Multifocal intra-cranial masses: Late presentation of an uncommon histiocytic disorder
Multifocal intra-cranial masses: Late presentation of an uncommon histiocytic disorder
Author links open overlay panelDylan Purkiss DO a, Dan Xu MD a, Lauren Borecky MD a, Adina Achiriloaie MD a, Kyle Hurth MD, PhD b, Alfred Yamamoto MD c, Ravi Raghavan MBBS, MD, MRCPath a
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Abstract
We present a case of a 59-year-old female with headaches and memory loss. Her history includes surgeries for hydronephrosis and a mediastinal mass initially diagnosed as retroperitoneal fibrosis. Imaging performed a few years later revealed multiple bilateral supratentorial masses. Biopsy confirmed Erdheim-Chester Disease (ECD), a rare, non-Langerhans cell histiocytosis with multi-system involvement, expression of histiocyte markers CD68 and CD163, and a BRAF-V600E mutation. This case emphasizes the importance of considering rare conditions in differential diagnoses and using a multimodal approach that integrates clinical, radiological, and histopathological data. Early identification and tailored treatment, including targeted molecular therapies, can significantly improve patient outcomes.
Keywords
Erdheim Chester
Pseudo-tumor
Histiocytic
Hairy kidney
Intracranial mass
Introduction
Multifocal nodular masses in the adult cranial cavity, especially if they are slow-growing or relatively asymptomatic, often raise alarms in the realm of neuroradiology. The primary concerns are typically high-grade malignancies, potential metastases from systemic neoplasms, or, more rarely, primary tumors. In certain clinical or geographic contexts, the differential diagnosis may also include infectious disorders, such as tuberculomas, or inflammatory conditions like tumefactive multiple sclerosis. However, on rare occasions, the actual culprit might be a “brain tumor mimic” or “pseudo-tumor.” Ensuring a correct diagnosis often requires a diligent, multimodal approach—integrating clinical history, imaging, and representative biopsy for histopathological analysis [1].
We present an unusual case of Erdheim-Chester Disease that displayed some early hallmarks but was overlooked until the cranial cavity became involved. This paper emphasizes the need to consider such rare differentials in the list of diagnoses when patients with unusual presentations are being evaluated.
Case presentation
Clinical: A 57-year-old Hispanic female schoolteacher presented with acutely worsening headaches, loss of balance, and difficulty focusing, expressing herself, and writing. Past medical and surgical history at time of admission was significant for hypertension, hyperlipidemia, congestive heart failure, and multiple corrective surgeries for recurrent hydronephrosis secondary to bilateral perirenal masses with ureter encasement. A mediastinal mass had also been found and biopsied around 4 years before this presentation. The masses were initially diagnosed as retroperitoneal fibrosis. Her family history was significant for an aunt with rectal adenocarcinoma, and a father who died from Alzheimer’s disease. A CBC, CMP, and UA were ordered, which were within normal limits. A brain MRI and CT of the chest, abdomen, and pelvis were ordered, and neurosurgery was consulted.
Imaging: MRI during the current admission showed multiple bilateral supratentorial extra-axial masses without evidence of edema, likely indicative of slow growth. The masses exhibited isointense signal to grey matter on T1 and T2 images and enhanced homogeneously and intensely with gadolinium (Fig. 1A). Several masses were associated with a dural tail. Chest CT also showed prominent mediastinal lymph nodes.
Further enquiry into the patient’s history confirmed that a CT chest and abdomen had been performed 4 years earlier and showed an additional mass surrounding the aortic root (Fig. 1B), with evidence in past radiographs of perinephric involvement and “sheathing of the thoracic aorta” with prominent perivascular soft tissue along the aortic arch and surrounding the origins of the great vessels. Additionally, diffuse, ill-defined perinephric retroperitoneal soft tissue stranding, atrophy of the right kidney, and an indwelling left ureteral stent for treatment of hydronephrosis was seen.
Perirenal involvement is present as well, showing the “hairy kidney” sign associated with ECD (Fig. 1C).
Pathology: Multiple metastases vs meningiomas were suspected of the intracranial lesions, and a biopsy was performed. The H&E stain revealed a large unencapsulated histiocytic lesion (Fig. 2) made up of cells containing uniform round to oval nuclei and foamy cytoplasm. Admixed lymphocytes, including small aggregates, were seen. No giant cells were identified, and plasma cells were scant. There was no significant necrosis or increase in mitotic activity. No emperipolesis was seen.
Review of the initial biopsy of the retroperitoneal mass showed similar findings: an unremarkable foamy macrophage proliferation, which was negative for Langerhans cell markers Langerin and S-100 with low Ki-67 proliferation index (Fig. 3).
Immunohistochemistry & molecular genetics: Standard immunohistochemical and gene sequencing methods were followed with appropriate controls.
The cellular components stained negatively for meningioma markers EMA and SSTR2, the solitary fibrous tumor marker STAT6, and had a low Ki-67 cell proliferation index. The lesional cells were immunopositive for histiocyte markers CD68 and CD163 and negative for Langerhans cell markers CD1a and S-100. Additionally, the cells stained positive for Factor XIII. The BRAF-V600E mutant product was demonstrable in the lesion by immunohistochemistry (Fig. 2).
Sanger sequencing confirmed the BRAF mutation (c 1799T>A [p V600E]). The lesion was negative for KRAS and MAP2K1 mutations.
Outcome
The brain and cardiac masses were ultimately diagnosed as Erdheim Chester Disease, and the patient underwent a craniotomy with removal of the right-sided tumors after completing 4 months of chemotherapy. 3 years later, her cardiac masses have decreased in size and the patient returned to work, now able to walk several flights of stairs without chest pain or shortness of breath, and endorses increased exercise capacity and decreased leg swelling after starting Entresto for management of her congestive heart failure.
Diagnosis and management: Previous differential diagnoses were excluded based on the findings above. For example, although a metastatic lesion would also show multiple masses throughout the brain and body, the histopathological findings would show features of the original tumor such as gland-forming tissue for metastatic colon carcinoma, and the clinical presentation would likely include B-symptoms such as fatigue and weight loss. A meningioma was also suspected due to the dural location, slow growth, and association with a dural tail; however, the histology would show syncytial tumor cells with abundant eosinophilic cytoplasm, numerous whorls, and intranuclear pseudoinclusions with positive EMA and SSTR2 staining on IHC. Further, the patient would display neurologic symptoms based on the location of the tumor. Similar to the presentation of this patient, an intracranial infection or abscess would also produce symptoms such as headache and acute change in cognition; however, clinical features of sepsis would also be expected, imaging would show a focus of peripheral enhancement with surrounding edema in the brain, and histology would show necrosis with an increase in neutrophils rather than the uniform increase in histiocytes seen in ECD.
Thus, correlation between the imaging, morphology, and staining pattern supported a diagnosis of Erdheim-Chester disease. The absence of Langerhans cell markers ruled out Langerhan’s Cell Histiocytosis, and the absence of emperipolesis, KRAS and MAPK mutations excluded Rosai Dorfman Disease. A retrospective histopathologic review of the original biopsies from the peri-aortic/perirenal tissues at the outside hospital confirmed the presence of similar histology, immunohistochemical staining characteristics, and the presence of a BRAF V600E mutation. Following diagnosis, the patient was started on Cobimetinib and Vemurafenib, a combination BRAF V600E therapy. The right sided tumor was removed surgically a year later without complications. Over the course of treatment, the patient’s periaortic mass decreased from 2.9 cm to 1.9 cm, 4 years later.
The patient has since been treated with BRAF inhibitor therapy and the lesions are currently stable. Although prognostic factors such as CNS and retroperitoneal involvement are correlated with a decrease in overall survival, the patient’s positive response to treatment, younger age at diagnosis, and stability of lesions are factors that improve her long-term prognosis [4]. The patient is currently maintaining intermittent follow up with no further progression of disease at this time.
Discussion
Timely diagnosis was beneficial for this patient’s treatment outcome. Diagnostic delay in such settings is common, with early manifestations like diabetes insipidus “of unknown origin” possibly appearing decades before a definitive ECD diagnosis [2]. Our patient's symptoms, such as congestive heart failure secondary to aortic root involvement and headaches from intracranial masses, underline the vast clinical spectrum of ECD presentations.
Distinct radiological signs like the “coated aorta” and “hairy kidneys,” resulting from specific histiocytic infiltration patterns, are useful cues of ECD [3]. While the latter was evident in our case, the patient did not show the former. Given the poor prognosis associated with neurologic and cardiac involvement, MRI of the brain and heart is recommended for all suspected or confirmed ECD patients [4].
Histologically, our findings were consistent with the typical presentation of ECD, characterized by specific histiocyte markers. However, as imaging alone cannot differentiate ECD histiocytic infiltration from non-ECD entities, biopsies with IHC staining and molecular studies are imperative. Over 50% of ECD patients, as exemplified in our case, harbor the BRAF-V600E mutation [3,5].
Recent therapeutic advancements have transformed the management of ECD. Targeted molecular therapies, notably the BRAF inhibitor vemurafenib, have shown clinical efficacy and are now fundamental in ECD management [[4], [5], [6]]. MEK inhibitors such as cobimetinib or trametinib are treatment options for symptomatic patients without BRAF-V600E mutations who are found to have mutations in the MAPK-ERK or PI3K-AKT pathways [12]. Additionally, some patients might benefit from newer agents like pexidartinib, while older therapies such as corticosteroids and radiation are reserved for acute symptom relief [[7], [8], [9], [10], [11]]. Neoplastic agents such as cladribine or interferon-α/pegylated interferon can also be considered for symptomatic patients without access to inhibitor therapies [12].
Conclusion
The diagnosis and management of Erdheim-Chester Disease presents significant challenges due to its rare occurrence and multifaceted clinical presentations. Our case underscores the potential for misdiagnoses or delayed interventions, especially when common differential diagnoses do not align with the clinical picture. The consensus guidelines created during the International Medical Symposia on ECD highlight the importance of integrating diagnostic testing such as biopsies and full body imaging with confirmation by molecular testing and immunohistochemistry studies in patients with lesions involving multiple organ systems in order to achieve early diagnosis and avoid misdiagnosis [4]. Thus, medical professionals must maintain a high index of suspicion for rare conditions, even when faced with familiar symptoms, and maintain a low threshold to biopsy lesional tissue followed by molecular testing when ECD is on the differential. By integrating clinical, radiological, and histopathological data in a holistic diagnostic approach, early identification and tailored treatments can be achieved.
Patient consent
Written informed consent was obtained from the patient of this case, expressly authorizing the use and disclosure of their Protected Health information for the purposes of the associated manuscript. The signed original document will be retained by the authors and is available upon request.
Appendix. Supplementary materials
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References
G. Starkebaum, P. Hendrie
Erdheim–Chester disease
Best Pract Res Clin Rheumatol, 34 (4) (2020), Article 101510
J. Haroche, F. Cohen-Aubart, Z. Amoura
Erdheim-Chester disease
Blood, 135 (16) (2020), pp. 1311-1318
M.J. Koster
Erdheim-Chester disease
J.H. Stone (Ed.), A clinician's pearls & myths in rheumatology, Springer International Publishing, Cham (2023), pp. 737-742
G. Goyal, M.L. Heaney, M. Collin, F. Cohen-Aubart, A. Vagalio, B.H. Durham, et al.
Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era
Blood, 135 (22) (2020), pp. 1929-1945
S.N. Aziz, L. Proano, C. Cruz, M.G. Tenemaza, G. Monteros, G. Hassen, et al.
Vemurafenib in the treatment of Erdheim Chester disease: a systematic review
Cureus., 14 (6) (2022), Article e25935
A.A. Acosta Medina, J.P. Abeykoon, S. Zanwar, G.J. Ruan, K.L. Rech, A. Ravindran, et al.
Efficacy of MEK inhibitors in Erdheim Chester disease
Blood, 140 (Supplement 1) (2022), pp. 9733-9734
E.L. Diamond, J.H. Francis, M.E. Lacouture, V. Rotemburg, M. Yabe, K. Petrova-Drus, et al.
CSF1R inhibition for histiocytic neoplasm with CBL mutations refractory to MEK1/2 inhibition
Leukemia, 37 (8) (2023), pp. 1737-1740
R.N. Prasad, P.J. Kobalka, H.K. Perlow, D.M. Prevedello, D.M. Blakaj, R.R. Raval, et al.
Craniospinal irradiation for respiratory failure secondary to central nervous system Erdheim-Chester disease
Radiat Oncol J, 40 (2) (2022), pp. 162-168
J. Qiao, R. Ma, X. Peng, W. He
Erdheim-Chester disease with bilateral orbital masses and multi-systemic symptoms: two case reports
World J Surg Oncol, 233 (21) (2023), pp. 1-9
S.A. Banks, J.C.S. Valinotti, R.S. Go, J.P. Abeykoon, G. Goyal, J.R. Young, et al.
Neurological manifestations of histiocytic disorders
Curr Neurol Neurosci Rep, 23 (6) (2023), pp. 277-286
A.V. Geerlinks, O. Abla
Treatment of Langerhans cell histiocytosis and histiocytic disorders: a focus on MAPK pathway inhibitors
Pediatr Drugs, 25 (4) (2023), pp. 399-409
O. Abla
Management of ECD: the era of targeted therapies
Blood, 135 (22) (2020), pp. 1919-1920