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Diagnosing mantle cell lymphoma (MCL)

MCL is diagnosed based upon detailed patient history, thorough clinical evaluation and a variety of specialised tests, including a biopsy of an affected lymph node or the bone marrow[1]. Such testing is necessary to[1]:

  • Confirm the specific type (and subtype) of NHL present
  • Assess the nature and extent of the disease
  • Determine the most appropriate treatments

Risk stratification and prognosis in patients

Because treatment may differ depending on disease stage, in-depth evaluation should occur at initial staging.[2][3]

The risk assessment can help plan the next steps for treatment of MCL by dividing it into[2][3]:

  • Indolent disease – watch and wait

OR

  • Aggressive disease – active treatment

MIPI

A way to predict the outlook for patients with MCL was developed – The Mantle Cell International Prognostic Index (MIPI). It is a classification tool that enables patients to be grouped as low, medium or high risk.[4][5]

Probability of overall survival (OS) over time in MCL patients based on the MIPI risk stratification[4]
Overall survival

Adapted from Vose et al. 2017.

The independent prognostic factors for shorter OS identified by MIPI were higher age, worse ECOG performance status, higher LDH, and a higher white blood cell count at diagnosis.[4][5]

Simplified MIPI Prognostic Index[4]
Points
Age (years)
ECOG PS
LDH/ULN LDH
WBC 109/L
0
<50
0-1
<0.67
<6.700
1
50-59
-
0.67-0.99
6.700-9.999
2
60-69
2-4
1.00-1.49
10.00-14.999
3

≥70

-

1.50

15.000

For each prognostic factor, 0–3 points were given to each patient to a maximum of 11.

  • Patients with 0–3 points in total were classified as low-risk, patients with 4–5 points as intermediate-risk, and patients with 6–11 points as high-risk
  • ECOG PS was weighted with 2 points if patients were unable to work or bedridden (ECOG PS 2–4)

Ki-67 index

Another strong predictor for the survival of patients with MCL is the Ki-67 proliferation index.[6] It is the most important prognostic factor used in routine clinical practice.[7] Ki–67 is a protein linked to cell proliferation, thus measuring Ki-67 provides an indication on the rate of cellular growth.[8] The Ki-67 proliferation index is the percentage of mantle cell lymphoma cells that express Ki-67.[9]

Ki-67 proliferation index (%).[9]
Median survival (months).[9]
<10
42
10-40
30
>40
15

The Ki-67 proliferation index is the % of mantle cell lymphoma cells that express Ki-67.[9]

MIPI-c

MIPI and Ki-67 can be combined to create the combined MIPI (MIPI-c).[4] The MIPI-c provides a more accurate representation of the predicted survival for patients with MCL compared with MIPI and divides patients into four groups: low, low-intermediate, high-intermediate or high risk.[7]

MIPI and Ki-67 index in MIPI-c classification[2]

MIPI risk group (weights in MIPI-c)
Ki-67 index (weight in MIPI-c)
MIPI-c risk group (sum of weights)
Low (0)
<30% (0)
Low (0)
Low (0)
≥30% (1)
Low-intermediate (1)
Intermediate (1)
<30% (0)
Low-intermediate (1)
Intermediate (1)
≥30% (1)
High-intermediate (2)
High (2)
<30% (0)
High-intermediate (2)
High (2)
≥30 (1)
High (3)

Clinical and molecular characteristics predict outcomes in MCL patients[10][11]

OS stratified by MIPI-c in the European MCL younger/MCL elderly cohort[10]
Graph OS stratified by MIPI-c in the European 
MCL younger/MCL elderly cohort
OS according to Ki-67 index[10]
Graph OS according to KI-67 index


OS according to blastoid vs non-blastoid cytology[10]
Graph OS according to blastoid vs non-blastoid cytology
Estimate of OS with or without TP53 deletions and mutations[11]
Graph Estimate of OS with or without TP53 deletions and mutations

Types of mantle cell lymphoma

For treatment purposes, MCL has been categorised into two major subgroups, which were included in the WHO 2016 update of lymphoid malignancies.[12] The subgroups of MCL are distinct in clinical presentation and molecular features.[12]

  • Conventional MCL (70–80% of MCL cases)[3]
    Symptomatic lymph adenopathy or symptomatic extra-nodal disease requiring systemic therapy. It is typically seen in 70–80% of patients with MCL.[3] This is a bulky nodal/extranodal variant with an aggressive disease course.[3]
  • Smouldering nodal/extra-nodal MCL and asymptomatic purely leukaemic non-blastoid MCL (10–20% of MCL cases)[3]
    Given that standard therapy does not appear to cure MCL, a ‘watch and wait’ strategy for elderly patients and those with asymptomatic or low MIPI MCL should be considered.[3] It is typically seen in 10–20% of patients with MCL.[3] In most cases, this type is generally associated with an indolent disease course and superior outcome.[3]
  • In situ MCL
    In situ MCL is rare and is characterised by the presence of CD5+ and cyclinD1+ small lymphocytes in the mantle zone of the follicle in a morphologically reactive lymph node.[7][12][13] Currently, patients with in situ MCL are monitored with a ‘watch and wait’ approach.[14]

Symptoms of mantle cell lymphoma

Patients with MCL may initially present in a primary care setting with persistent but non-specific symptoms, including swelling of lymph nodes, unintentional weight loss or night sweats.[3] It should be noted that asymptomatic presentation accounts for around 10–20% of MCL cases.

At this stage, the primary care physician should take the patient’s medical history, perform a physical examination and request initial blood tests, including complete blood count and blood film.[3][7] If lymphoma is suspected, a referral will then be made.

Symptoms to note include[6]:
fever

Fever

pain

Abdominal pain

bleeding

Bleeding

fatigue
Fatigue
Atypical lymphocytes
Atypical lymphocytes
Hepatomegaly
Hepatomegaly
itching
Itching
CNS involvement
CNS involvement
Unintentional weight loss

Unintentional weight loss

enlarged spleen
Enlarged spleen
night sweats
Night sweats

Diagnostic pathway


Confirming a diagnosis of MCL can involve several steps and a series of investigative tests.[2][3][4]

Primary care[3][7]

  • Palpable lymph nodes
  • Blood analyses (CBC with differential, blood smear) showing abnormal cytomorphology
arrow


Specialist testing[2][7][15]

  • Essential:
    – Surgical specimen, preferably a lymph node biopsy
    – Immunohistochemistry and cytology: CD5/10/19/20/23, BCL2/6, cyclin D1, Ki-67
  • Useful in certain circumstances:
    a. Radiology testing
    – CT scan (neck, thorax, abdominal, pelvic)
    b. In leukaemic cases
    – Bone marrow biopsy: FACS (CD5/19/20Þ) and FISH t(11;14), t(14;18)
    – LDH
    – Uric acid
    – Liver function
    – Renal function
    c. If indolent disease considered: SOX11 or IGHV
arrow


Evaluation[2][7][15]

  • Specialist determines prognosis using MIPI-c
  • Watch and wait
  • Start treatment
arrow


First-line therapy choice[2][7][15]

  • Regimen chosen based on the nature of the lymphoma, patient age, physical fitness and local/national/international guidelines

Mantle cell lymphoma diagnostic test

To confirm an MCL diagnosis, a biopsy or analysis of a sample may undergo a few tests.[4][7]

A biopsy or sample can be taken from[4][7]

  • An involved lymph node or extranodal site (e.g., the colon, stomach or salivary gland)
  • Bone marrow
  • Peripheral blood in cases where malignant B cells are present in the circulation
Diagnosis of MCL
Microscopic examination
Immunophenotypic evaluation
Genetic testing

Microscopic examination of involved lymph node or tissue is a key part of the diagnosis of MCL.

A diagnosis of MCL requires histopathological confirmation of lymph node infiltration. A part, or all, of an easily accessible, enlarged lymph node is removed.[2]

The histological report should give the diagnosis according to the WHO classification and Ki-67, a proliferation marker, the most established histomorphological risk factor.[2]

Most tumours have a classic structure of small-medium sized cells with irregular nuclei. However, malignant lymphocytes may present in a variety of forms.[2]

In some cases, MCL cells can resemble other forms of B-cell malignancy in appearance, making diagnosis more challenging.[7] Examples include[9]

  • A small cell variant (3.6% of cases)
  • A blastoid variant (2.6% cases)
  • A pleomorphic variant (5.9% cases)

Clinical presentation

MCL subtype
Clinical features[3]

Conventional MCL

  • Symptomatic bulky/nodal/extra-nodal disease
  • Classic or blastoid/pleomorphic cytomorphology
  • Signs of clinical progression

Smouldering nodal/extra-nodal MCL

  • Lack of B symptoms (drenching night sweats, unintentional weight loss in ≤6 months of >10% of normal body weight, fever >38°C)
  • Normal serum LDH, β-2 microglobin levels
  • WBC <30,000 x WBC 109/
  • Low MIPI score
  • Ki-67 ≤30% on lymphoma cells in non-marrow tissue biopsy
  • Non-blastoid pleomorphic cytomorphologic pattern in tissue biopsy
  • Max lymph node diameter <3 cm, spleen size <20 cm
  • PET scan showing the maximum SUV <6
  • DNA sequencing lacks TP53 or NOTCH1/2 mutations
  • FISH testing shows no deletion 17p or MYC translocation and an absence of complex karyotype

Asymptomatic purely leukaemic non-blastoid MCL

  • Monocloncal B lymphocytosis (with MCL immunophenotype and non-blastoid morphology) in peripheral blood or in bone marrow with/without splenomegaly

ESMO guideline recommendations[2]

Diagnosis should be based on a surgical specimen, preferably a lymph node biopsy. Core biopsies should only be carried out in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the heterogeneity of MCL. 

In rare cases with leukaemic manifestation only, a bone marrow biopsy may be sufficient if additional diagnostic measures are applied, immunophenotype (CD5+, CD19/20+), detection of t(11;14)(q13;q32) and overexpression of cyclin D1. Fine needle aspirations are inappropriate for a reliable evaluation of additional risk factors (cytology, cell proliferation). 

A histological report should give the diagnosis according to the WHO classification and Ki-67 as the most established histomorphological risk factor. 

Most tumours have a classic morphology of small-medium sized cells with irregular nuclei. However, the malignant lymphocytes may present with a spectrum of morphological variants, including small round (resembling chronic lymphocytic leukaemia), marginal zone-like, pleomorphic and blastoid cells. 

In the updated WHO classification, a leukaemic non-nodal subtype has been characterised based on the clinical presentation usually with a more indolent clinical course. As only the minority of these cases is correctly diagnosed based on classical histology only, review by an expert haematopathologist is advised. In particular, additional immunohistochemistry for detection of cyclin D1 overexpression is mandatory. 

In the rare cyclin D1–negative cases, detection of SOX11 may help to establish the diagnosis.

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CBC=complete blood count; CT=computerised tomography; DNA=deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; ESMO=European Society for Medical Oncology; FACS=fluorescence-activated cell sorting; FISH=fluorescence in situ hybridisation; LDH=lactate dehydrogenase; NHL=non-Hodgkin lymphoma; PET=positron emission tomography; SUV=standardised uptake value; WBC=white blood cell; WHO=World Health Organization.

This site has been developed by Janssen-Cilag International NV. Janssen-Cilag International NV is the responsible editor of this document.

ITEM CODE: CP-233134 | DATE OF PREPARATION: June 2021

References

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