The treatment of hematologic malignancies is specifically challenging. Hematologic malignancies have a diverse and heterogeneous etiology and genetic pathophysiology. This exceptional diversity results in complex diagnoses and treatments of these cancers.

The three most common blood cancers are leukemia, multiple myeloma, and lymphoma. While these malignancies all start in the bone marrow, major differences exist among these cancers. This overview compares the symptoms, diagnostic workup, and treatment options for multiple myeloma, leukemia, and lymphoma.

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How Rare Are Hematologic Malignancies?

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The American Cancer Society projects that approximately 1.9 million patients will be diagnosed with cancer in the US in 2022. Hematologic malignancies comprise approximately 10% of these total incident cancer cases [1]. Lymphoma accounts for roughly 50%, leukemia 30%, and multiple myeloma 20% of all incident hematologic cancers.

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Lymphoma

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Lymphoma is divided into Hodgkin and Non-Hodgkin Lymphomas (NHL). Hodgkin lymphoma usually affects young adults, most commonly young men, except for one variant (nodular sclerosis), which affects young females. Symptoms of Hodgkin lymphoma include fever, diaphoresis, pruritis, and leukocytosis. Hodgkin Lymphoma is characterized by the presence of Reed-Sternberg, or “popcorn” cells, and has a better prognosis than NHL. The Reed-Sternberg cell variants get their name from their multi-lobated, or extremely folded nucleus.  Hodgkin lymphomas are further classified as “classical” and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).  

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Non-Hodgkin lymphoma is a malignant neoplasm that arises from lymphoid tissues originating from B-cells and T-cells. Common B-cell Non-Hodgkin lymphoma subtypes are follicular lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma. Common T-cell lymphomas include Adult T-cell lymphoma and mycosis fungoides. Overall, Non-Hodgkin lymphoma tends to affect adults older than 60 years of age at the time of diagnosis. Non-Hodgkin lymphoma patients typically present with complaints of fever, weight loss, or night sweats as well as peripheral lymphadenopathy [2].

Biopsies are taken, and a histopathological examination is done to confirm the type of lymphoma. Both Hodgkin and Non-Hodgkin lymphoma have many sub-variants, complicating the diagnosis. With modern staging systems and aggressive treatment therapies, both types of lymphoma can be treatable if diagnosed early [4].

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Diagnosing Lymphoma

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Non-Hodgkin lymphoma is the most common lymphoma variant Hematopathologists play an important role in diagnosing these cases properly. Lymph node biopsy is usually taken, and the specimen is examined to look for characteristic findings. Generally, the tests below are leveraged:

• Physical examination
• Lymph node biopsy
• Immunophenotyping
• Blood tests
• Flow cytometry
• Cytogenetic analysis
• Gene expression profiling and microarray analysis

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Leukemia

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Leukemia describes many different malignancies associated with a lymphoid or hematopoietic origin. The total number of circulating leukocytes is generally increased in leukemia patients. Leukocytes abnormally infiltrate the bone marrow and often encroach on the normal hematopoietic cells resulting in infections, anemia, or hemorrhage. These abnormally proliferating leukocytes also infiltrate various organs of the body like the liver, spleen, lymph nodes, and other organs. Much like lymphoma, leukemia can be split into several subtypes: acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

Acute lymphocytic leukemia (ALL) usually occurs in children (it is considered th emost common malignancy in children) although a second spike occurs usually after the age of 60 [6].   Risk factors associated with ALL are in utero radiation, Down syndrome, and ataxia-telangiectasia [7]. Symptoms usually arise abruptly and are associated with bone marrow suppression or hepatosplenomegaly. The most common symptoms are bone pain and generalized enlargement of lymph nodes.

Acute myeloid leukemia (AML) is characterized by the predominance of myeloblasts in the circulating blood. AML typically occurs in adults and has a poor prognosis, despite the approved therapies for the disease. Symptoms of AML typically include easy bruising, fatigue, shortness of breath, and/or weight loss [8]. Moreover, few identifiable risk factors are involved, although certain drugs, radiation, and Down Syndrome have been associated with AML.

Chronic leukemias are characterized by abnormal proliferation of mature cells. In Chronic lymphocytic leukemia (CLL), proliferating lymphoid cells infiltrate widely into bone marrow, liver, spleen, and other organs. CLL is most common in men and occurs after 60 years of age and has survival of 5 to 10 years after diagnosis in most cases [5].

Hairy cell leukemia is another variant of leukemic cells with hair-like projections. Its prominent symptoms are splenomegaly and pancytopenia. It most commonly affects middle-aged people and responds to various drug therapies.

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Chronic myeloid leukemia has a characteristic presence of the Philadelphia chromosome in the genotype of the affected individuals. It is also mostly seen in middle-aged men, is associated with splenomegaly, and can lead to blast crises. 

Diagnosing Leukemia

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There are multiple types of leukemias, and the diagnosis of these malignancies is based on many factors, including history, examination, hematologic investigations, and genetic and radiographic investigations. Histological evidence is also sometimes required to diagnose the condition accurately. Blood and bone marrow testing is typically the first line of investigation performed for diagnosing these malignancies.  

• Blood and bone marrow testing
• Bone marrow aspiration and biopsy
• Blood or bone marrow cell assessment
• Flow cytometry
• Genetic testing
• Cytogenetic analysis
• Fluorescence in situ hybridization
• Polymerase chain reaction

Overall, the diagnosis of leukemia is made by visualizing the type of blast cell present in the blood smear. Lymphoid types would have lymphocytes whereas myeloid types would have myeloblastic cells. Hairy cell type will have evidence of hair-like projections in B-cells. Similarly, Philadelphia chromosomes and other genetic mutations also manifest in genetic testing, which further helps in supporting and proving a diagnosis.

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Multiple Myeloma

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Multiple myeloma, also called plasma cell myeloma or plasmacytoma, is a malignant plasma cell tumor, that usually affects older persons. The disease typically involves the bones and is particularly associated with urinary protein abnormalities (e.g., Bence Jones proteins). The tumor cells can produce lytic lesions in the bone, commonly in the skull and axial skeleton. They may be represented radiographically as diffuse demineralization of bone (osteopenia). MM patients experience severe bone pain, and their bones are prone to spontaneous fractures.

Multiple myeloma causes a marked increase in serum immunoglobulins due to increased and abnormal protein production. The neoplastic encroachment on hematogenous cells leads to anemia, leucopenia, and thrombocytopenia. Patients with this disorder have impaired immune function, which increases their susceptibility to infections [3]. Kidney function is also compromised because of an associated condition called myeloma nephrosis. Multiple Myeloma can also result in interstitial infiltration of malignant plasma cells.

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Diagnosing Multiple Myeloma

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Several tests can play a significant role in diagnosing multiple myeloma. They include but are not limited to the following:

There is no single test that can diagnose multiple myeloma. A diagnosis is typically made by examining the blood, urine, bone marrow, or other tissues by a doctor.

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How do you treat Hematologic Malignancy?

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The treatment of a hematologic malignancy varies by subtype and the severity of the disease. An oncologist may rely on NCCN Guidelines or UpToDate for guidance when accessing treatment options. These sources provide recommended treatment algorithms and the corresponding data to support these algorithms. An oncologist may use a wide variety of therapeutic approaches, including chemotherapy, immunotherapy, CAR T, cell therapy, radiation, and stem cell transplant when treating a patient with blood cancer.

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Common Challenges with Hematologic Malignancy

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Despite significant advancement in the diagnosis and treatment modalities of hematological malignancies, the prognosis may be poor depending on the treatments used and the disease subtype. This alludes to the fact that there are still several significant challenges in treating these types of cancers. They include:

• Many of the chemotherapy agents used to treat hematologic malignancies can lead to serious side effects, so it can be a challenge to balance the benefits of these drugs with their potential complications.
• Research is progressing quickly, making it difficult for doctors to keep up with the latest advances and guidelines.
• Many patients who are diagnosed with cancer also have other comorbidities that must be considered when deciding the course of treatment.

Because of the challenges associated with treating blood cancers, it can be helpful to tap into the collective wisdom of a community of oncologists with diverse experiences in hematologic malignancies. Oncologists currently engage in a network of peers through curbside consults and tumor boards.

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Primum has built a network of experts in malignant and benign hematology who can help community physicians handle complex cases. Our network of sub-specialists is here to help community oncologists stay up to date with rapidly evolving diagnoses and treatments. Learn more about how Primum can help here.

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Sources

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[1] Siegel et. al, “CancerStatistics, 2022.” CA: A Cancer Journal for Clinicians, January 2022.

[2] Sapkota et. al, “Non-Hodgkin Lymphoma” StatPears [Internet], May 2022.

[3] Rajkumar, S. Vincent, Meletios A. Dimopoulos, Antonio Palumbo, Joan Blade, Giampaolo Merlini, María-Victoria Mateos, Shaji Kumar et al. "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma." The lancet oncology 15, no. 12 (2014): e538-e548.

[4] Mugnaini, Emiliano N., and Nilanjan Ghosh. "Lymphoma." Primary Care: Clinics in Office Practice 43,no. 4 (2016): 661-675.

[5] Kaseb H, Tariq MA, Gupta G. Lymphoblastic Lymphoma. In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 23, 2022.

[6] Huang, Furong, Peiwen Guang, Fucui Li, Xuewen Liu, Weimin Zhang, and Wendong Huang. "AML, ALL, and CML classification and diagnosis based on bone marrow cell morphology combined with convolutional neural network: A STARD compliant diagnosis research." Medicine 99,no. 45 (2020).

[7] Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review [published correction appears in Environ Health Perspect.2010 Sep;118(9):A380]. Environ Health Perspect. 2007;115(1):138-145

[8] Hasserjian RP. Acute myeloid leukemia: advances in diagnosis and classification. Int J Lab Hematol.2013;35(3):358-366.

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