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Q1. Compare and contrast the diagnosis, prognosis and treatment of Hodgkin Lymphoma and
Multiple Myeloma.
Introduction
Haematological malignancies are a distinct group of liquid cancers that disturb the blood, bone
marrow and lymphatic system. Hodgkin Lymphoma (HL) and Multiple Myeloma (MM) are
two examples of haematological cancers which affect the lymphoid progenitor lineage
originating from the hematopoietic stem cells (figure 1). HL is an uncommon yet aggressive
cancer that develops in the lymphatic system and leads to clonal expansion of neoplastic B
cells. It afflicts approximately 2,100 people each year in the UK and can be easily treated,
resulting in a very low mortality rate (~1%) [1]. On the other hand, MM is known for a rapid
accumulation of neoplastic plasma cells in the bone marrow (IgM or IgG) and accounts for 2%
of all new cancer cases. Besides being more prevalent, it results in 3,100 deaths in the UK
every year and leads to severe disability within society [2]. This essay will discuss the diagnosis,
prognosis, and treatment of these two different yet similar blood cancers.
Figure 1. Haematopoietic stem cell
lineages, indicating the lymphoid
progenitor lineage and cells being
affected in multiple myeloma
(MM) and Hodking Lymphoma
(HL)
Diagnosis- identification of Hodgkin Lymphoma and Multiple Myeloma
Medical diagnosis is the process of identifying a disease or condition from its signs and
symptoms. A correct diagnosis for both cancer types is crucial for monitoring disease
progression and planning treatment options. Therefore, we need to avoid false negatives, where
patients are undertreated or false positives, where patients are mistreated. Although HL and
MM are diagnosed differently, they both require recording a person’s medical history and
performing a physical exam. The pathological hallmark for HL is the presence of massive
malignant multinucleated Reed-Sternberg cells derived from B-lymphocytes in the reactive
cellular background of affected lymph nodes (figure 2). These are recognised during an
excisional biopsy where the lymph node is removed and analysed [3]. The main diagnostic
criterion for MM also requires a fine-needle aspiration or core-needle biopsy to check for >10%
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clonal plasma cells in the bone marrow. Sometimes in both MM and HL, aspirations are
inadequate because they do not represent the whole architecture of the lymph node or bone
marrow, which leads to incorrect counts or misdiagnosis [4]. Consequently, MM requires
additional confirmation with the presence of one or more CRAB criteria. In the hospital,
patients undergo blood analysis to test for elevated serum calcium (C) indicative of calcium
degradation in bones. Renal impairment (R) is tested in a urine sample by looking at high
creatinine and albumin ratios indicative of poor renal filtration. Low serum albumin (A) and
low red blood cell counts (anaemia) in blood tests are also essential for diagnosis. Lastly,
doctors use X-rays to look for lytic bone lesions (B) caused by low calcium levels. Symptoms
can be non-specific yet help doctors decide what to look for next to piece together all the
information and conclude a diagnosis. Unlike HL, MM requires further diagnosis to identify
over-proliferated antibodies that arose from monoclonal plasma cells. Serum protein
electrophoresis (SPE) is used to check for distinct bands in either beta or gamma regions
indicative of heavy chain clonality (figure 3). Immunofixation electrophoresis (IFE) provides
further specificity on the clonal involvement of light protein chains, kappa (κ) or lambda (λ)
[5]
. These tests combined can diagnose the patient as having MM instead of similar diseases
such as monoclonal gammopathy of undetermined significance (MGUS) and specify the
lambda or kappa light chains, which are essential when deciding on treatment options and
tracking the disease.
Figure 2. Micrograph showing a Reed-Sternberg cell vs
normal lymphocyte from a biopsy of a lymph node
Figure 3. Clonality: monoclonal gammopathy
shown in serum protein electrophoresis (SPE)
Prognosis- Likely course of Hodgkin Lymphoma and Multiple Myeloma
Cancer prognosis predicts disease development to help stratify treatment options and identify
patients at risk of failure or relapse. Scientists recently developed new HL prognostic factors
based not only on tumour burden but also on age, gender, serum albumin levels, WBC count,
etc. (table 1) [6]. Prognostication using the criterion allows individuals with the disease to be
categorised with an IPFP risk factor staging ranging from 0 to 5. Depending on the number of
risk factors from figure 4, the chance of commutative survival varies (figure 4), meaning that
patients with 5-7 IPFP factors are more likely to not respond to treatment. This model that tests
for different biomarkers is very effective as it allows for a rolling baseline where the IPFP score
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remeasure after three years for patient stratification. Although it cannot predict relapse, new
serum markers such as IL-6, TNF, IL-10 and TARC seem promising at prognosticating during
treatment and determining how patients respond to treatment [7].
Table 1. Prognostic factors for patients
with Hodgkin’s Lymphoma identified
by IPFP [6]
Figure 4. Time to progression for adult patients
with advanced-stage Hodgkin lymphoma and
their cumulative survival depending on IPFP
risk factor number [6]
Like in HL, staging systems also exist for MM, indicating the extent of the disease and allowing
predictions. The most common one is the International staging system (ISS) based on two main
blood test factors: beta2-microglobulin and albumin [8].
MGUS is an asymptomatic condition with a very similar diagnosis to MM, where all patients
present with MGUS do not necessarily progress to cancer, however, all MM cases develop
from an MGUS patient. A huge difference with HL is that we can prognosticate MGUS to
identify patients likely to progress to MM, which allows for a unique prognosis before disease
development and early detection of the disease. Table 2 shows the three main factors and cutoffs required for possible disease progression. FCL ratio calculated using immunopareis is one
of the most powerful monitoring and prognostic tools in oncology. Immunopareis is an isotypematched paired suppression where antibody lambda can suppress the kappa isotype and vice
versa. This leads to abnormal rations, which indicate the levels of polyclonal light chains and
indicate MM development. Depending on the risk factors present in MGUS patients, the
probability of progression varies (table 3). In contrast with HL, MM FLC ratios calculated with
immunoparesis can anticipate and predict relapse caused by clonal evolution or clonal tiding
[9]
. This technique allows disease identification at the maximal response when there is a
minimal residual disease and low tumour burden. Therefore, it is a suitable prognosis method
for possible relapses after treatment before clinical symptoms arise.
Table 2. Prognostic Factors for MGUS
patients to progress into Multiple
Myeloma Patients [10]
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Table 3. Risk stratification schemes
for MGUS where the number of risk
factors indicates the probability of
progression to MM [10]
Treatment: medical options for Hodgkin Lymphoma and Multiple Myeloma
Over the past century, HL has become a highly curable cancer in approximately 90% of patients
worldwide due to a very efficient treatment developed. The current standard of care or firstline therapy is the chemotherapy regime, ABVD: Adriamycin (A) is an intercalating agent,
Bleomycin (B) breaks DNA strands, Vinblastine (V) disrupts microtubule arrangement, and
Dacarbazine (D) alkylates DNA. Together, these drugs are given via a peripheral intravenous
line to kill cancerous cells by triggering different cell division stages and inducing apoptotic
mechanisms. Although it has a high survival rate with relatively low toxicity, some patients do
not respond to this treatment and are alternatively given the second-line treatment BEACOPP
(Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin and Procarbazine).
Although this treatment has a better initial tumour control and leads to fewer relapses, it leads
to severe hematologic toxicity, infertility and chemotherapy-related death [11].
On the other hand, there is no cure for MM, so treatment aims to reduce tumour burden, reduce
the level of monoclonal antibody produced (M spike) and improve quality of life so the patient
can enter complete remission. Although chemotherapy is also used in MM, there are other
treatments such as targeted therapy, immunotherapy and corticosteroids, which work at
reducing tumour burden. The main drugs utilised for the first-line treatment include Melphalan,
an alkylating agent and Bortezomib (Velcade) and Carfizomib which are proteasome
inhibitors. Lenalidomide/Pomalidomide/Thalidomide are teratogenic compounds involved in
immune modulation and death of rapidly replicating cells, and finally Dexamethasone is also
used as a steroidal anti-inflammatory agent [12]. Due to MM having no cure, there are more
chances of patient relapse in comparison with HL. However, the way relapses are dealt with is
very similar in both haematological cancers as it involves the combination of first- and secondline treatments with some newly introduced drugs. During MM treatment, it's essential that
immunopareis completely stops so the patient does not relapse or form secondary clones in the
background resistant to the chemotherapy previously given. The only solution to this is to
check FCL ratios that tell doctors if patients will relapse before they have any clinical
symptoms and allow quicker therapy to try to knock down the tumour again. Unlike HL, with
MM, there is an ethical debate about the possibility of treating the disease even before it
develops, therefore acting as a prevention therapy. Several studies [13] argue that because a
precursor state consistently precedes MM, the development of strategies for high-risk MGUS
could prevent myeloma development. Although smaller trials have begun to investigate
treatments with benign side effects such as targeted IL-1 receptor antagonist or curcumin, they
have not been implemented because of the ethical complications of treating healthy individuals.
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Conclusion
Hodgkin Lymphoma and Multiple Myeloma are very diverse hematologic malignancies with
a different diagnosis, prognosis and treatment. Understanding the differences between the two
cancers is essential for correctly identifying the disease and correctly managing it to offer
patients particular and efficient care. On the other hand, knowing similarities between the two
could allow scientists to understand some of the cellular mechanisms behind blood cancers and
possibilities for new treatments.
Wordcount: 1441 words
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