The Liquid Tumor: Why Leukemia Defies Everything We Know About Cancer

A deep dive into the biology of blood cancer and why it plays by entirely different rules

When we think about cancer, we imagine a lump. A mass. Something that can be grown in a location, something a surgeon can find and cut out and give to a pathologist in a steel bowl. Even the language we use in oncology- “excision”, “resection”, “margin-free surgery” assumes or builds around the idea of a solid, tangible target, which assumes that cancer has a location.

Leukemia laughs at all of this.

It does not lump. It has no primary site. It can’t be removed. It can be born everywhere; swimming in the bloodstream, hiding in bone marrow, seeding within organs. It’s quite literally a liquid tumour — cancer in the very fluid that sustains life. But this one thing, leukemia is a cancer of blood, not tissue — alters everything about the nature of the disease, its ability to escape treatment and our strategies for overcoming it.

What Even Is a Liquid Tumor?

To appreciate the peculiarity of leukemia, it’s helpful to begin with what “normal” cancer looks like. Most cancers — breast, lung, colon, prostate, etc. start as a mutation in a stationary cell. That cell becomes cancerous and multiplies out of control, accumulating additional mutations and eventually growing into a tumour that penetrates adjacent tissues and, over time, spreads to other parts of the body as rogue cells (metastases) carried in the bloodstream. This has been the basis of the whole structure of oncology: TNM staging, tumor margins, local radiation etc.

Leukemia inverts this model entirely.

It develops in the blood-forming tissues, particularly the bone marrow, which is the site of production of red blood cells (RBCs), white blood cells, and platelets from stem cells known as hematopoietic stem cells (HSCs). If a mutation occurs in one of these stem or progenitor cells, it doesn’t create a lump. It simply continues to multiply, creating defective immature white blood cells (known as blasts) that enter the bloodstream, where they kill off healthy blood cells and invade organs. No stage 1 leukemia is crouched in a corner of the body. It is systemic from the time it starts. The bloodstream is not just how it spreads — it is its habitat.

As one clinical summary puts it, leukemia is “a cancer of blood and blood-forming cells” that “can spread through the bloodstream, affecting many organs at once” and crucially, “doesn’t form a primary tumor like other cancers do.”

Credit- Med. pract. Dana Hreus M.A.

Why the “Solid Tumor” Playbook Fails: A Cancer Without an Address

In oncology, the term primary tumor is very important. This provides information about the location of the cancer, the type of cells from which it developed, the characteristics of the cancer cells and the drugs that might be effective against the cancer. The treatment of the patient depends on the address: lung cancer, breast cancer, colon cancer.

Leukemia doesn’t have an address.

It originates from within the bone marrow, a diffuse spongy tissue throughout the skeleton and cells are born here and immediately enter the circulation. Leukemic blasts are likely to be found in the peripheral blood, liver, spleen, lymph nodes and central nervous system by the time the patient is diagnosed. It’s not a metastasis in the later stages. This is Day one of the disease. This has significant consequences: Surgery is irrelevant. No trimming to be done. Radiation is limited. Specific organs can be irradiated (the brain, for CNS involvement; the body, as preparation for stem cell transplant) but not “zapped” leukemia, like one would a breast tumour. Staging fails. The staging system (Tumor, Nodes, Metastasis) for solid cancers makes no sense. Leukemia is classified in different systems altogether, depending on cell morphology, cytogenetics and molecular markers. In breast or colon cancer, “remission” often means the mass is gone or stable. In leukemia tracking, remission requires looking at systemic kinetics; counting deep, residual molecular signatures down to one in a million cells using techniques like flow cytometry.

The Bone Marrow Microenvironment: A Fortress Built for the Enemy

One of the most revelatory insights of modern leukemia research is the role of the bone marrow microenvironment (BMME) — the complex ecosystem of stromal cells, blood vessels, cytokines and extracellular matrix that normally regulates healthy blood cell production.

In leukemia, the cancer doesn’t just reside in this environment. It hijacks it.

As described in the study published in JBMR Plus (2021), leukemia cells claim the same niches as healthy hematopoietic stem cells and reprogram the surrounding niche architecture to promote their survival. The BMME in leukemia is stimulated by a pro-inflammatory context with cytokines like tumour necrosis factor (TNF), Il-1B, CCL3, and CXCL2. Exosomes from leukemic cells also carry microRNAs that change the surrounding stromal cells to inhibit normal hematopoiesis, while protecting leukemic cells. The outcome: The bone marrow becomes an impenetrable fortress. The leukemic cells have literally created a microenvironment to feed, protect, and shield them from the chemotherapy. This is a very significant difference in the manner in which solid tumors interact with their environment.

The microenvironment of a breast tumour is a neighbourhood that is local to the tumour. The body’s blood factory is the microenvironment of leukemia.

In addition, multi-omic studies have shown that the interstitial fluid in the bone marrow (the fluid surrounding the cells in the marrow) is biochemically different from peripheral blood plasma and has more extracellular vesicle components and significant protease dysregulation during active leukemia, indicating a much more complex compartment than the stroma of a solid tumor, and a compartment that is much harder to therapeutically access.

Why Treatment Is So Difficult

All these are unique characteristics of leukemia treatment compared to the treatment of nearly all other cancers. Chemotherapy is the main treatment in most subtypes. It acts by overwhelming the body with cytotoxic agents, which kill rapidly dividing cells. However, since leukemia is a systemic disease, chemotherapy needs to be administered throughout the body where cancer may be present: blood, bone marrow, spleen, liver and CNS.

The toxicity is immense. The healthy rapidly dividing cells, such as the gut lining, hair follicles and the bone marrow are damaged as well. Patients who receive induction chemotherapy are often kept in the hospital for weeks and are at risk of infection due to very low numbers of neutrophils.

Specific subtypes have been changed by targeted therapies. Imatinib (Gleevec) is the drug that targets the BCR-ABL fusion protein in CML and is perhaps the biggest success story in oncology. A disease that once progressed inevitably to blast crisis now has patients achieving deep molecular remissions and living near-normal lives. Drugs targeting FLT3, IDH1, IDH2 and BCL-2 mutations have similarly improved outcomes in subsets of AML.

The big obstacle to targeted therapy is leukemia’s clonal heterogeneity. If a drug eliminates cells bearing one mutation, it may spare or even accelerate cells bearing a different mutation.

CAR -T cell therapy is a treatment that has had dramatic success in some leukemias, using a patient’s T cells that are genetically modified to target and destroy cancer cells with specific antigens. CD19-directed CAR-T has achieved remission rates that seem miraculous after 10 years in the field of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). AML, the more prevalent and fatal adult acute leukemia, has been more resistant to CAR-T therapies so far, due to the absence of a clean leukemia-specific surface antigen like the B-ALL.

Other targets, such as CD33, CD123 and CLL1, are found on normal hematopoietic stem cells as well; if the stem cells are damaged, the patient may lose the ability to make blood. In an effort to overcome this challenge, novel engineering strategies that target both CD33 and CD112 (dual targeting CARs) as well as inhibitory CAR designs were presented at the 2024 American Society of Hematology (ASH) Annual Meeting, but clinical efficacy in AML has yet to be seen in broad clinical use.

For most high-risk leukemias, the most effective curative treatment is stem cell transplantation, in which the patient’s bone marrow is completely replaced by donor stem cells. It is harsh, only offered to qualified patients, and has its own life-threatening side effects, such as graft-versus-host disease. Incredibly, one of the key factors of a transplant’s success is that the donor’s immune system identifies and destroys any leukemia cells that remain another form of immunity, known as graft-versus-leukemia effect.

The Promise of Liquid Biopsy — Cancer Monitoring the Liquid Way

The liquid biopsy is one of the most exciting technologies in modern oncology, and there’s a poetic irony in that.

Cell-free DNA, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), microRNAs and extracellular vesicles are all types of fragments of DNA that are shed from solid tumors into the bloodstream. These fragments are now being used to develop blood tests to diagnose cancer earlier, monitor treatment response and detect recurrence; all without the need for needles, scalpel or tissue biopsies. In solid tumor oncology, liquid biopsy will be a revolutionary change: it transforms something intangible, the molecular fingerprint of the cancer (the fingerprint of the “biggest crime in the world”) into a blood test. Liquid biopsy is an enhancement of current tools in leukemia, already a blood cancer.

Leukemic blasts can be detected directly by blood tests. Now the frontier is in the detection of the few remaining leukemic cells, called minimal residual disease (MRD). Now, researchers are working on cell-free DNA, circulating tumor DNA and sensitive molecular markers to create assays that can detect just one leukemia cell in a million normal cells, which would help doctors determine if a “remission” is real or a harbinger of relapse.

A review in Cancers in 2025 highlighted the potential of liquid biopsy biomarkers, such as ctDNA, microRNAs and extracellular vesicles, for the early detection of relapse, real-time assessment of clonal evolution and evaluation of the efficacy of leukemia treatment, applicable to all leukemia subgroups. This represents a paradigm shift: from treating the disease you can see, to chasing the disease you cannot

Living With the Paradox

Leukemia is a cancer with no lump, a disease without a location; a tumor that is also a fluid. Born in the organ system whose sole function is to circulate all over, it does so with ruthless efficiency.

It defies surgery. Not stageable. It changes its genetic makeup when treated. It relies on the manipulation of its microenvironment. Yet within the many types of leukemia, it has also proved to be the disease that has seen some of the finest progress in oncology medicine come to the forefront, including kinase inhibitors, CAR-Ts, MRD monitoring and epigenetic drugs.

It’s the disease that makes cancer biology work harder, more dynamically and more systemically. Maybe that’s the last piece of advice leukemia offers cancer isn’t always a hard lump that awaits discovery and removal. At times, it is already omnipresent in the very blood of the people. To cure it, medicine has to become as fluid as the cancer, as adaptable as the cancer, as systemically aware as the cancer.

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