAS and MAP2K1 mutations, but this is only seen in about one-third of patients.[19]
Sporadic RDD is often self-limited with a good outcome, especially in classical form.
However, 5 to 11% of patients may die due to their disease.[17] Because of the critical impact on spinal elements, and the magnitude of the symptoms,
surgery is usually the optimal approach in these manifestations of RDD.[20] Steroid treatment has shown some therapeutic benefit in a few reported cases with
CNS involvement.[8] In our case, it led to a decrease in spinal cord edema on follow-up imaging done
1 month later with no significant clinical benefit to the patient.
Conclusion
Isolated spinal intramedullary RDD is an extremely rare disease, and the diagnosis
is overwhelmingly difficult. Imaging characteristics still vary between cases and
immunohistochemistry is still the only reliable basis for diagnosis. Further imaging
studies need to be continued for better characterization of RDD spinal and brain lesions,
thus guiding adequate curative management.
