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iMCD: The spectrum of disease and clinical behaviour - Diagnosis

James Cavet, Consultant Haematologist discusses the different pathways to diagnose iMCD.

Introduction to iMCD

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Castleman disease (CD) is a spectrum of lymphoproliferative disorders with a common histopathology.1-5

The idiopathic Multicentric Castleman Disease (iMCD) subtype is characterised by abnormal lymphoproliferation in multiple lymph node sites..1

iMCD is a rare and devasting disease that can cause multiple organ dysfunction which can lead to death - one in three patients die within 5 years of diagnosis.1,2

Cytokine storms, which often include elevated levels of IL-6, play a central role in the pathophysiology of iMCD and drive symptoms.5
Patients experience symptoms of systemic inflammation – such as fever and fatigue - that can significantly interfere with daily-life.1 Significant organ damage can also occur due to excessive and uncontrolled release of pro-inflammatory cytokines.

iMCD affects all populations, with diagnosis in patients in an age range of 2 – 80 years.1 There is limited epidemiological data on iMCD, however in the United States, approximately 540 – 960 new cases of iMCD are diagnosed each year.1

iMCD has a serious and significant impact on patient health and survival:

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  • Severe organ damage: If uncontrolled iMCD can lead to severe organ damage.1
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  • Increased risk of developing cancer: In a study of 128 patients with iMCD, the prevalence of cancer was 3-fold higher in patients with iMCD relative to age-matched controls.2
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  • Poor survival: 1 in 3 patients die within five years of diagnosis.1

Suspected iMCD

Patients with iMCD often present with a mix of symptoms which can look like an infection, and/or autoimmune/autoinflammatory disease and/or malignancy. Suspect iMCD if the patient presents with a combination of common signs and symptoms shown in Figure 1.

Figure 1: Common signs and symptoms of iMCD (note, not all iMCD patients will present all of these symptoms)

Figure 1: Common signs and symptoms of iMCD (note, not all iMCD patients will present all of these symptoms

Patients with iMCD may also have a history of fatigue, abdominal pain, cough/shortness of breath, flu-like fever, fluid accumulation and night sweats.

Other symptoms and signs that are indicative of iMCD and can be helpful in leading towards a diagnosis include:1

  • Elevated IL-6, sIL-2R, VEGF, IgA, IgE, lactate dehydrogenase and/or beta-2 microglobulin (B2M)
  • Reticulin fibrosis of bone marrow
  • Diagnosis of disorders that have been associated with iMCD: paraneoplastic pemphigus, bronchiolitis obliterans organising pneumonia, autoimmune cytopaenias, polyneuropathy (without diagnosis of POEMS-associated MCD), glomerular nephropathy, inflammatory myofibroblastic tumour

Diagnostic criteria

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Prompt and accurate diagnosis of iMCD

Prompt and accurate diagnosis of iMCD is important to reduce treatment delays and ultimately improve clinical outcomes and survival.1 Many patients are initially misdiagnosed.

Correct diagnosis is often delayed due to a combination of factors including:

  • the rarity of the disease
  • non-specific clinical symptoms
  • non-specific histopathologic features
  • lack of specific biomarkers.1,3
Because of these disease features, an iMCD diagnosis is based on clinical symptoms, laboratory results, pathology results and excluding other conditions with shared (or similar) symptoms and signs. Close collaboration between treating physicians and colleagues in pathology can support a timely and accurate diagnosis. International guidelines have been published on the diagnosis of iMCD. These guidelines recommend that patients with suspected iMCD should be examined for major and minor diagnostic criteria (covering lymph node pathology, clinical symptoms and laboratory abnormalities), as well as excluding conditions that mimic iMCD.1
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MAJOR CRITERIA: DEFINED LYMPH NODE ABNORMALITIES

For an iMCD diagnosis the patient must have:1

  • Lymph node histopathology: abnormal lymph node pathology consistent with the iMCD spectrum on an excisional lymph node biopsy. See Lymph node histopathology
  • Multicentric lymphadenopathy: Enlarged lymph nodes (short axis diameter ≥ 1cm) in 2 or more lymph node stations (determined by imaging such as computed tomography [CT] scan). See Multicentric lymphadenopathy

Both criteria must be met.

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MINOR CRITERIA: PRESENCE OF CERTAIN CLINICAL SYMPTOMS AND LABORATORY ABNORMALITIES

For iMCD the patient must present with ≥2 signs, one of which must be a laboratory abnormality.1

See Clinical symptoms and laboratory abnormalities

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EXCLUSION CRITERIA: EXCLUSION OF OTHER DISEASE WITH SIMILAR SYMPTOMS TO iMCD

Due to shared symptoms, a number of diseases must be excluded for an iMCD diagnosis.1

See Diseases for exclusion

iMCD - TAFRO patient

There is a more severe form of iMCD called the TAFRO subtype. Patients with this form of the disease have the following symptoms and signs:4

TAFRO

Patients can also have renal dysfunction and typically normal immunoglobulin levels.1

Other features of TAFRO-iMCD include:

  • High prevalence of hypervascular and mixed histopathologic features over the plasmacytic type)1
  • Platelet count is often a marker of iMCD activity – a drop in platelet count can indicate a disease flare1
  • In a study by Liu et al, 2 year-survival was 85% for this sub-type,versus 92% for non-TAFRO iMCD patients (p=0.16)2

Prompt diagnosis is especially important for these patients, as mortality in the first 6 months increases much more rapidly than in non-TAFRO patients.2

References
1. Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-57.
2. Liu AY, Nabel CS, Finkelman BS, Ruth JR, Kurzrock R, van Rhee F, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-75.
3. Sitenga J, Aird G, Ahmed A, Silberstein PT. Impact of siltuximab on patient-related outcomes in multicentric Castleman’s disease. Patient Relat Outcome Meas. 2018;9:35-41.
4. Srkalovic G, Marijanovic, I., Srkalovic, M.B., Fjagenbaum, D.C.,. TAFRO syndrome: New subtype of idiopathic multicentric Castleman disease. Bosn J Basic Med Sci 2017 [Available from: http://www.bjbms.org/ojs/index.php/bjbms/article/view/1930].
5. Nishimoto N, Kishimoto T, Yoshizaki K. Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis. 2000;59 Suppl 1:i21-7.

IL-6, Interleukin 6; sIL-2R, Soluble interleukin 2 receptor; VEGF, Vascular endothelial growth factor; IgA, Immunoglobulin A; IgE, Immunoglobulin E