Fibrosi Retroperitoneale Idiopatica

Transcription

GRAND ROUND
Giovedì 13.11.2014
Presentazione caso . Dr.ssa J. TURRA
Tutors: Dr. R. MIONI – Prof. R. VETTOR
Clinica Medica 3 – DIMED
La fibrosi retroperitoneale idiopatica, una
malattia rara che colpisce ogni anno circa
1.3 persone ogni milione di abitanti
(circa 800 casi al mondo)
…E’ caratterizzata dalla presenza di un tessuto
fibro-infiammatorio che generalmente
circonda l’aorta addominale e può causare
compressione degli ureteri con conseguente
insufficienza renale.
Involvement of the following sites, in order of decreasing frequency:
● Long bones (95 %)
● Maxillary sinus, large vessels, and retroperitoneum (59 % each)
● Heart (57 % )
● Lungs (46 %)
● Central nervous system (41 %)
● Skin (27 %)
● Pituitary gland and orbit (22 % each)
Empirical therapy includes cor$costeroids, tamoxifen, and azathioprine; experimental therapy includes azathioprine, cyclophosphamide, mycophenolate-‐mofe$l, cyclosporin, medroxyprogesterone acetate, and progesterone. Glucocor6coids and azathioprine are most useful in pa6ents with signs of inflamma6on (eg, raised ESR and WBC count and posi6ve ANA results). Treatment Idiopatica
Fibrosi Retroperitoneale
Medical: Glucocor6coids and azathioprine. Pts with s/s of inflamma6on (high ESR, white count, (+) ANA) benefit most oOen used in conjunc6on with surgery Mycophenolate mofe6l: case report of MM used in conjuc6on with steroids resulted in cure. Tamoxifen: a propor6on of desmoid tumors (benign fibro6c tumors) respond to tamoxifen. Mechanism unclear. Being used in idiopathic retroperitoneal fibrosis with promising results. Surgical: Relief of mechanical obstruc6on by lysis and removal of fibrosis. Allows for biopsy and adequate exclusion of malignancy. Usually medical therapy is combined with surgical approaches +/-‐ IR sten6ng of structures being compressed by fibrosis or percutaneous nephrostomy tube placement. Cor6costeroids Fibrosi Retroperitoneale Idiopatica
In 1958, Ross and Tinckler first reported the use of cor6costeroids in the treatment of retroperitoneal fibrosis. The beneficial effect is thought to be due to an6-‐inflammatory ac6on and the ability to inhibit fibro6c 6ssue matura6on. Despite their proven success, using steroids as a first-‐line therapy in retroperitoneal fibrosis remains controversial because many clinicians believe that mul6ple deep biopsies are s6ll essen6al to exclude malignancy. A standard protocol is prednisolone at 40-‐60 mg/d tapered to 10 mg/d within 2-‐3 months and discon6nued aOer 12-‐24 months. Timely dose reduc6ons and cessa6on are important because of the adverse effects associated with long-‐term steroid use. The combina6on of glucocor6coid and azathioprine is most useful in pa6ents with signs of inflamma6on (raised ESR, posi6ve ANA results, posi6ve PET findings). Steroids can be used in combina6on with surgery. Concomitant use of steroids with surgery reduced the rate of ureteric restenosis from 48% to 10%. Complica6ons of cor6costeroid treatment include obesity, Cushingoid features, striae, retarded growth, and an increased suscep6bility to infec6ons, hypertension, osteoporosis, cataracts, pep6c ulcer disease, and diabetes mellitus. Fibrosi Retroperitoneale Idiopatica
Mycophenolate mofe$l To block the prolifera$on of T cells and B cells, a combina$on of mycophenolate mofe$l (MMF) and steroid appears to be a promising op$on. Swartz et al (2008) reported their experience with high-‐dose cor$costeroid and MMF in 21 pa$ents. They used prednisone 60 mg or 120 mg qid for 3-‐6 months and tapered the dose upon clinical improvement. In addi$on, steroid-‐sparing therapy with MMF (1000 mg bid) was recommended, with discon$nua$on aNer 6-‐12 months of therapy. Complica$ons of MMF therapy included recurrent urinary infec$ons and upper gastrointes$nal disturbance. Tamoxifen Fibrosi Retroperitoneale
Idiopatica
In 1991, Clarke et al were the first to use tamoxifen, a nonsteroidal an$estrogen, in the treatment of retroperitoneal fibrosis. Tamoxifen increases the synthesis and secre$on of transforming growth factor–beta (TGF-‐b), an inhibitory growth factor, by human fetal fibroblast in vitro. In retroperitoneal fibrosis, fibroblast and immune cells in the inflammatory mass may increase their secre$on of TGF-‐b, which may then decrease the size of the fibrous plaque. Other possible mechanisms of ac$on include inhibi$on of protein kinase C, reduc$on of epidermal growth factor produc$on, inhibi$on of calmodulin, and blockage of growth-‐promo$ng histaminelike receptor. Various authors have used tamoxifen with a variable protocol (10-‐40 mg for 6 mo to 3 y). Compared with steroids, the adverse effect profile of tamoxifen is low; thus, clinicians consider tamoxifen a reasonable treatment op$on. However, the adverse effects of tamoxifen, especially an increased risk of thromboembolism and ovarian cancer, should be carefully considered for each pa$ent. Fibrosi Retroperitoneale Idiopatica
Azathioprine Azathioprine has been used when steroid therapy has failed and as a steroid-‐sparing drug. Cogan and Fastrez used a 6-‐week course of azathioprine (150 mg/d) in a pa6ent whose condi6on recurred soon aOer prednisone treatment was discon6nued. They observed a significant response with azathioprine. McDougal and MacDonell reported successful outcome in combina6on with prednisolone in a 14-‐year-‐old girl. Fibrosi Retroperitoneale Idiopatica
Prednisone + Methotrexate Prednisone given at 0.5–1 mg/kg/day depending on flare severity, tapered to 12.5–10 mg/day by month 3, 7.5–5 mg/day by month 6 and maintained at 5–2.5 mg/day un$l month 12. Methotrexate given at 15–20 mg/week un$l month 12. ANer month 12, free to con$nue or withdraw the treatment. Fibrosi Retroperitoneale Idiopatica
(A) Kaplan–Meier estimate of relapse-free survival in the 16 enrolled patients with relapsing
idiopathic retroperitoneal fibrosis.
Alberici F et al. Ann Rheum Dis 2013;72:1584-1586
Erdheim Chester Disease (ECD)
EPIDEMIOLOGY
• Erdheim-Chester disease (ECD) is a rare histiocytic disorder and the
incidence is unknown. Fewer than 500 cases have been reported in
the published literature.
• ECD has been diagnosed in all age groups, but is most common in
adults. The mean age at diagnosis is 53 years.
• There is a slight male predominance.
• Although there is speculation that ECD and other histiocyte disorders
may represent an aberrant response to infection, no infectious
etiology has been identified.
• There is no evidence that ECD is an inheritable genetic
disorder.
(Cavalli G. et al. Ann Rheum Dis 2013; 72:1691.)
Differential Diagnosis
● Langerhans cell histiocytosis
● Paget’s disease and POEMS syndrome –
● Hemophagocytic lymphohistiocytosis
● Juvenile xanthogranuloma (JXG
● Rosai-Dorfman disease (RDD, sinus histiocytosis with massive
lymphadenopathy)
• Langerhans cell histiocytosis (LCH) and ECD are both
histiocytic diseases that can involve multiple sites, most commonly
bones. Skin involvement is more common in LCH. The two entities can
usually be distinguished by morphologic and immunohistochemical
evaluation. ECD tumor cells lack central nuclear grooves and Birbeck
granules typical of LCH cells, and unlike Langerhans cell histiocytosis,
they do not express CD1a or S100
(Dagna L, et al. Rheumatology (Oxford) 2010; 49:1203.)
• Cases of concomitant LCH and ECD (ie, mixed histiocytosis) have been
described
(Hervier B. et al. Blood 2014; 124:1119.)
• Paget’s disease and POEMS syndrome
(Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes)
• the osteosclerotic lesions of bone in ECD can be confused for a variety
of metabolic bone disorders, including Paget’s disease and the POEMS
syndrome, the latter of which also causes endocrine abnormalities, thus
adding to the confusion. While the bone abnormalities of ECD often are
confined to bilateral and symmetric osteosclerosis of the diaphysis of the
long bones, Paget’s disease and POEMS syndrome generally cause less
symmetric bone abnormalities with less specific localization. ECD can
readily be distinguished from Paget’s disease and POEMS syndrome by
histologic and immunophenotypic findings on biopsy.
• Hemophagocytic lymphohistiocytosis and the related
macrophage activation syndrome are systemic disorders that
demonstrate tissue infiltration by non-neoplastic histiocytes. Unlike
ECD, these disorders demonstrate prominent hemophagocytic
activity in the biopsy, and are also characterized by a number of
other findings including fever, hypertriglyceridemia,
hypofibrinogenemia, hyperferritinemia, and bicytopenia
• Juvenile xanthogranuloma (JXG) is a benign proliferative
disorder of histiocytic cells of the dermal dendrocyte phenotype.
• JXG belongs to the broad group of non-Langerhans cell
histiocytoses and is typically a disorder of early childhood.
• JXG presents in the first two years of life as a solitary reddish or
yellowish skin papule or nodule, most often on the head, neck, and
upper trunk. Histologically and immunophenotypically, JXG is
indistinguishable from ECD.
• JXG generally follows a benign course with spontaneous resolution
over a period of a few years. Less commonly, skin lesions can be
multiple. Extracutaneous or systemic forms (brain, lung, kidney,
spleen, liver, bone marrow, and retro-orbital tumors) are
exceedingly rare and can be associated with considerable morbidity
• Rosai-Dorfman disease (RDD, sinus histiocytosis with
massive lymphadenopathy) - is a macrophage-related disorder that
most often presents as a systemic disorder involving lymph nodes
and other organs, or rarely can be limited to the skin. Unlike ECD,
skin lesions are firm, indurated papules. Although the pathologic
cells in RDD are the macrophages (CD14+, CD1a-, S100+/-,
CD68+), RDD is histologically distinct from the other histiocytic
diseases because the macrophages have normal-appearing
lymphocytes residing in the macrophage cytoplasm (emperipolesis).
MANAGEMENT (I)
• Not all patients with Erdheim-Chester disease (ECD) require treatment
at the time of diagnosis.
• Active treatment is typically reserved for patients with symptomatic
disease, symptomatic or asymptomatic central nervous system (CNS)
involvement, evidence of organ dysfunction, or impending organ
dysfunction.
• Treatment is suggested for patients with asymptomatic CNS
involvement because it is an independent predictor of a worse outcome
(Diamond EL, Dagna L et al. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease.
Blood 2014; 124:483)
MANAGEMENT (II)
• There is no standard treatment regimen for patients with symptomatic
ECD.
• Patients should be encouraged to enroll in a clinical trial.
• Outside of a clinical trial, treatment options include:
-
Interferon alpha
Systemic chemotherapy
Corticosteroids
Radiation therapy (only in lesion of skin)
Surgery has no clear role in the management of ECD except to address
mechanical complications, such as ureteral obstruction.
Blood 2014; 124:483)
MANAGEMENT (III)
• For most patients with ECD, we recommend the use of conventional
or pegylated interferon-alpha rather than systemic chemotherapy or
glucocorticoids.
• Systemic chemotherapy can be considered for patients who either fail
to respond to interferon-alpha or develop intolerable side effects.
• Glucocorticoids are generally reserved for patients who cannot
tolerate more aggressive systemic therapies or for patients who have
very mild symptoms and wish to avoid the potential side effects
associated with more aggressive therapies
Blood 2014; 124:483)
Treatment:
Interferon alpha:
• Conventional or pegylated interferon alpha is our preferred treatment
option for patients with newly diagnosed, symptomatic ECD outside of
a clinical trial.
• The optimal duration of treatment is unclear, but patients are usually
treated until disease progression or intolerable side effects occur.
• The risk-benefit ratio of interferon should be revisited periodically in
patients who are on treatment for more than two years
(Dagna L et al. Blood 2014; 124:483)
Treatment:
Interferon alpha:
•  Pegylated interferon alpha is started at 135 ug weekly and the dose is titrated
upwards as tolerated if patients are not responding to the initial dose to a maximum
dose of 200 ug weekly.
•  Conventional interferon alpha is started at 3 million international units (MIU) 3/
week and the dose is titrated upwards as tolerated if patients are not responding to
the initial dose to a maximum dose of 9 MIU 3/week.
•  In the largest and most comprehensive series of 53 patients with ECD, 87 % were
treated with interferon alpha for a median of 19 months. Doses ranged from 3 MIU
to 9 MIU three times weekly with conventional interferon, or 135 to 200 micrograms
weekly with pegylated interferon. Fourteen patients (26 %) died after a median
follow-up of 56 months (range, 14 to 198 months) from symptom onset, and 27
months (range, 0.7 to 165 months) from diagnosis. The one-year and five-year
survival rates were 96 and 68 percent, respectively
(Arnaud L et al. Blood 2011; 117:2778; Haroche J, et al. Arthritis Rheum 2006; 54:3330)
Treatment:
Systemic Chemotherapy (I):
The most commonly used regimen is
•  vinblastine weekly and etoposide for six weeks followed by
•  vinblastine and etoposide every three weeks until week 24.
•  Prednisone is incorporated into this regimen, as is daily 6-mercaptopurine (starting
at week nine). This regimen has demonstrated activity in other histiocytic disorders;
however, patients with ECD were not included in the published reports.
•  We consider systemic chemotherapy for patients who fail to respond to interferon
alpha or who develop intolerable side effects on interferon alpha.
(Arnaud L et al. Blood 2011; 117:2778; Haroche J, et al. Arthritis Rheum 2006; 54:3330)
Treatment:
Systemic Chemotherapy (II):
•  Methotrexate may have activity in ECD and has been used for other histiocyte
disorders High dose systemic methotrexate with leucovorin rescue may be useful in
ECD with CNS involvement given the ability of methotrexate to cross the blood brain
barrier, although this approach has not been studied
(Jeon IS Pediatr Blood Cancer 2010; 55:745)
•  Cyclophosphamide may also be active in these patients with pulmunary
infiltrations. More efficacy was observed in association with prednisone
(Bourke SC Thorax 2013; 58:1004)
Treatment:
Glucocorticoids:
• prednisone 60 mg daily for two to four weeks followed by a slow taper over 3-6
months. Patients on long term glucocorticoids should receive prophylaxis for
Pneumocystis jiroveci (previously Pneumocystis carinii) infection and may benefit from
prophylaxis for gastrointestinal ulcers
• Glucocorticoids have demonstrated clinical activity in ECD, but have not demonstrated a
survival benefit
• Glucocorticoids are generally reserved for patients who cannot tolerate more aggressive
systemic therapies or who have very mild symptoms.
(Arnaud L et al. Blood 2011; 117:2778)
Treatment:
New Biologics (Drugs):
•  anakinra is a recombinant IL-1RA. IL-1-Ra production is stimulated by
interferon-alpha and there is a case report that showed a significant
response in a small group of patients who could not tolerate interferon
alpha.(Doses; 100 mg sc/daily)
(Aouba A et al. Blood 2010; 116:4070)
•  Imatinib in the mesylate form is a plateled-derived growth factor receptor
Beta (+) that has demonstrated activity of in ECD, though the exact role of
imatinib in the treatment paradigm remains undefined. Imatinib is
considered a therapy for patients who fail to respond to or are intolerant of
interferon-alpha and vinblastine based regimens.(Doses: 400 mg os/daily)
(Haroche J et al. Blood 2008; 111:5413)
•  Infliximab is a TNF-alfa inhibitor and several reports described clinical
responses in two cases of ECD with cardiac involvement (Doses: 5-7 mg/kg
every two months.
(Dagna L et al. J Clin Oncol 2012; 30:e286)
•  Vemurafenib is a B-Raf enzyme inhibitor, used in melanoma disease, it
has been recently reported in three patients with multisystemic and
refractory ECD, carrying the BRAF V600E gene mutation, to induce a partial
clinical responses (Doses: 1920 mg/d b.i.d. after tapering 960/d b.i.d.)
• 
Treatment:
• anakinra is a recombinant IL-1RA. IL-1-Ra production is stimulated by
interferon-alpha and there is a case report that showed a significant response
in a small group of patients who could not tolerate interferon alpha
• Imatinib in the mesylate form is a plateled-derived growth factor receptor
imatinib in the treatment paradigm remains undefined. Imatinib is considered a
therapy for patients who fail to respond to or are intolerant of interferon-alpha
and vinblastine based regimens.
• Infliximab is a TNF-alfa inhibitor and several reports described clinical
responses in two cases of ECD with cardiac involvement (Dose: 5-7 mg/kg
every two months)
• Vemurafenib is a B-Raf enzyme inhibitor, used in melanoma disease, it has
been recently reported in three patients with multisystemic and refractory ECD,
carrying the BRAF V600E gene mutation, to induce a partial clinical responses
(Dose: 1920 mg/d b.i.d. after tapering 960/d b.i.d.)
• 
Treatment:
• anakinra is a recombinant IL-1RA. IL-1-Ra production is stimulated by
interferon-alpha and there is a case report that showed a significant response
in a small group of patients who could not tolerate interferon alpha
• Imatinib in the mesylate form is a plateled-derived growth factor receptor
imatinib in the treatment paradigm remains undefined. Imatinib is considered a
therapy for patients who fail to respond to or are intolerant of interferon-alpha
and vinblastine based regimens.
• Infliximab is a TNF-alfa inhibitor and several reports described clinical
responses in two cases of ECD with cardiac involvement (Dose: 5-7 mg/kg
every two months)
• Vemurafenib is a B-Raf enzyme inhibitor, used in melanoma disease, it has
been recently reported in three patients with multisystemic and refractory ECD,
carrying the BRAF V600E gene mutation, to induce a partial clinical responses
(Dose: 1920 mg/d b.i.d. after tapering 960/d b.i.d.)
Treatment:
Radiotherapy:
•  Radiotherapy has been used for local palliation, though ECD seems to be
much less responsive to radiotherapy than Langerhans histiocytosis, and
lack of response or in-field recurrence is fairly common.
•  The optimal dose and field are unknown. It has generally used doses
appropriate for aggressive lymphomas (40 to 50 Gy) when feasible rather
than the much lower doses utilized for LCH.
PROGNOSIS:
•  There is no known cure for Erdheim-Chester disease (ECD).
•  Historically the prognosis has been poor.
•  Case series of patients treated with interferon therapy have reported
five-year overall survival rates of approximately 70 -76 percent.
•  In the future the subsequent discoveries regarding the presence of
BRAFV600E mutations, in a significant fraction of patients and the
availability of BRAF inhibitors, can induce more promising resultes
(
• 
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SUMMARY AND RECOMMENDATIONS
●Erdheim-Chester disease (ECD) is a rare histiocyte disorder most commonly characterized by multifocal
osteosclerotic lesions of the long bones demonstrating sheets of foamy histiocytes infiltrates on biopsy with or
without histiocytic infiltration of extraskeletal tissues. (See 'Epidemiology' above and 'Pathogenesis' above.)
●The clinical presentation of patients with ECD varies depending upon the sites of involvement. Most patients
with ECD will have osseous involvement at the time of diagnosis and the vast majority will also have at least one
non-osseous site of involvement with the most common sites being the maxillary sinus, heart and great vessels,
retroperitoneum, lungs, and central nervous system (including the pituitary gland and orbit). (See
'Clinical manifestations' above.)
●ECD is diagnosed based upon the pathologic evaluation of involved tissue interpreted within the clinical context.
ECD can be difficult to diagnose since it is a very rare disease that can affect many organ systems. A biopsy of an
osteosclerotic bone lesion is generally preferred, when possible. (See 'Pathologic features' above and
'Diagnosis and differential diagnosis' above.)
●Not all patients with ECD require treatment at the time of diagnosis. For patients who are asymptomatic without
evidence of central nervous system (CNS) involvement or organ dysfunction, we suggest a period of observation
rather than immediate treatment (Grade 2C).
●There is no standard treatment regimen for patients with symptomatic ECD and patients should be encouraged
to enroll in a clinical trial. We use the following approach for the management of patients outside of a clinical trial
(see 'Clinical trials' above):
•For most patients with ECD, we recommend the use of conventional or pegylated interferon-alpha rather than
systemic chemotherapy or glucocorticoids (Grade 1C).
•For patients who fail to respond to or cannot tolerate interferon-alpha, we suggest treatment with vinblastine,
etoposide, prednisone, and 6-mercaptopurine modeled after protocols used for Langerhans cell histiocytosis
(Grade 2C). Glucocorticoids are generally reserved for patients who cannot tolerate more aggressive systemic
therapies. Radiotherapy may be used for local palliation.
●Patients with ECD are at risk of developing potentially life-threatening complications due to the compression of
normal structures. Mechanical measures such as percutaneous nephrostomy and cardiac valve replacement may
also become necessary in select patients. In addition, a high percentage of patients will develop diabetes insipidus
and other endocrinopathies due to hypopituitarism. Regardless of systemic therapies, endocrinopathies including
diabetes insipidus should be corrected. Pre-existing diabetes insipidus and endocrinopathies typically persist, even
with radiographic regression of disease.

Fibrosi Retroperitoneale Idiopatica

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