Expert Guide: How Can Lymphoma Misdiagnosis Be Avoided? What Patients and Families Can Do to Support a More Accurate Diagnosis

Summary: Prof. Zifen GAO of the GoBroad Diagnostic Center and Dr. Yuehui LIN of Beijing GoBroad Boren Hospital explain why lymphoma pathology can be complex and why an integrated diagnostic approach is important. The article describes how morphology, immunophenotyping, and molecular testing are interpreted together; reviews common causes of diagnostic error, including inadequate specimens, atypical disease features, and incomplete testing; and uses a real case to illustrate the full diagnostic process in a difficult lymphoma case. It also offers practical guidance on how patients and families can prepare specimens and medical records for consultation and cooperate with additional testing when needed.

In lymphoma care, the pathology diagnosis is one of the most important factors guiding treatment. Yet many patients and families are left with the same questions:

Why can a biopsy still fail to provide a clear diagnosis? Why might pathology slides need to be reviewed at more than one hospital?

To address these concerns, Prof. Zifen GAO of the GoBroad Diagnostic Center and Dr. Yuehui LIN of Beijing GoBroad Boren Hospital explain why lymphoma can be difficult to diagnose and how integrated diagnostics can improve accuracy.

1. Key Features of Lymphoma

There are three important characteristics of lymphoma that patients and families may find helpful to understand:

1. It can occur in many parts of the body. Lymphoma can involve almost any site other than structures such as hair and nails, including lymph nodes, the head and neck, chest, abdomen, skin, and bone.

2. Many types are highly treatable. Lymphoma is among the malignancies that can respond particularly well to treatment, and some subtypes can achieve high cure rates with approaches such as chemotherapy and targeted therapy.

3. Diagnosis can be difficult. Lymphoma cells may look very similar to normal lymphocytes under the microscope. Unlike many solid-tumor cells, which may show obvious abnormal morphology, lymphoma cells can resemble lymphocytes at different stages of differentiation. For this reason, morphology alone is often not enough to determine whether a lymphoid proliferation is benign or malignant.

2. Why Integrated Diagnosis Matters

Lymphoma diagnosis should not rely on microscopic appearance alone. Several types of information usually need to be interpreted together:

1. Morphology is the foundation. Hematoxylin and eosin (H&E) staining allows pathologists to assess cell size, shape, arrangement, and tissue architecture and to begin distinguishing inflammation, reactive hyperplasia, and neoplasia. However, morphology alone has limitations and may not reliably establish the lineage or maturation stage of abnormal cells.

2. Immunophenotyping is critical. Antibody-based testing can identify abnormal cells at the cellular level through flow cytometry and at the tissue level through immunohistochemistry (IHC). Markers such as Ki-67, anaplastic lymphoma kinase (ALK), MYC, and lineage-associated proteins can help determine whether a process is malignant and define the immunophenotype and differentiation stage of the tumor cells. Distinguishing T-cell lymphoma from B-cell lymphoma is especially important because treatment approaches can differ substantially.

3. Molecular testing provides additional evidence. Some abnormalities are not apparent at the protein level and may require tests such as fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or next-generation sequencing (NGS). These tests can identify tumor-associated genetic alterations and provide molecular evidence that supports the diagnosis.

Importantly, molecular results should not be interpreted in isolation from morphology and immunophenotyping. They are most useful as part of the overall diagnostic picture.

Bringing these elements together - morphology, protein expression, and molecular findings - is what is meant by an integrated diagnosis. Clinical presentation and laboratory findings are also important parts of the final interpretation.

In many countries with established hematopathology systems, integrated hematologic cancer diagnoses are issued by pathologists, with the relevant diagnostic laboratories coordinated within pathology services. In China, different testing platforms have historically been distributed across separate departments, which can make integration more challenging. Even so, the integrated diagnostic model is increasingly being adopted because it can improve the precision of lymphoma diagnosis.

3. How Diagnostic Wording Affects Clinical Decisions

The wording in a pathology report can indicate how certain the diagnosis is and whether it is ready to guide treatment:

1. Definitive diagnosis: Wording such as a specific lymphoma subtype indicates that the available evidence is sufficient for a clear conclusion. This type of diagnosis can be used by the clinical team to plan treatment.

2. Qualified or uncertain diagnosis: Wording such as "consistent with," "consider," "favor," or "possibly" indicates that some uncertainty remains. A report at this level may require additional investigation before it is used to guide definitive treatment. Starting treatment on an uncertain diagnosis can be risky if the underlying disease has been classified incorrectly.

Pathologists are deliberately cautious because an incorrect diagnosis can lead to ineffective treatment and, in some cases, irreversible harm.

4. Common Reasons Lymphoma Can Be Misdiagnosed

Diagnostic discrepancies are not uncommon in lymphoma. The source article cites a series of more than 2,000 patients with refractory or relapsed lymphoma in which the initial diagnosis was incorrect in nearly 40% of cases. It also cites a French study involving more than 30,000 cases, in which close to 20% of diagnostic revisions had the potential to alter treatment. These findings highlight why expert review can be important in difficult cases.

Common causes include:

1. Specimen-related problems: A needle biopsy may miss the actual lesion, or delayed fixation may allow tissue autolysis and reduce specimen quality.

The main ways to obtain tissue include excisional biopsy, core needle biopsy, and fine-needle aspiration. For a suspicious malignant lymph node, excisional biopsy is often preferred because it provides intact tissue architecture; the source article reports a diagnostic and staging accuracy of 96.8%. Core needle biopsy is widely used and can be highly informative, but in some cases the sample may be too limited or may not fully represent the lesion. Fine-needle aspiration is generally not recommended as the sole method for diagnosing lymphoma because it mainly provides individual cells without the tissue architecture that is often essential for lymphoma classification.

2. Atypical disease features: Some cases have unusual morphology and are difficult to classify.

3. Incomplete testing: Essential immunophenotypic markers or molecular studies may not have been performed.

4. Technical limitations: Some institutions may have limited testing platforms or variable quality-control systems.

5. Experience-related factors: Pathologists without dedicated hematopathology experience may have less familiarity with unusual lymphoma patterns.

For difficult cases, specialist pathology consultation can therefore be an important step toward a more accurate diagnosis.

5. Integrated Diagnosis in Practice: A Case Example

The following case illustrates how the different parts of an integrated diagnosis come together.

Case Example

The patient was a 22-year-old man who developed facial swelling, thickened lips, and enlargement of the liver and spleen beginning in December 2019. He later developed slurred speech and behavioral or mental-status changes. Over the next two years, he was evaluated at several hospitals in Shanghai and underwent a lip biopsy, tonsillectomy, and stereotactic brain biopsy, but no definitive diagnosis was reached.

In September 2021, he was referred to the hospital where Prof. Gao was practicing. The team reviewed his previous pathology slides. The lip biopsy showed a dense cellular proliferation, but the morphology was atypical. The brain biopsy contained abnormal cells, but there were insufficient immunophenotypic markers to determine their nature.

A skin biopsy showed no abnormality. The team recommended another biopsy. With the family's cooperation, an ultrasound-guided biopsy was obtained from an area of thickened muscle around the shoulder and upper arm.

The new evaluation showed:

Morphology: Normal muscle fibers were extensively destroyed and replaced by a relatively uniform population of abnormal, medium-to-large cells with clear cytoplasm. The morphology strongly suggested a T-cell neoplasm.

Immunophenotype: The abnormal cells were CD8-positive cytotoxic T cells, with a high Ki-67 proliferation index and loss of additional T-cell markers.

Molecular and flow-cytometric findings: Flow cytometry and gene-rearrangement testing both demonstrated a monoclonal T-cell population, supporting a malignant diagnosis.

The final diagnosis was mature T-cell lymphoma. The subtype was too rare to be classified more specifically, but the evidence clearly established a malignant tumor of T-cell origin.

Once the diagnosis was clarified, the clinical team developed a targeted treatment plan. At reassessment two months later, lesions throughout the body had largely resolved, the brain lesions had improved substantially, and the patient's symptoms were markedly better.

This case shows why an accurate diagnosis is the foundation of precision treatment, and why integrated diagnostics can be especially valuable in complex cases.

6. How Patients and Families Can Help Support an Accurate Diagnosis

Patients and families can help in several practical ways:

1. Help obtain the best possible specimen. When a lymph node biopsy is needed, clinicians generally select the most abnormal node - considering features such as firmness and imaging findings, not simply size. When several lymph-node regions are involved, the source article describes a preference for supraclavicular, cervical, axillary, and then inguinal nodes when clinically appropriate. An intact lymph node with a short-axis diameter of about 1.5-2 cm may provide a useful specimen. Needle biopsies can carry a risk of sampling error, and tissue should be fixed promptly after collection to reduce autolysis.

2. When seeking a pathology review, try to obtain the original stained slides when possible. Some institutions provide only unstained slides rather than lending the original H&E and immunohistochemistry slides. Unstained slides are cut from different levels of the tissue block and are not exact copies of the original section, so they may not fully represent the same area of disease. Original stained slides can therefore be especially valuable for expert review.

3. Bring complete medical records to the consultation. This should include previous pathology reports, imaging studies, and a clear treatment history. Information showing that a previous treatment did not work can be particularly important because it may prompt reconsideration of the diagnosis.

4. Complete additional testing when recommended. If the pathologist or treating team recommends further immunohistochemistry or molecular testing, these studies may be necessary to clarify the diagnosis and guide the next treatment decision.

7. What Integrated Hematologic Cancer Diagnosis Aims to Achieve

An integrated diagnostic approach has three main goals:

1. Provide a clear diagnosis so the clinical team can select an appropriate treatment plan.

2. Provide prognostic information, such as the proliferation index or genetic alterations associated with higher-risk disease.

3. Help guide treatment selection by identifying potential therapeutic targets and relevant drug options.

Precision treatment depends on precision diagnosis, and an individualized treatment plan can only be built on a sufficiently accurate understanding of the disease.

Conclusion

Pathologists have traditionally worked largely behind the scenes. Today, specialist consultations and more direct communication with patients and families are helping both sides better understand the diagnostic process. Pathology teams across centers continue to advance integrated diagnosis with the goal of providing more accurate and timely answers for patients.

Disclaimer: Expert opinions are provided for general reference only. Please consult your treating physician for individualized diagnosis and treatment decisions.