Mantle Cell Lymphoma: Diagnosis and Differentiation

Germinal centers (red bracket) are sites within secondary lymphoid organs where B cells proliferate, differentiate, and undergo somatic hypermutation and class-switch recombination during an immune response. They develop dynamically after the activation of follicular B cells by activated T cells. B cells of the germinal center are subjected to selection by follicular helper T cells and dendritic cells. Some B cells become memory B cells that are enriched in the mantle zone (yellow bracket). Others differentiate into plasmablasts and plasma cells that migrate into the medullary area of the lymph node. Naive pregerminal B cells are also located in the mantle zone (yellow bracket).

Image courtesy of Lauren C Pinter-Brown, MD.

In many ways, mantle cell lymphoma (MCL) has an appearance similar to that of a reactive lymph node. Residual germinal centers are visible in this specimen from a patient with MCL (arrows).

Image courtesy of Lauren C Pinter-Brown, MD.

MCL is a mature B-cell non-Hodgkin lymphoma (NHL) derived from a subset of naive pregerminal center B cells localized in primary follicles or in the mantle region of secondary follicles. MCL accounts for 2-10% of all NHLs, with an incidence of approximately 4-8 cases per 1,000,000 persons per year.^[1] The male-to-female ratio in MCL is 4:1, and the median age at diagnosis is 68 years.^[2] BL = Burkitt lymphoma; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MALT = mucosa-associated lymphoid tissue; NK = natural killer; SLL = small lymphocytic lymphoma.

Image courtesy of Medscape.

A 50-year-old man presents to the clinic and reports experiencing a 20-lb weight loss and drenching night sweats. On physical examination, palpable lymphadenopathy is noted. An excisional lymph node biopsy is performed, and the results are suggestive of a lymphoma.

In this scenario, which of the following might be useful for differentiating MCL from other types of lymphoma?

1. Appearance under light microscopy with hematoxylin-eosin (H&E) staining
2. Immunophenotyping by flow cytometry or immunohistochemical staining
3. 11;14 translocation
4. Cyclin D1 expression on immunohistochemistry

Image courtesy of Medscape.

Answer: All are helpful in supporting the diagnosis.

Immunophenotyping is very helpful in differentiating MCL from other small B-cell lymphomas. The slide depicts results of flow cytometry of peripheral blood, showing a CD10-negative, CD5-positive, CD19-positive population, which is typical for MCL (this particular one is kappa-restricted). MCL is typically CD23-negative. About 5% of patients have CD5-negative disease and can present a diagnostic challenge. Cyclin D1 (CCND1, PRAD1, or BCL1) is overexpressed and can be a helpful test, but it is not diagnostic. An excisional lymph node biopsy is essential for documenting nodal architecture. Fine-needle aspiration (FNA) and core biopsy are not preferred.

Image courtesy of Lauren C Pinter-Brown, MD.

MCL cells are monoclonal B cells that express surface immunoglobulin (immunoglobulin M or D). They are characteristically CD5-positive and pan–B-cell antigen–positive (eg, CD19, CD20, and CD22) but lack expression of CD10 and CD23. Cyclin D1 is overexpressed. The two main lymphomas that can mimic MCL are FL and CLL. CD10 negativity helps differentiate MCL from FL, and CD23 negativity helps distinguish MCL from CLL. HCL = hairy cell leukemia; LPL = lymphoplasmacytic lymphoma; MZL = marginal zone lymphoma; PLL = prolymphocytic lymphoma; sIg = surface immunoglobulin; SLVL = splenic lymphoma with villous lymphocytes.

Image courtesy of Lauren C Pinter-Brown, MD, adapted from Medscape.

Most cases of MCL are associated with chromosome translocation t(11;14)(q13;q32), but this association is not 100% specific. The translocation involves the immunoglobulin heavy-chain gene on chromosome 14 and the BCL1 locus on chromosome 11. The molecular consequence of translocation is overexpression of cyclin D1 (coded by the PRAD1 gene located close to the breakpoint). Cyclin D1 plays a key role in cell cycle regulation and progression of cells from G1 phase to S phase through activation of cyclin-dependent kinases. Shown here is a fluorescence in situ hybridization (FISH) study for t(11;14), with fusion of the signals in yellow, indicating translocation.

Image courtesy of Lauren C Pinter-Brown, MD.

Lymph node biopsy of MCL is shown. There is diffuse effacement of nodal architecture, as evidenced by the many pink histiocytes visible on low-power magnification (×4, H&E; left). At higher magnification (×40, H&E; right), the node is replaced by a proliferation of small lymphoid cells with mild-to-moderate nuclear irregularity, clumped chromatin, and small nucleoli. Note the increased vessels and histiocytes. Mitotic activity is low.

Image courtesy of Lauren C Pinter-Brown, MD.

The immunohistochemistry stain for BCL1 (cyclin D1) is strongly positive (brown).

Image courtesy of Lauren C Pinter-Brown, MD.

Staging should be done before any treatment and should include positron emission tomography with computed tomography (PET-CT). Staging is according to the Ann Arbor criteria, as shown on the slide. Note that all cases are subclassified to indicate the absence (A) or presence (B) of the systemic B symptoms—namely, unexplained fever (>38°C), drenching night sweats, or unexplained weight loss exceeding 10% of body weight during the 6 months preceding diagnosis. In addition, the designation E may be used; this generally refers to extranodal contiguous extension (ie, proximal or contiguous extranodal disease) that can be encompassed within an irradiation field appropriate for nodal disease of the same anatomic extent. A single extralymphatic site as the only site of disease should be classified as stage IE rather than stage IV.

Colonoscopy and upper gastrointestinal (GI) endoscopy are recommended to confirm early-stage disease. Evaluation of the central nervous system (CNS) with magnetic resonance imaging (MRI) and lumbar puncture is not routinely done in the absence of concerning symptoms unless the patient has blastoid-variant MCL, which has a tendency to invade the CNS.

Image courtesy of Lauren C Pinter-Brown, MD.

A bone marrow biopsy (shown) is part of routine staging. Stage IV disease is present on diagnosis in 70% of patients. B symptoms (see slide 10) are present in 40% of patients. Less common symptoms can be caused by extranodal involvement of the GI tract, lungs, and CNS. Fatigue from symptomatic anemia could be present.

Image courtesy of Medscape.

A 74-year-old man has cytopenias, and a few small nodes are palpable. A bone marrow biopsy is performed and shows scattered paratrabecular and nonparatrabecular lymphoid aggregates (top left). A higher-power view of aggregates shows small atypical lymphoid cells (bottom left). The cells are small with moderate irregularity and nuclear convolutions, often with prominent nucleoli. Stains for CD20 (top right) and BCL1/cyclin D1 (bottom right) are positive. A lymph node biopsy is also performed.

Which of the following is a relatively new marker that can help with diagnosing MCL?

1. SOX11
2. BCL6
3. TET2
4. PAX5
5. MUM1

Image courtesy of Lauren C Pinter-Brown, MD.

Answer: SOX11 is a relatively new marker that has specificity for MCL and can be especially useful in BCL1-negative cases.

In this case, SOX11 is strongly positive (brown) on immunohistochemical staining (×20). The use of SOX11 for prognostic purposes is currently being investigated.^[3]

Image courtesy of Lauren C Pinter-Brown, MD.

A 40-year-old man presents with an unintentional 20-lb weight loss and is found to have palpable left inguinal lymphadenopathy in the clinic. Biopsy is performed and shows MCL. PET-CT shows fluorodeoxyglucose (FDG)-avid left inguinal (shown) and iliac lymphadenopathy with multiple enlarged FDG-avid lymph nodes involving the neck, chest, abdomen, and pelvis.

How should this patient be treated?

1. Nordic II regimen (rituximab with maxi-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] alternating with HiDAC [high-dose cytarabine])
2. Rituximab and bendamustine with maintenance rituximab
3. Rituximab and CHOP (R-CHOP) with maintenance rituximab
4. Rituximab alone
5. Watchful waiting with frequent surveillance

Image courtesy of Lauren C Pinter-Brown, MD.

Answer: No standard front-line regimen exists; the choice depends on individual circumstances.

The occasional patient with clinically indolent, low-risk disease may not need treatment at all and may simply be observed initially. Patients with extensive disease that is clinically progressive or symptomatic, however, should be treated. Because MCL is not generally curable, the goal is to prolong remission and extend survival. For younger, fit patients, the Nordic II regimen culminates in an autologous stem cell transplant and yields encouraging results in terms of response rates and progression-free survival (PFS).^[4,5] If a patient requires treatment but, because of age or the presence of comorbid conditions, is not a good candidate for a more aggressive approach, rituximab and bendamustine is preferred to R-CHOP as a first-line treatment approach because of its superior PFS and toxicity profile.^[6] Maintenance rituximab after first best response has been shown to reduce the risk of progression and death.

Image courtesy of Lauren C Pinter-Brown, MD.

A 64-year-old man presents with a mass involving the orbit of the right eye and some blurry vision. Examination reveals palpable cervical adenopathy, and an excisional lymph node biopsy is performed. MRI of the brain yields the image shown.

If the lesion is MCL, which subtype would you be concerned about?

1. MCL with peripheral blood predominance
2. Blastoid MCL
3. Diffuse-type MCL
4. Nodular-type MCL

Image courtesy of Lauren C Pinter-Brown, MD.

Answer: The histology (×100, shown) was initially concerning for blastoid MCL on the basis of the morphology and increased mitoses (yellow arrows). Brain biopsy confirms the presence of this MCL subtype.

Image courtesy of Lauren C Pinter-Brown, MD.

On Ki-67 staining (×20), the Ki-67 index reaches up to 60% in the most active areas (brown), a finding consistent with blastoid MCL. The Mantle Cell Lymphoma International Prognostic Index (MIPI) can be applied to determine the prognosis in a treatment-naive patient using age, Eastern Cooperative Oncology Group (ECOG) performance status, lactic dehydrogenase (LDH), white blood cell (WBC) count, and Ki-67 cell proliferation index.

Image courtesy of Lauren C Pinter-Brown, MD.

Depicted is the MIPI.^[7] For each of the four variables shown, a score of 0-3 points may be given, for a potential total score of 0-12 (top). These scores are used to stratify patients into three risk groups (bottom), which differ with respect to median and 5-year survival. ULN = upper limit of normal.

Image courtesy of Lauren C Pinter-Brown, MD.

Advanced-stage disease is common at diagnosis (70% of patients). About 75% of patients initially present with lymphadenopathy, though extranodal disease is common and is the primary presentation in the remaining 25%. Common sites of extranodal involvement include the bone marrow (>60%), blood, GI tract (often as lymphomatous polyposis), and orbit. In fact, some studies show that microscopic evidence of MCL can be found in 84% of patients with normal visual (macroscopic) findings on lower GI endoscopy and in 45% of patients with macroscopically normal findings on upper GI endoscopy. More than 90% of newly diagnosed patients with MCL have detectable MCL cells in the blood (shown), though most have a low level of circulating MCL cells.^[2]

Image courtesy of Lauren C Pinter-Brown, MD.

This PET-CT scan shows that lacrimal glands are enlarged and FDG-avid bilaterally, involved with MCL.

Image courtesy of Lauren C Pinter-Brown, MD.

In this specimen from a patient with MCL of the prostate, tumor cells show an infiltrative pattern.

Image courtesy of Medscape.

Slides show clinical and histopathologic features of skin involvement by MCL. Patient 1 has infiltrated erythematous papules on the front of the thorax (top left), and pathologic evaluation demonstrates perivascular and appendageal involvement by monotonous small lymphoid cells (bottom left). Patient 2 has a diffuse eruption of the trunk composed of small purpuric macules and papules (top right) with moderate perivascular infiltration of the upper dermis (H&E, ×200; bottom right). The inset shows blastoid morphologic features, pleomorphic type, of lymphoid cells with irregular nuclei and immature chromatin (H&E, ×1000; bottom right).

Image courtesy of Medscape.

A 69-year-old man diagnosed with stage IVB MCL is initially treated with the Nordic II regimen; he has a complete response and undergoes autologous stem cell transplant. Two years later, he presents with abdominal pain, nausea, and weight loss. On examination, he is found to have a large abdominal mass. PET-CT reveals extensive multilevel intensely FDG-avid lymphadenopathy from the neck to the pelvis, abnormal perirenal soft tissue, and masslike thickening of a long segment of ileum (shown), all FDG-avid. Biopsy confirms relapse.

At this point, which of the following is the most appropriate treatment for this patient?

1. Lenalidomide
2. Bortezomib
3. Ibrutinib
4. RICE (rituximab, ifosfamide, carboplatin, etoposide)
5. R-GemOx (rituximab, gemcitabine, oxaliplatin)

Image courtesy of Lauren C Pinter-Brown, MD.

Answer: Unfortunately, no standard options exist in this setting; any of the answers would be reasonable.

On the basis of a trial that reported a 68% overall response rate, the US Food and Drug Administration (FDA) approved ibrutinib for use in relapsed MCL if patients have received at least one previous therapy.^[8] The oral route of administration and the favorable toxicity profile make this agent an attractive second-line therapy. Many drugs have been studied for relapsed MCL, including bortezomib, lenalidomide, rituximab, and bendamustine. Other salvage chemotherapy regimens (usually including rituximab) that have been studied include hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), ICE (ifosfamide, carboplatin, etoposide), and ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), along with others. Allogeneic stem cell transplant after salvage therapy remains controversial, but data for nonmyeloablative transplants are encouraging.

Image courtesy of Lauren C Pinter-Brown, MD, adapted from Medscape.