Lymphomas: from hematopathology to cell therapy

A 34-year-old teacher notices a lump in her neck that does not go away after a month. She has itching at night and has lost some weight. The clinician orders an ultrasound and then a fine needle aspiration, which comes back with the report "lymphoproliferative process, lymphoma cannot be excluded". She wants to know whether she can start treatment already, whether she will be able to get pregnant afterward and why the hematologist ordered another, larger biopsy before any decision. The scene is fictional and was written for teaching.

This text uses the case as a setting for clinical reasoning for students and health professionals. The topic is how the team organizes itself in lymphoma care, from the correct biopsy and review by hematopathology to cell therapy in relapses, including nuclear medicine, radiotherapy, infection prevention, fertility and long-term follow-up. The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you will recognize the challenge: the clue that seems sufficient does not always close the diagnosis.

Key points

• Lymphoma is a large group of diseases, and the right subtype depends on enough tissue and an experienced hematopathologist.
• Excisional lymph node biopsy remains the reference, and fine needle aspiration alone is not enough to classify a lymphoma.
• PET-CT helps stage the disease and adjust treatment according to response, which can spare radiotherapy and toxicity.
• Screening for hepatitis B before anti-CD20 antibodies is a simple measure that still fails often.
• Fertility needs to be discussed before the first cycle, including before CAR-T therapy.
• Cell therapy and bispecific antibodies require different logistics, and the choice depends on the patient and the center.

Why lymphoma is a team effort

Lymphoma is not a single disease. The name brings together dozens of subtypes that arise from B, T or NK lymphocytes, with very different behaviors. There are lymphomas that grow slowly for years and can simply be observed, and there are aggressive lymphomas that need treatment within days. Hodgkin lymphoma, common in young adults, has its own biology and treatment. Diffuse large B-cell lymphoma, the most frequent aggressive subtype in adults, calls for another strategy. Follicular lymphoma, the most common indolent one, calls for yet another.

This variety explains why care depends on several areas working together. Hematology coordinates the plan, but does not decide alone. Hematopathology defines the subtype. The extent of the disease and the response to treatment are handled by nuclear medicine and radiology, and radiotherapy comes in for specific situations. Infectious diseases helps prevent complications that can be serious. Reproductive medicine protects life plans that treatment may threaten. The transplant and cell therapy center comes in when the disease returns. Nursing, pharmacy, nutrition and psychology sustain all of this day to day.

For the teacher in the scene, each of these areas has a different question. The exact subtype is the first. Then how far the disease has spread, whether there is any virus that can reactivate with treatment, what to do about fertility before starting and, finally, what to follow after everything is over. The topic connects with the text on interprofessional clinical reasoning, which discusses how different professions see the same patient.

Who usually takes part

• Hematology or clinical oncology, which coordinates the plan and talks with the patient.
• Hematopathology, which classifies the lymphoma using morphology, immunohistochemistry and molecular tests.
• Nuclear medicine and radiology, which stage the disease and assess response.
• Radiotherapy, which treats localized or bulky disease in selected situations.
• Infectious diseases and hepatology, which screen for and prevent infections and viral reactivations.
• Reproductive medicine, which advises on and carries out fertility preservation.
• Transplant and cell therapy team, plus nursing, pharmacy, nutrition and psychology.

The right biopsy from the start

The first possible error happens before any slide reaches the pathologist: taking too little tissue. Fine needle aspiration draws out a few loose cells, which may be enough to show that something is abnormal, but rarely shows the architecture of the lymph node, which is essential to classify many lymphomas. The European Hematology Association guideline for follicular lymphoma considers excisional lymph node biopsy the reference standard, accepts core needle biopsy when excision is not feasible and advises against fine needle aspiration for diagnosis.

In practice, this means that head and neck surgery, general surgery or interventional radiology need to know that the suspicion is lymphoma. The chosen lymph node should be the most representative, preferably the largest or the one with the most uptake on PET-CT when the exam has already been done. The material should arrive fresh or properly fixed, with enough clinical information, so that hematopathology can perform immunohistochemistry, flow cytometry and molecular tests when needed.

For the professor in the scene, asking for a new biopsy is not excessive caution. It is the way to avoid starting treatment for the wrong subtype. A treatment started with an incomplete diagnosis can be hard to correct later, because chemotherapy and corticosteroids change the tissue and can mask the disease in a later biopsy.

What goes with a good biopsy

• A medical request that clearly states the suspicion is lymphoma.
• Choice of the most representative lymph node, guided by imaging when possible.
• Enough material for architecture, immunohistochemistry and molecular tests.
• Fast delivery to the laboratory, with no corticosteroid before collection whenever it is safe to wait.
• Direct communication between the person who collects and the person who reads, to resolve doubts without delay.

Hematopathology and second opinion

Classifying a lymphoma is one of the hardest tasks in pathology. The most used classifications, from the World Health Organization and the international consensus, bring together many entities and combine morphology, surface markers, genetic alterations and clinical data. A general pathologist sees few lymphomas per year compared with a hematopathologist at a reference center, and the difference in exposure shows in the results.

In a Chinese study that reviewed 2291 diagnoses of hematolymphoid neoplasms sent to a specialized center, about 40 in every 100 original reports did not match the specialists' final diagnosis. In the same study, about 61 in every 100 of these disagreements involved the wrong classification of the lymphoma subtype, which can change treatment completely. The numbers come from a reference service that receives precisely the difficult cases, and they do not describe the average of all laboratories, but they show the size of the problem.

That is why the European follicular lymphoma guideline recommends review by an experienced hematopathologist, following the current classifications. In many services, review by a reference center is part of the routine, by physical shipment of the slides or by digital pathology. Asking for a second opinion is not distrust of the colleague. It is recognition that rare and complex diseases benefit from those who see many of them.

The reasoning of hematopathology is similar to that of a differential diagnosis at the bedside. An enlarged lymph node can be a reaction to infection, autoimmune disease, metastasis of another cancer or lymphoma, and each hypothesis calls for a different marker. The text on how to train differential diagnosis with clues shows how to organize these alternatives without closing too early.

Nuclear medicine and PET-CT

After diagnosis, the next question is how far the disease has spread. In most lymphomas that take up glucose, FDG PET-CT is the central staging exam. It shows affected lymph nodes and organs more accurately than CT alone and, in many cases, spares a bone marrow biopsy for staging Hodgkin lymphoma and diffuse large B cell lymphoma.

The role of PET-CT does not end at staging. Scans done during treatment, called interim PET, allow the intensity to be adjusted according to response. Reading uses the Deauville scale, from 1 to 5, which compares uptake in the lesions with that of the mediastinum and the liver. Low scores indicate a good response. High scores suggest disease that is still active.

The HD0607 study, with more than ten years of follow-up in advanced Hodgkin lymphoma, included 782 patients and found a negative PET after two cycles in 81 out of every 100 of them. In the same study, 83 out of every 100 patients with a negative interim PET were progression-free at ten years, versus 58 out of every 100 among those with a positive PET, which shows the prognostic value of the exam.

The scale also evolves. A validation study of the new Deauville 5a score in advanced Hodgkin lymphoma found this pattern in 4 to 6 out of every 100 interim scans and sought to better separate patients with very high uptake. For the team, this means the nuclear medicine report must be read with attention to the criterion used, and that doubts about the score should be discussed in a meeting, with the images on screen.

When the report arrives, the team checks the reading criterion and the Deauville score of the main lesions, compares it with the previous exam, preferably done on the same equipment, and remembers that inflammatory uptake, such as after vaccines, infections or growth factors, can mimic disease. When residual uptake would change management, biopsy is usually the safest way to decide.

Radiotherapy: when it helps and when it can be spared

Radiotherapy is very effective against lymphomas, because lymphocytes are sensitive to radiation. In some settings, it is the main treatment. The European guideline for follicular lymphoma recommends radiotherapy, with or without rituximab, for localized disease, in which there is a chance of prolonged control.

The other side is late toxicity. Radiation to the chest of young people increases, years later, the risk of heart disease, thyroid problems and second cancers, such as breast cancer. For this reason, much of recent research seeks to identify who can go without radiotherapy without losing disease control. In the HD0607 study, patients with bulky disease and a negative PET at the end of chemotherapy who were randomized not to receive consolidation radiotherapy had no more relapses than those who received 30 Gy.

This does not mean radiotherapy should be abandoned. It means the decision becomes shared among hematology, nuclear medicine and radiotherapy, with the PET result in hand. For a young patient like the one in the scene, this conversation weighs even more, because the benefit must be compared with decades of life ahead.

Infectious diseases and hepatitis B before treatment

Many treatments for B cell lymphoma include rituximab or another anti-CD20 antibody. These drugs deplete B lymphocytes for months and can allow the hepatitis B virus, kept in the liver of those who had contact in the past, to multiply again. Reactivation can cause severe hepatitis, liver failure and interruption of cancer treatment. Prevention is simple: test beforehand and give an antiviral to those who need it.

Even so, screening often fails. In an Israeli population study of 11,888 patients treated with rituximab over 17 years, only about 10 in every 100 were tested in the 90 days before starting, and almost half were never tested. In the same study, 6 in every 100 of those tested had current or past infection with the virus, only about 1 in every 3 of them received prophylaxis, and reactivation occurred in about 1 in every 100 patients, mainly among those who had not been tested.

The problem also appears in academic centers. In a retrospective study at a tertiary hospital of 611 patients who started rituximab, about 61 in every 100 hematology patients had complete serology before starting, and all seven recorded reactivations occurred in patients with lymphoma. The common thread is that the failure is rarely one of knowledge. It is one of process: no one was responsible for checking the test before the first dose.

For this reason, many services put screening into a fixed protocol, with a check by pharmacy or nursing before the antibody is released. Infectious disease and hepatology specialists help interpret ambiguous results and define how long to keep the antiviral, which usually continues for months after the end of treatment.

Before the first anti-CD20 antibody

• Serology for hepatitis B, including surface antigen and antibody against the viral core.
• Viral load when any serology comes back positive.
• Antiviral prophylaxis defined before the first dose when indicated.
• Tests for hepatitis C and HIV according to the local protocol.
• A named person responsible for checking the results before the medication is released.

Fertility before the first cycle

Hodgkin lymphoma and several aggressive lymphomas often affect adolescents and young adults. For these people, the question "will I be able to have children?" can be as important as the question about cure. Some chemotherapy regimens and pelvic radiotherapy affect ovaries and testicles, and the time to act is before the first cycle, while there is still time to freeze eggs, embryos, sperm or ovarian tissue.

Access, however, is unequal. A systematic review on access to fertility preservation in adolescents and young women with cancer found rates of conversation on the topic that ranged from 9 to 75 in every 100 patients across studies. The variation shows that guidance depends heavily on the service and on who provides care, and not only on the patient's needs.

Cell therapy brought a new challenge. In an international survey by the European society for transplantation on fertility after CAR-T therapy, 99 centers responded, and 83 in every 100 offered counseling before treatment, while 17 in every 100 did not routinely inform patients. The same authors pointed to the urgency of bridging treatment and the fact that many patients had already received more than three lines of treatment as barriers, and recorded 18 live births among patients who became pregnant after therapy.

For the professor in the scene, referral to reproductive medicine should happen in the same week as diagnosis, in parallel with staging tests. In very aggressive lymphomas, there is not always time for every technique, but the conversation always fits and should be recorded in the medical chart.

Relapse, transplant, CAR-T and bispecifics

Most people with Hodgkin lymphoma and a good part of people with diffuse large B-cell lymphoma are free of the disease after the first treatment. When it comes back, or does not respond, the path becomes more complex and involves centers with transplant and cell therapy. The topic was already discussed in the text on lymphoma relapse and how not to delay transplant or CAR-T, and the team logic repeats here.

CAR-T therapy uses the patient's own T lymphocytes, modified in the laboratory to recognize the lymphoma. Real-world results approach those of the studies. In a Korean analysis with propensity score matching between tisagenlecleucel and salvage chemotherapy in relapsed or refractory diffuse large B-cell lymphoma, complete response was 60 in every 100 patients with CAR-T versus 22 in every 100 with standard treatment. In the same study, median survival was 11.9 months with CAR-T and 3.3 months with standard treatment, in a group of heavily treated patients with a difficult prognosis.

The therapy requires a long chain: cell collection by apheresis, manufacturing, bridging treatment while the product is being prepared, lymphodepleting chemotherapy, infusion and monitoring for cytokine release syndrome and neurologic toxicity. The text on CAR-T in myeloma and the typical toxicities details these events, which follow similar principles in lymphoma.

Bispecific antibodies are another option. They bind the patient's T lymphocyte to the lymphoma cell without individual manufacturing. A published debate on CAR-T versus bispecific antibodies in B-cell lymphoma highlights that bispecifics are available right away, are given largely in the outpatient setting, some have a fixed duration, such as glofitamab over 12 cycles, and they may be preferred in people aged 70 or older or who are frail. The choice depends on the subtype, prior lines, clinical condition, distance to the center and family support.

Aspect	CAR-T therapy	Bispecific antibody
Product	Made with the patient's own cells	Ready-made drug, the same for everyone
Time to start	Weeks of manufacturing, with bridging treatment	Available immediately
Setting	Accredited center, with hospitalization in most cases	Largely outpatient, with hospitalization for the first doses in some regimens
Duration	Single infusion	Repeated cycles, for a fixed time or until progression
Toxicities to watch	Cytokine release syndrome, neurologic toxicity, cytopenias, infections	Cytokine release syndrome, usually milder, and infections
Who coordinates	Hematology and the cell therapy team	Hematology, with support from the referral center

Survival and late effects

Finishing treatment does not end care. Lymphoma survivors, especially those treated young, live for decades with effects that may appear years later, such as chronic fatigue, heart disease, thyroid changes, infertility and second cancers. Follow-up needs to shift focus, from monitoring for relapse to preventing these effects.

In a Norwegian study of long-term survivors of Hodgkin lymphoma, 40 in every 100 participants reported three or more late effects. In the same study, 64 in every 100 wanted information on lifestyle and rehabilitation, and 58 in every 100 wanted follow-up specific to late effects, which shows a need the system does not always cover.

This follow-up is another team effort. Primary care often takes over care over the years, but it needs a written plan from the center that treated the patient: which drugs and doses were used, whether there was radiotherapy and in which region, which tests to do and when. Cardiology, endocrinology, gynecology, breast care and psychology come in according to the treatment received.

Written survivorship plan

• Summary of the diagnosis, subtype and treatments, with cumulative doses when they matter for follow-up.
• Radiotherapy fields and doses, if any.
• Schedule of tests for the heart, thyroid and screening for second cancers.
• Guidance on vaccines, physical activity, smoking and reproductive health.
• Contact of the referral center for questions from primary care.

How NEXO helps train this reasoning

NEXO uses fictional cases with a real clinical presentation, with up to six clues, to train step-by-step decision-making. In lymphoma, the skill is similar: do not accept the first clue as enough, request the right tissue, and remember that each stage of treatment opens new questions for other areas. The text on overdiagnosis helps you think about when an indolent lymphoma can be observed, and the post on retrospective bias and outcome bias discusses why judging a decision by its outcome misleads.

The Researcher track explores the mechanisms behind the clues in depth, the Closer profile helps you measure your own accuracy, the Curator organizes case curation, and Creators brings together those who produce medical content. Usage limits are at /economy.

Frequently asked questions

Why is fine needle aspiration not enough to diagnose lymphoma?

Because it aspirates loose cells and almost never shows the architecture of the lymph node, which is essential for classifying many subtypes. Excisional biopsy, or core needle biopsy when excision is not feasible, provides enough material.

Does requesting a biopsy review delay treatment?

In general, the review takes a few days and, in aggressive lymphomas, can run in parallel with staging. The risk of treating the wrong subtype is usually greater than that of waiting a few days.

Does every patient with lymphoma have a PET-CT?

In most lymphomas that take up glucose, such as Hodgkin and diffuse large B-cell lymphoma, PET-CT is the reference exam for staging and assessing response. In some subtypes that take up little, other exams are more valuable.

Why test for hepatitis B before rituximab?

Because rituximab can reactivate the virus in people who had contact in the past, even without symptoms. The test identifies who needs preventive antiviral therapy before the first dose.

Can fertility still be preserved if the lymphoma is aggressive?

Often yes, with faster techniques such as freezing sperm or ovarian tissue. Even when there is no time, the conversation should happen and be recorded.

CAR-T or bispecific, which is better?

There is no single answer. The choice depends on the subtype, previous treatments, clinical condition, access to an accredited center and patient preferences, and should be discussed with the cell therapy team.

Take-home messages

• Excisional or core needle biopsy, with a request that states the suspected lymphoma.
• Review by an experienced hematopathologist, with the current classification.
• Staging PET-CT with the reading criterion stated in the report.
• Hepatitis B serologies checked before the first anti-CD20 antibody.
• Conversation about fertility and referral recorded before the first cycle.
• Decision on radiotherapy made together, with the PET result.
• Early contact with the cell therapy center in high-risk or relapse cases.
• Written survivorship plan given to the patient and to primary care.

Play the case of the day on NEXO and practice asking for the clue that really closes the diagnosis.

References

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2. Baker FA, Tatour M, Yehya A, et al. Hepatitis B Screening, Antiviral Prophylaxis, and Reactivation Risk in Rituximab-Treated Patients: A 17-Year Population-Based Cohort Study Highlighting Current Practices and Gaps. Dig Dis Sci. 2026. PMID 42240959.
3. Barefah AS, Raslan OM, Alahwal HM, et al. HBV Serologic Testing Practices and Reactivation Outcomes Before Rituximab Initiation: A Retrospective Observational Study at an Academic Tertiary Care Centre. J Clin Med. 2026. PMID 42589866.
4. Byeon S, Choi S, Jung S, et al. Real-World Outcomes of Tisagenlecleucel Versus Standard-of-Care Salvage Chemotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Propensity Score-Matched Analysis From Korea. J Korean Med Sci. 2026. PMID 42642819.
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6. Ladetto M, Bolaños N, Bouguet G, et al. Newly diagnosed and relapsed follicular lymphoma: EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Hemasphere. 2026. PMID 42903357.
7. Leiders S, Ufton D, Kaul H, et al. Validation of the newly introduced Deauville score 5a for patients treated for advanced-stage classic Hodgkin lymphoma. Blood Adv. 2026. PMID 42379221.
8. Martino M, Marafioti V, Pitea M, et al. The Great Debate: CAR-T-Cell Therapy Versus Bispecific Antibodies in B-Cell Lymphoma. Cancers (Basel). 2026. PMID 42588728.
9. Orofino G, Sánchez-Ortega I, Mota JS, et al. Fertility management and outcomes after CAR T-cell therapy: an international survey from the Cellular Therapy and Immunobiology working party of the European Society for Blood and Marrow Transplantation. EClinicalMedicine. 2026. PMID 42317792.
10. Visentin A, Cellini A, Rossi A, et al. Long-term results of the HD0607 trial on interim PET-adapted treatment of advanced-stage Hodgkin lymphoma beyond 10 years of follow-up. EClinicalMedicine. 2026. PMID 42666946.
11. Willumsen LH, Smeland KB, Eikeland S, et al. Self-reported late effects and chronic fatigue, information needs and follow-up in long-term survivors of Hodgkin lymphoma-a cross-sectional study. Support Care Cancer. 2026. PMID 41951854.