Frequency of isolated nervous system involvement at initial presentation in histiocytic neoplasms

Isolated nervous system involvement at initial presentation was seen in 19/377 (5%) adults with histiocytic neoplasms. This included 6/228 (3%) with LCH, 7/103 (7%) with ECD, and 6/46 (13%) with RDD.

Demographics, clinical features, and laboratory characteristics

The median age at symptom onset was lowest in those with LCH (28.5 years, range 21–55) and highest in those with RDD (47.5 years, range 38–70) (Supplementary Table 1). There was a median delay of 7 months from symptom onset to final diagnosis, with the time to diagnosis being most delayed in LCH (13.5 months, range 1–60) and least delayed in RDD (7 months, range 1–20). The most common neurological symptoms and signs were headache (11/19, 58%), weakness (8/19, 42%), and diabetes insipidus (7/19, 37%) (Supplementary Table 2).

BRAF V600E mutation testing was completed in 14/19 patients via tissue immunohistochemistry (11/14), tissue PCR (2/14), serum or urine cell-free DNA (6/14), and next-generation sequencing (4/14). Genetic testing results are summarized in Fig. 1i. Some samples were verified using multiple tests.

Fig. 1: Genetic mutations and MRI findings in different types of primary histiocytic neoplasms.

i Genetic mutations in patients with primary nervous system histiocytic neoplasms. The flow chart illustrates the number of patients in the series tested for genetic mutations and the associated pathways activated by these mutations. ii MRI findings in Langerhans cell histiocytosis (LCH). a Coronal brain MRIs of a man in his 20s with LCH presenting with diabetes insipidus. T2-weighted MRI (left image) and T1-weighted post-gadolinium MRI (right image), showing enhancement of infundibulum (yellow arrow). b Sagittal brain MRIs of a man in his 20s with LCH presenting with fatigue, weight gain, hypogonadism, and diabetes insipidus. T1-weighted pre-gadolinium MRI (left image) and T1-weighted post-gadolinium MRI (right image) demonstrate an ovoid heterogeneously enhancing lesion involving the hypothalamus (red arrow). iii MRI findings in Erdheim-Chester disease (ECD). a Axial brain MRIs of a woman in her 50s with ECD (BRAF N486_P490del). T2-weighted MRI (left image) and T1-weighted post-gadolinium MRI (right image) showing diffuse heterogenous enhancement of an enlarged pons. This was initially diagnosed as diffuse intrinsic pontine glioma. b Axial brain MRIs of a woman in her 30s with ECD (BRAF V600E+). T2-weighted MRI (left image) and T1-weighted post-gadolinium MRI (right image) shows an enhancing mass involving the left middle cerebellar peduncle and left cerebellar hemisphere with mass effect onto the 4th ventricle. c Sagittal spinal cord MRIs of a woman in her 30s with ECD (BRAF V600E+). T2-weighted MRI (left image) and T1-weighted post-gadolinium MRI (right image) show an enhancing intramedullary expansile mass at T12-L1 involving the conus (yellow arrows). iv MRI findings in Rosai-Dorfman disease (RDD). A woman in her 40s presented with progressive right leg weakness and imbalance and focal onset seizure with impaired awareness. Axial brain FLAIR MRI (left image) and T1-weighted post-gadolinium MRI (right image) demonstrate an extra-axial homogeneously enhancing mass with mass effect in the left frontal lobe. v MRI findings in ECD associated with CSF1R mutation. a Lumbar spine MRIs of a woman in her 20s presenting with progressive left leg weakness found to have ECD associated with CSF1R mutation. Sagittal lumbar spine T1-weighted post-gadolinium MRI (top left image) shows multiple enhancing nodules involving the cauda equina nerve roots (red arrows) with leptomeningeal enhancement of the lower thoracic cord and conus (yellow box). Axial lumbar spine T1-weighted post-gadolinium MRI (bottom left image) shows enhancing nodules (red arrows). b Lumbar spine MRIs of a woman in her 20s presenting with bilateral lower extremity numbness, gait imbalance, and neurogenic bladder and bowel, found to have ECD associated with CSF1R mutation. Sagittal lumbar spine T1-weighted post-gadolinium MRI (top right image) shows leptomeningeal enhancement of the lower thoracic cord and conus (yellow box). Axial lumbar spine T1-weighted post-gadolinium MRI (bottom right image) shows an enhancing cauda equina nerve root (red arrow).

Systemic imaging

All 19 patients underwent systemic imaging confirming the absence of systemic histiocytic neoplasm. F-18 fluorodeoxyglucose body PET/CT was undertaken in 16/19 patients. Tc99m methylene diphosphonate bone scan and CT of chest, abdomen, and pelvis were undertaken in 2/19 patients. Four of 19 patients had body PET/CT, nuclear bone scan, and CT of the chest, abdomen, and pelvis. One patient had a radiographic bone survey and CT of the chest.

The most recent time systemic imaging was completed after confirmation of nervous system involvement was a median of 30.7 months (range 0–225 months). In 3/19, systemic imaging was only completed at the time of CNS involvement. Sixteen of the 19 patients (84%) had sustained isolated nervous system involvement, with the latest median time of systemic imaging after nervous involvement being 7.5 months (range 0–225 months). Among the 3/19 patients (16%) who later developed systemic involvement, 2 had ECD with systemic involvement being detected at 5 months (bone involvement) and 11 months (widespread lymphadenopathy) after isolated nervous system involvement. One had LCH with systemic involvement detected 69 months (cutaneous involvement) after isolated nervous system involvement.

MRI features

Abnormal enhancement of specifically affected regions was seen in all 19 patients (Supplementary Table 3). Thirteen of 19 (68%) had mass effect present.

In LCH, there was primarily pituitary (5/6) and hypothalamic involvement (4/6), seen as thickening and/or enhancement of the infundibulum (Fig. 1(ii)) or hypothalamus (Fig. 1(ii)). In ECD, the brainstem (5/7) (Fig. 1(iii)) and cerebellum (4/7) (Fig. 1(iii)) were primarily involved. An illustrative example of an ECD patient having an intramedullary expansile spinal cord mass is shown (Fig. 1(iii)). Four of 7 ECD patients had spinal nerve root disease; no patients with LCH or RDD had peripheral nervous system involvement. In RDD, isolated dural involvement was seen in the majority (5/6), which could present as a mass lesion (Fig. 1(iv)).

Treatment and outcomes

Treatments undertaken included surgery, radiation, steroids, chemotherapy, other immunotherapy, BRAF inhibitors, and mitogen-activated protein kinase (MEK) inhibitors. Treatments used and clinical and radiologic responses are summarized (Table 1).

Table 1 Summary of Histiocytosis Involvement, BRAF V600E Mutation Status, Treatments Used, and Outcomes.

Among the 4 BRAF V600E-positive patients, 2 were treated with a BRAF inhibitor (vemurafenib). In 6/19 cases, an MEK inhibitor was used, which included cobimetinib, trametinib, or binimetinib. All 6 LCH cases had some response to treatment radiologically, but most remained with stable clinical disease given ongoing diabetes insipidus and endocrinopathies requiring replacement.

Eighteen patients had available clinical and radiologic follow-up data at 3 months and beyond. At the last clinical follow-up, 44% (8/18) had a response to treatment (complete, partial), 33% (6/18) had stable disease, and 22% (4/18) had progressive disease. At the last imaging follow-up, 61% (11/18) of patients had any response to treatment (complete, partial), 6% (1/18) had stable disease, and 33% (6/18) had progressive disease.

CSF1R mutation-associated histiocytic neoplasms

Two ECD patients had a gain of function CSF1R mutation. They had a conserved clinical and MRI phenotype with leptomeningeal and lumbar nerve root involvement (Fig. 1(v)). They did not harbor any other myeloid neoplasm. Both were treated with pexidartinib. One patient had a partial response [3] for 3.5 years and then developed progressive disease; the other had a response for 1 year, but then developed progressive disease due to the development of malignant histiocytosis with TP53 mutation.