Parkway Hospital CME: Extranodal Lymphomas – Presentation, diagnosis and tailored treatment
Date: 9 Jul 2021 (Friday)
Time: 1-2pm (GMT +8)
Hosted by: IHH Healthcare, Parkway Hospital
Introduction by: Dr Dawn Mya
- Senior Consultant, Haematologist, Parkway Cancer Centre, Singapore
Speaker: Dr Colin Phipps Diong
- Senior Consultant, Haematologist, Parkway Cancer Centre, Singapore
Different forms of extranodal lymphomas
- Primary CNS and intra-ocular lymphoma
- Ocular adnexal lymphoma & MALT lymphoma
- Primary testicular lymphoma
- Primary breast lymphoma / Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)
- Primary effusion lymphoma
- Cutaneous T-cell lymphoma
Primary CNS and intra-ocular lymphomas
Case 1
- 65yo man
- 3 weeks headache, 2 weeks instability
- MRI Brain: showed lesions
- PET-CT Scan: shows no other areas involved
- LDH: a marker of how fast the lymphoma cells grow (as well as tumour volume) –> in the CNS, there is only a finite space for cells to grow
- Isolated CNS lesion
- Biopsy: Immunostains show the malignant cells to be positive for LCA, CD20,CD79a, CD10, bcl 6 and Mum 1. Negative for CD3, CD5, CD30, bcl 2, and myeloperoxidase
- Diagnosis: Diffuse large B cell lymphoma (DLBCL), without leptomeningeal involvement (CSF studies (cytology and flow cytometry) were negative for lymphoma cells)
International Extranodal Lymphoma Study Group-32 phase 2 trial (Ferreri AJM et al. Lancet Haematol 2017;4:510-23)
Problem: many medications and chemotherapy cannot penetrate blood brain barrier. Hence, more is more.
Relapse rates (early and late) for extranodal lymphomas are of a bigger issues. Typically, for nodal lymphoma, we do do 6 cycles of chemotherapy, and then we stop.
However, for CNS lymphoma, we need a plan for consolidation: either radiotherapy or autologous stem cell transplantation.
- Radiotherapy group: Significant impairment in some attention and executive functions at 2 years.
- In summary: for patients who are suitable, do transplant rather than whole brain RT.
Intra-ocular lymphoma
Primary CNS lymphoma goes in hand with ocular lymphoma (retina, vitreous, optic nerve):
- Pathology is aggressive, usually DLBCL
- Hence, ocular lymphoma should be treated with the same intention as primary CNS lymphoma.
- If not, there is usually a high chance of relapse in CNS
Others
Primary dural lymphoma (i.e. intracranial lymphoma) is considered very rare.
- Indolent lymphoma
- Marginal zone pathology
- Treat differently: only use radiotherapy / surgery +/- rituximab
Ocular adnexal lymphoma & MALT lymphoma
Case 2
- 36yo female
- 3 months history of tearing, conjunctival swelling, salmon pink coloured
- Ophthalmology and conjunctival biopsy done reported as small B-cell lymphoma. Atypical lymphoid infiltrate which was CD20+, PAX5+, CD23+, BCL2+, CD10-, BCL6-, CCND1-; K1-67 10%
- Ocular adnexal lymphoma: common places of occurrence in the eye
Ki-67 is a growth or proliferation index. Small number = low growth.
MALT lymphoma
A form of small growing lymphomas, characteristics of marginal zone lymphoma. Other types in ocular adnexa tumours.
Therapy options for low grade lymphoma (do not give multiple agents chemotherapy):
- Radiotherapy
- Empiric antibiotics (e.g. doxycycline)
- Single-agent rituximab
- Watch and wait
- Intra-lesional rituximab
MALT: More commonly seen in stomach, and has association with H. pylori. First-line treatment is to eradicate H. pylori, in the hope that the marginal zone lymphoma will resolve. This has shown to be the case in almost half of the MALT lymphoma in the stomach. But if more severe types (e.g. with mutations), eradication of H. pylori will not be enough
Site of MALT/MZL: stomach, lung, ocular adnexa, spleen etc. For MALT/MZL located in the spleen:
- Usually associated with enlarged spleen (primary splenic lymphoma, usually marginal zone lymphoma)
- Also has associations with hepatitis C infections: some sort of chronic antigenic effect, where the immune system tries to kill the infection, but turns out unsuccessful. The immune system responses by changing driving lymphoma-genesis
- Hence, eradication of hepatitis C infection can usually resolve marginal zone lymphoma of the spleen.
- In summary, when a patient is diagnosed with marginal zone lymphoma, doctors must check for presence of infection, and treat accordingly.
Primary testicular lymphoma
Case 3
- 63yo man
- Presented with painless testicular swelling, no other symptoms
- CT scan: right testicular mass without abnormal FDG-uptake in other areas
- Orchidectomy: primary testicular lymphoma (only testes involved)
Primary testicular lymphomas are typically aggressive (usually DLBCL). Some characteristics and treatment modality of primary testicular lymphoma:
- Most common testicular tumour in males >60yo
- Strong tropism for CNS involvement and spread to contralateral testis, pleura, skin (not common spaces where lymphomas spread) –> important to rule out CNS involvement (lumbar puncture, MRI brain)
- Treatment: immunochemotherapy (R-CHOP)
- CNS prophylaxis (using high-dose methotrexate)
- RT to contralateral testis
- Long-term follow up, as the relapses can occur very late (up to 10 years)
Primary breast lymphoma / BIA-ALCL
Case 4
- 53yo lady, mass in left breast after self-examination
- No discharge from nipple
- Skin retraction
- Diagnosis: Pri breast lymphoma
Primary breast lymphoma
Typically aggressive (DLBCL), with propensity for CNS involvement. Treatment for primary breast lymphoma usually involves using R-CHOP, with intrathecal methotrexate.
BIA-ALCL
- Uncommon: first case reported in 1997
- Observations from reported cases: related to the type of implants. Usually associated with textured implants. (Adams WP. Plast Reconstr Surg. 2019;143:1293-94)
- Long duration between implants and presentation of BIA-ALCL: median about 8 years.
- Presentation: Late-onset peri-implant seroma (fluid-collection)
- HSA release warning (10 May 2019): cautionary statement with textured breast implants and BIA-ALCL
- Diagnosis: fluid collection (seroma): use fine-needle aspiration (FNA)
- In contrast to other types of lymphomas
- Usually: using FNA has a high propensity to miss diagnosis, and also cannot see architecture of lymphoma (impact treatment choice)
- However, for BIA-ALCL, we can use FNA due to the fluid collection
- Treatment depends on TNM stage of lymphoma
- T: Tumour extent
- N: Lymph node involvement
- M: Metastasis
- Early stages (IA, IB, IC) have usually no relapse events. However, relapse event increases to 14% at stage IIA
- IA, IB, IC, IIA: complete surgical excision – implant, fibrous capsule, assocaited capsular mass prolongs OS
- IIB, III: BV single agent
- IV: BV-CHOP (modified CHOP)
Primary Effusion lymphoma
- No mass to biopsy, and usually only presents with effusion which is usually unilateral (without lymphadenopathy)
- Do not express pan B-cell markers (e.g. CD20-)
- Diagnosis: using gel block, cytology, IHC, flow cytometry
- More rare than the other lymphomas. This type of extranodal lymphoma is usually only seen in very specific situations, for example:
- Severely immunocompromised patients (e.g. HIV, or HHV8 infected patients)
- Patients post-transplant
Cutaneous lymphomas
Cutaneous T-cells lymphomas
Majority (80%) of cutaneous lymphomas belongs to T-cells, as opposed to nodal lymphomas, where majority is B-cell. Cutaneous B-cell lymphoma takes up the other 20%
- Mycosis fungoides
- Usually diagnosed by dermatologist
- Lymphoma of effector memory T-cells
- Development: Patch –> plaque –> tumour/erythroderma (advanced)
- Variants inclue: bullous,and folliculotropic
- Treatment:
- Early stage – skin-directed treatment (e.g. topical steroids, topical chemotherapy, UVA or UVB)
- Late stage – systemic therapy
- CD30+ lymphoproliferative disease
- Sezary syndrome
- Lymphoma of central memory T-cells
- Presentation: generalised erythroderma, lymphadenopathy, sezary cells in peripheral blood (brain folds in the lymphocytes) – not all always present.
- Real way to count is by flow cytometry
- Treatment:
- ECP
- Targeted therapy
- Allogenic stem cell transplant
- Note that ECP and targeted therapy usually low response
Q&A
Q1: What are the risk factors, and how to screen for lymphomas?
Dr Colin: There is nothing much we can do to prevent, really. In certain situations, patients are at risks. E.g. MALT lymphomas: there are strong associations with chronic infections of H. pylori and hepatitis C infections. Patients who are immunocompromised or post-transplant are also at risk.
Apart from these, there isn’t really a way to prevent lymphomas. Certain lymph nodes regions are more reactive (e.g. inguinal regions, neck). The ones to check are the significant supraclavicular lymph node. Also, if the lymph node gets very large, it is advisable to get it checked.
Q2: I have once managed patient with glaucoma with WBC >20,000. Subsequently, the patient was diagnosed with lymphoma, but asymptomatic. What are your comments on incidental lymphoma?
Dr Colin: Those patients with WBC high at presentation, are usually low grade B-cell lymphoma, which are usually completely asymptomatic. Others may include: follicular lymphoma, which can present incidentally with high WBC.
More aggressive forms (e.g. DLBCL): by the time there is bone marrow involvement and circulate in blood, the patient could already quite sick and usually also comes with fever and LDH raised. A more rare type of NK-cell proliferation can also raise WBC count.
Q3: I have had 2 patients treated for cardiac lymphoma. Do you have any similar experience to share?
Dr Colin: Over the years there are a few that have pericardial involvement with DLBCL (not common to have that as the only presentation), and also intra-cardiac tumour. There is a risk of rupture, and can be fairly dangerous, hence there is a need to monitor well.
Q4: What are the signs of lymph node that is ominous for malignancy?
Dr Colin: It is difficult to say. Usually lymph nodes that are 3cm or more will have to be watched closely. But the site is also important. Lymph nodes-associated lymphomas are usually also not painful to palpation
Q5: How to advice patients with lymphomas with regards to COVID-19 vaccinations?
Dr Colin: The issues are with the chemotherapy, especially rituximab. It is not whether the vaccine is dangerous, but more of whether the vaccines will be effective or not. What I advice is for a 3 months minimum from last dose of rituximab (although we know the effect can last 6 months).
For targeted treatment (e.g. ibrutinib): patients still can go for vaccinations.
