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Clinical considerations and key issues in the management of patients with Erdheim-Chester Disease: a seven case series.

Mazor RD, Manevich-Mazor M, Kesler A, Aizenstein O, Eshed I, Jaffe R, Pessach Y, Goldberg I, Sprecher E, Yaish I, Gural A, Ganzel C, Shoenfeld Y - BMC Med (2014)

Bottom Line: Infliximab facilitated pericardial effusion volume reduction.Cladribine improved cerebral blood flow originally compromised by perivenous lesions.ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

View Article: PubMed Central - PubMed

Affiliation: The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel. shoenfel@post.tau.ac.il.

ABSTRACT

Background: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management.

Objectives: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients.

Methods: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness.

Results: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-α treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions.

Conclusions: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

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Related in: MedlinePlus

Skin lesions of patients #2 and #3. (A) Yellowish periorbital xanthelasma-like lesions in patient #3. (B) A red yellow papule, 8 mm in size, over the right flank of patient #2.
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Fig8: Skin lesions of patients #2 and #3. (A) Yellowish periorbital xanthelasma-like lesions in patient #3. (B) A red yellow papule, 8 mm in size, over the right flank of patient #2.

Mentions: A 50-year-old man of Iraqi descent presented to an outpatient dermatology clinic in September 2010, complaining of asymptomatic skin lesions which had been recurring and remitting over the past seven years (Figure 8B). Upon an elaborated history, the patient disclosed suffering from mild lower limb pain, loss of libido and increased thirst and urination for the past seven years, as well. On examination, 10 red-yellow papules, 4 to 8 mm in size, were observed over his trunk and extremities. Laboratory findings revealed decreased levels of testosterone (3 nmol/L), lutenizing hormone (LH) (0.3 mIU/mL) and follicle-stimulating hormone (FSH) (0.4 mIU/mL). A 24 hour urine collection concluded in increased urine volume (3.2 L) and decreased urine osmolality. These findings led to the diagnosis of central diabetes insipidus and hypogonadotropic hypogonadism; thus, the patient initiated treatment with intranasal desmopressin and monthly intramuscular injections of choriogonadotropin alfa. Other laboratory tests including a complete blood count, thyroid hormones, lipid profile, viral serologies, protein electrophoresis, purified protein derivative (PPD), angiotensin-converting enzyme (ACE) and tumor markers were without pathological findings. Several imaging studies were conducted. Plain radiography demonstrated marked osteosclerosis of the tibiae and fibulae. A 99mTc bone scintigraphy revealed intense symmetric bilateral uptake of tracer in the diametaphyseal regions of the distal femurs and proximal tibiae (Figure 1B). A brain MRI demonstrated thickening of the pituitary stalk and several cluster-like nodular enhancing lesions involving the left cerebellum in close proximity to the fourth ventricle (Figure 6D,E). Also, multiple punctate hypointensities were noted in the basal ganglia in SWI sequence (Figure 3G). This pattern is not typical of senile calcifications. The most prominent finding in this patient’s workup was that of intracranial soft tissue infiltrating posterior to the confluence of sinuses and sheathing the superior sagittal and left transverse sinus (Figure 3H-I). A whole body CT scan showed infiltration of the perirenal fat and bilateral enlargement of the adrenal glands. Three biopsies were eventually conducted: one of a skin lesion and two bone marrow biopsies. Surprisingly, both of the bone marrow biopsies exhibited normal bone marrow. However, the skin biopsy revealed histiocytes of varied morphology embedded in a lymphocytic infiltrate. The histiocytes stained positive for CD68 and negative for CD1a and Factor XIIIa. Electron microscopy of the specimen showed clusters of lipid droplets, with no evidence of Birbeck granules. These pathological findings were supportive of the diagnosis of ECD. Since his diagnosis in October 2010, the patient deteriorated on several occasions, exhibiting a repertoire of signs and symptoms. Among them were both constitutional and neurological symptoms. The various emerging phenomena included episodes of increased intracranial pressure with papilledema, ataxia, dysarthria, pathological crying and laughing, hyper-reflexia and nystagmus. The variety of these symptoms prompted a more thorough evaluation of cerebral blood flow. Both CT venography and later MR venography demonstrated attenuated flow in the superior sagittal sinus due to external compression on the vessel, displacing it from the skull. Also, a complete collapse of the left transverse sinus was noted. Over the three years following the diagnosis the patient was treated with monthly four to five day courses of cladribine IV, administered intravenously at dosages of 4.5 to 4.8 mg daily (0.07 mg per kg of body weight daily). The patient received a total of 13 courses of cladribine, which resulted in a significant improvement in his fatigue and weakness. In addition, a decrease in the episodes of papilledema and stabilization of his neurological symptoms were noted along with an evident radiological decrease in the amount of infiltrative tissue compressing the superior sagittal sinus.Figure 8


Clinical considerations and key issues in the management of patients with Erdheim-Chester Disease: a seven case series.

Mazor RD, Manevich-Mazor M, Kesler A, Aizenstein O, Eshed I, Jaffe R, Pessach Y, Goldberg I, Sprecher E, Yaish I, Gural A, Ganzel C, Shoenfeld Y - BMC Med (2014)

Skin lesions of patients #2 and #3. (A) Yellowish periorbital xanthelasma-like lesions in patient #3. (B) A red yellow papule, 8 mm in size, over the right flank of patient #2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4248471&req=5

Fig8: Skin lesions of patients #2 and #3. (A) Yellowish periorbital xanthelasma-like lesions in patient #3. (B) A red yellow papule, 8 mm in size, over the right flank of patient #2.
Mentions: A 50-year-old man of Iraqi descent presented to an outpatient dermatology clinic in September 2010, complaining of asymptomatic skin lesions which had been recurring and remitting over the past seven years (Figure 8B). Upon an elaborated history, the patient disclosed suffering from mild lower limb pain, loss of libido and increased thirst and urination for the past seven years, as well. On examination, 10 red-yellow papules, 4 to 8 mm in size, were observed over his trunk and extremities. Laboratory findings revealed decreased levels of testosterone (3 nmol/L), lutenizing hormone (LH) (0.3 mIU/mL) and follicle-stimulating hormone (FSH) (0.4 mIU/mL). A 24 hour urine collection concluded in increased urine volume (3.2 L) and decreased urine osmolality. These findings led to the diagnosis of central diabetes insipidus and hypogonadotropic hypogonadism; thus, the patient initiated treatment with intranasal desmopressin and monthly intramuscular injections of choriogonadotropin alfa. Other laboratory tests including a complete blood count, thyroid hormones, lipid profile, viral serologies, protein electrophoresis, purified protein derivative (PPD), angiotensin-converting enzyme (ACE) and tumor markers were without pathological findings. Several imaging studies were conducted. Plain radiography demonstrated marked osteosclerosis of the tibiae and fibulae. A 99mTc bone scintigraphy revealed intense symmetric bilateral uptake of tracer in the diametaphyseal regions of the distal femurs and proximal tibiae (Figure 1B). A brain MRI demonstrated thickening of the pituitary stalk and several cluster-like nodular enhancing lesions involving the left cerebellum in close proximity to the fourth ventricle (Figure 6D,E). Also, multiple punctate hypointensities were noted in the basal ganglia in SWI sequence (Figure 3G). This pattern is not typical of senile calcifications. The most prominent finding in this patient’s workup was that of intracranial soft tissue infiltrating posterior to the confluence of sinuses and sheathing the superior sagittal and left transverse sinus (Figure 3H-I). A whole body CT scan showed infiltration of the perirenal fat and bilateral enlargement of the adrenal glands. Three biopsies were eventually conducted: one of a skin lesion and two bone marrow biopsies. Surprisingly, both of the bone marrow biopsies exhibited normal bone marrow. However, the skin biopsy revealed histiocytes of varied morphology embedded in a lymphocytic infiltrate. The histiocytes stained positive for CD68 and negative for CD1a and Factor XIIIa. Electron microscopy of the specimen showed clusters of lipid droplets, with no evidence of Birbeck granules. These pathological findings were supportive of the diagnosis of ECD. Since his diagnosis in October 2010, the patient deteriorated on several occasions, exhibiting a repertoire of signs and symptoms. Among them were both constitutional and neurological symptoms. The various emerging phenomena included episodes of increased intracranial pressure with papilledema, ataxia, dysarthria, pathological crying and laughing, hyper-reflexia and nystagmus. The variety of these symptoms prompted a more thorough evaluation of cerebral blood flow. Both CT venography and later MR venography demonstrated attenuated flow in the superior sagittal sinus due to external compression on the vessel, displacing it from the skull. Also, a complete collapse of the left transverse sinus was noted. Over the three years following the diagnosis the patient was treated with monthly four to five day courses of cladribine IV, administered intravenously at dosages of 4.5 to 4.8 mg daily (0.07 mg per kg of body weight daily). The patient received a total of 13 courses of cladribine, which resulted in a significant improvement in his fatigue and weakness. In addition, a decrease in the episodes of papilledema and stabilization of his neurological symptoms were noted along with an evident radiological decrease in the amount of infiltrative tissue compressing the superior sagittal sinus.Figure 8

Bottom Line: Infliximab facilitated pericardial effusion volume reduction.Cladribine improved cerebral blood flow originally compromised by perivenous lesions.ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

View Article: PubMed Central - PubMed

Affiliation: The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel. shoenfel@post.tau.ac.il.

ABSTRACT

Background: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management.

Objectives: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients.

Methods: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness.

Results: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-α treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions.

Conclusions: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

Show MeSH
Related in: MedlinePlus