When Lymphoma Plays Dress-Up: The Cellular Imposter That Fooled Pathologists

Level 1 of "Diagnose This Cancer" seemed straightforward enough: patient shows up with swollen lymph nodes, biopsy reveals big weird cells that look like the infamous "owl-eyed" Reed-Sternberg cells of Hodgkin lymphoma, and everyone calls it a day. Except some cancers have apparently unlocked a secret character skin, and what looks like Hodgkin lymphoma is actually ALK-negative anaplastic large cell lymphoma wearing a very convincing disguise.

The Cellular Con Artist

Here's the situation: ALK-negative anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (CHL) are two completely different diseases. They come from different cell lineages (T-cells versus B-cells, respectively), respond to different treatments, and have different prognoses. And yet, under a microscope, they can look almost identical. Both feature Reed-Sternberg-like cells surrounded by an inflammatory cocktail of immune cells. Both light up for CD30, a protein marker that pathologists use to identify these cancers.

One might assume decades of medical advancement would make telling them apart trivially easy. One would be charmingly optimistic.

The JAK2 Plot Twist

Enter the case reported in Blood: a 51-year-old woman with cervical lymphadenopathy whose biopsy looked for all the world like nodular sclerosing Hodgkin lymphoma. The cells even expressed CD15, a marker that typically helps seal the Hodgkin diagnosis. But molecular testing revealed a T-cell receptor gene rearrangement and, crucially, a JAK2 rearrangement with an ATXN2L::JAK2 fusion.

JAK2 rearrangements appear in roughly 6% of CD30-positive, ALK-negative T-cell lymphomas, and they seem particularly fond of cases that mimic Hodgkin lymphoma. It's as if these cancer cells specifically evolved to mess with pathologists.

Why Getting It Right Actually Matters

This isn't merely an academic exercise in cellular taxonomy. ALCL and Hodgkin lymphoma are treated with different chemotherapy regimens. The patient in this case received CHOP chemotherapy followed by autologous stem cell transplantation and remained disease-free for 105 months. Had she been misdiagnosed with Hodgkin lymphoma and treated accordingly, outcomes might have differed substantially.

The broader implications are even more intriguing. JAK2 rearrangements create druggable targets. A recent case report in npj Precision Oncology described a child with relapsed ALK-negative ALCL harboring the same ATXN2L::JAK2 fusion who achieved complete remission on ruxolitinib monotherapy. Ruxolitinib. A single drug. For relapsed lymphoma.

The Diagnosis Detective Kit

So how do you unmask these cellular imposters? A few key tools:

PAX5: This B-cell marker is weakly positive in most Hodgkin lymphomas but negative in ALCL. When PAX5 abandons you, things get complicated.

T-cell receptor gene rearrangement: ALCL, being a T-cell malignancy, will show clonal T-cell receptor rearrangements. Hodgkin lymphoma will not.

FISH for JAK2: Fluorescence in situ hybridization can detect JAK2 rearrangements, flagging cases that might benefit from JAK inhibitor therapy.

The authors' message is essentially: if something looks like Hodgkin lymphoma but feels off, molecular testing isn't optional. It's how you catch the imposter before it gets treated with the wrong chemotherapy.

The Bigger Picture

ALK-negative ALCL already has a reputation as the less favorable cousin of ALK-positive ALCL, with overall survival rates of 40-60% compared to 70-80%. Identifying specific genetic alterations like JAK2 rearrangements not only sharpens diagnosis but opens doors to targeted therapies. Phase 2 trials have shown ruxolitinib provides meaningful benefit in about 50% of T-cell lymphoma patients with JAK/STAT pathway activation.

The cancer biology lesson here: cells that look alike under a microscope can have completely different origin stories and vulnerabilities. Molecular testing has become the cheat code for getting the diagnosis right and finding the boss's weak point.

References:

1. Jaye DL, Feldman AL. ALK-negative anaplastic large cell lymphoma with JAK2 rearrangement mimicking classic Hodgkin lymphoma. Blood. 2023;141(17):2160. DOI: 10.1182/blood.2023019979 | PMC10163305

2. Hapgood G, Savage KJ. ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis. Cancers. 2021;13(18):4667. PMC8472588

3. Moskowitz AJ, et al. A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood. 2021;138(26):2828-2837. PMC8718625

4. Complete remission of relapsed ATXN2L::JAK2 fusion positive anaplastic large cell lymphoma following ruxolitinib monotherapy. npj Precision Oncology. 2026. Link

5. Patel AB, et al. ALK Negative Anaplastic Large Cell Lymphoma. StatPearls. 2024. NBK519019

Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.