A 70-year-old man with no significant medical history presented with progressive headache and visual disturbances. Head imaging demonstrated bilateral, symmetric masses involving the retrobulbar orbital soft tissue. Clinical evaluation showed no evidence of sarcoidosis, lymphoproliferative disease, monoclonal proteins, or elevated serum IgG4. The patient was treated with prednisone and showed partial improvement of the symptoms. A biopsy of the left orbital lesion was performed.
The correct answer is ...
Erdheim-Chester disease (ECD) is a rare and aggressive histiocytic proliferative disorder that affects most frequently men between the fourth and seventh decades of life. ECD is multisystemic and can affect essentially any organ with relative sparing of liver, spleen, and lymph nodes. Bilateral, symmetric involvement of long bones is characteristic, while perinephric and periaortic infiltration is present in approximately 50% of cases. Pituitary, central nervous system (CNS), lung, heart, and skin involvement can also be seen. ECD may be asymptomatic or may present with symptoms that vary significantly depending on the extent and distribution of the lesions. These include fatigue, fever, long bone pain, diabetes insipidus, neurologic, and respiratory symptoms.
Ophthalmic involvement by ECD was first described by Alper et al in 1983 and occurs in up to 30% of cases. Patients typically present with bilateral exophthalmos, pain, and ophthalmoplegia due to orbital involvement. Other ocular manifestations include palpebral xanthelasmas, anterior uveitis and/or vitritis, edema and atrophy of the optic disk, recurrent retinal detachments, drusen-like deposits, and atrophy of the retinal pigmented epithelium. Imaging studies usually demonstrate hypodense, infiltrating retro-orbital lesions encasing the optic nerve and extraocular muscles. Extraconal and preseptal extension, secondary involvement of the lacrimal gland, and osteosclerosis of skull and facial bones are uncommonly seen.
Histologically, ECD typically consists of an infiltrative histiocytic proliferation composed of cells with abundant, foamy (xanthomatous) cytoplasm admixed with Touton multinucleated giant cells, variable lymphoplasmacytic inflammation, and neutrophils. Background fibrosis is frequently observed and may represent the dominant component, which may lead to misinterpreting it as a reactive process. By immunohistochemistry, ECD histiocytes are positive for CD68 and CD163 and may show Factor XIIIa expression. Langerin, CD1a, S100, and OCT2 are negative. Most ECD cases harbor somatic alterations that result in activation of the mitogen-activated protein kinase (MAPK) cell signalling pathway. Among these, BRAF p.V600E mutation is present in approximately 50%–60% of cases, followed by other BRAF, ARAF, NRAS, KRAS, MAP2K1, or PIK3CA mutations. Therefore, the BRAFV600E (VE1) antibody is a useful surrogate marker to assess for this BRAF mutation, which can be subsequently confirmed by targeted sequencing.
In the orbit, the differential diagnosis of ECD includes a number of neoplastic and nonneoplastic lesions that are also rich in xanthomatous histiocytes. This group of lesions referred as orbital xanthogranulomatous disease (AXD) include: 1) adult-onset xanthogranuloma (AOX), 2) adult-onset asthma with periocular xanthogranuloma (AAPOX), and 3) necrobiotic xanthogranuloma (NBX). All three lesions show sheets of mononuclear, foamy (xanthomatous) histiocytes admixed with variable amounts of Touton multinucleated giant cells and lymphoplasmacytic inflammation. By immunohistochemistry, these histiocytes are positive for CD68, CD163, and variably for Factor XIIIa, and lack CD1a, langerin, and S100 expression.
AOX presents clinically as a localized process without systemic involvement.
AAPOX, usually bilateral and anteriorly located in the orbit, show in addition to the foamy histiocytes presence of lymphoid follicles. As its name implies, a defining feature of this entity is an association with adult-onset asthma, which may develop concomitantly or months to years following the onset of the ocular symptoms.
NBX shows areas of geographic necrosis surrounded by palisading epithelioid histiocytes and interstitial mucin deposits, which can be highlighted by Alcian blue and mucicarmine stains. NBX presents with indurated nodules and plaques, most commonly involving eyelids and periocular skin, which can ulcerate over time, leading to local tissue destruction. NBX is typically associated with paraproteinemia, multiple myeloma, B-cell lymphoma, and other lymphoproliferative disorders, so regular surveillance of these patients should be granted.
Interestingly, increased numbers of IgG4 positive cells might be seen in association with these lesions raising consideration that there is an association among IgG4 related disease and these entities. When IgG4-related disease is suspected, an increase in absolute numbers of IgG4+ plasma cells and/or increase in the IgG4+/IgG+ plasma cell ratio should be evaluated by immunohistochemistry in the affected tissue, along with clinical and serological correlation.
Lastly, ECD must be distinguished from other histiocytic neoplasms including Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). The presence of CD1a and langerin-positive histiocytes supports the diagnosis of LCH, while strong, diffuse S100 immunoreactivity is consistent with RDD. A subset of cases of ECD can occur concurrently with LCH (so-called overlap syndrome or mixed histiocytosis) or show histologic and immunohistochemical overlap with Rosai-Dorfman disease, with many of these cases also showing mixed clinical and radiological features.
The development of new therapies has drastically improved prognosis of patients with ECD. Nonetheless, prognosis is still influenced by the site and extent of infiltration, with patients showing CNS involvement carrying a worse outcome. Currently, combined targeted therapy with BRAF/MEK-inhibitors is the standard regimen of treatment, as it overcomes the limitations of using monotherapy with BRAF-inhibitors and leads to a better response, significant delay in development of treatment resistance, and longer progression-free survival. The combined use of BRAF/MEK inhibitors may also be beneficial in patients harboring other non-BRAF p.V600E mutations. Although prednisone and azathioprine are at times successful in controlling the disease, they can also delay the diagnosis if ECD is not suspected.
In summary, the diagnosis of ECD must be based on a detailed clinical, radiological, and histopathological analysis. Histologic evaluation is essential not only to confirm the diagnosis, but also to assess for the BRAF gene mutational status, as this carries significant therapeutic implications.
Maria Adelita Vizcaino Villalobos, M.D.
Fellow, Anatomic & Neuropathology
Jorge Trejo-Lopez, M.D.
Senior Associate Consultant, Anatomic Pathology
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
Diva Salomao, M.D.
Consultant, Anatomic Pathology
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science