Limfoma Hodgkin

01Pathophysiology

Hodgkin lymphoma originates from germinal center or post-germinal center B lymphocytes that have undergone malignant transformation. The hallmark of this disease is the Reed-Sternberg (RS) cell, a large binucleated or multinucleated cell with prominent eosinophilic nucleoli that give it the classic "owl-eye" appearance. Despite being the neoplastic cell, the RS cell typically constitutes only about 1-2% of the tumor mass. The remainder of the tumor is composed of a reactive inflammatory infiltrate of lymphocytes, eosinophils, macrophages, plasma cells, and fibroblasts.

The RS cells evade immune destruction through several mechanisms. They overexpress PD-L1 (programmed death-ligand 1), which binds PD-1 on cytotoxic T cells and effectively disables the immune attack. This is the rationale behind the use of checkpoint inhibitors like nivolumab and pembrolizumab in relapsed disease. Additionally, RS cells secrete cytokines (IL-5, IL-10, TGF-beta) that recruit the surrounding inflammatory cells and suppress effective antitumor immunity. The cytokine milieu explains the systemic symptoms: IL-1 and TNF-alpha drive fever and night sweats, while the catabolic state causes weight loss.

The disease characteristically spreads in a contiguous, predictable pattern along lymph node chains, which distinguishes it from Non-Hodgkin lymphoma (NHL), where spread is noncontiguous and often involves extranodal sites early. This orderly spread is why radiation therapy can be effectively applied to involved fields. Mediastinal involvement is very common, particularly in the nodular sclerosis subtype, which is the most frequent subtype overall and often presents as a large anterior mediastinal mass in a young woman.

Epstein-Barr virus (EBV) plays a pathogenic role in a significant subset of cases. The EBV latent membrane protein (LMP-1) mimics CD40 signaling and activates NF-kB, promoting B-cell survival and proliferation. EBV-positive cases are more common in the mixed cellularity subtype and in patients from developing countries.

02Classification and Clinical Manifestation

Histological Subtypes (WHO Classification)

Clinical Staging (Ann Arbor / Lugano)

Each stage is further classified:

• A: No systemic symptoms

• B: Presence of B symptoms (fever >38C, drenching night sweats, weight loss >10% body weight over 6 months)

• X (or "bulky"): Bulky disease, defined as a mass >10 cm or mediastinal mass greater than one-third of the thoracic diameter

B Symptoms and Other Constitutional Features

03Diagnostic Workup

The diagnostic pathway begins when a patient, most often a young adult, presents with painless lymphadenopathy that has been progressively enlarging over weeks to months. The first step is to perform a thorough history and physical examination, looking for B symptoms and evaluating all lymph node basins, the liver, and the spleen.

The best initial diagnostic step when lymphoma is suspected in a patient with a persistent, unexplained lymph node is an excisional (or incisional) lymph node biopsy. This is critical because the diagnosis depends on identifying the RS cell within the context of its surrounding reactive infiltrate, and this architectural information is lost with FNA or core needle biopsy. Vignettes that offer FNA as a choice are testing whether you know that it is inadequate for an initial lymphoma diagnosis.

On histopathology, the classic RS cell is a large cell with bilobed or multilobed nuclei, each containing a prominent eosinophilic nucleolus, surrounded by a clear halo. The immunophenotype of classical Hodgkin lymphoma is CD15+ and CD30+, with CD20 typically negative. This contrasts with NLPHL, where the "popcorn" (LP) cells are CD20+, CD15-, CD30-, an important distinction because NLPHL can be treated with rituximab (anti-CD20).

Once the diagnosis is confirmed histologically, PET-CT is the imaging modality of choice for staging. Hodgkin lymphoma is highly FDG-avid, making PET-CT extremely sensitive for detecting disease above and below the diaphragm, as well as in extranodal sites. The Deauville 5-point scale is used to interpret PET-CT results during and after treatment to assess response.

Baseline labs should include CBC, ESR, LDH, comprehensive metabolic panel (including albumin, liver function tests, creatinine), and hepatitis B serology (given risk of reactivation with rituximab if NLPHL). Bone marrow biopsy has been largely replaced by PET-CT for marrow staging but may still be performed in resource-limited settings.

The International Prognostic Score (IPS) for advanced-stage Hodgkin lymphoma includes seven adverse factors: age ≥45, male sex, stage IV, hemoglobin <10.5 g/dL, albumin <4 g/dL, WBC ≥15,000/microL, and lymphocyte count <600/microL or <8% of WBC.

04Management and Treatment

First-line therapy for classical Hodgkin lymphoma is built around the ABVD regimen, which remains the global standard due to its favorable balance of efficacy and toxicity. Each cycle is 28 days, with drugs administered on days 1 and 15.

For early-stage favorable disease, the current approach uses 2 cycles of ABVD followed by involved-site radiation at 20 Gy. For early-stage unfavorable disease (defined by the presence of bulky mediastinal disease, elevated ESR, extranodal extension, or involvement of 3 or more nodal areas), 4 cycles of ABVD are administered followed by 30 Gy of radiation.

For advanced-stage disease, 6 cycles of ABVD are given. A key concept is PET-adapted therapy: after 2 cycles, an interim PET-CT is performed. If the interim PET is negative (Deauville 1-3), bleomycin can be dropped from the remaining cycles (AVD only) to minimize pulmonary toxicity without compromising efficacy. If the interim PET remains positive (Deauville 4-5), this suggests chemoresistance, and the clinician should consider escalating to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone).

Important toxicities to know:

Fertility counseling must be addressed before starting treatment. Men should be offered sperm cryopreservation, and women should be offered oocyte or embryo cryopreservation or ovarian suppression with GnRH agonists.

For relapsed or refractory disease, the standard pathway is salvage chemotherapy (ICE: ifosfamide, carboplatin, etoposide; or DHAP: dexamethasone, high-dose cytarabine, cisplatin) followed by autologous stem cell transplantation. Patients who relapse after transplant or are not transplant candidates may receive brentuximab vedotin (targets CD30 on RS cells) or PD-1 checkpoint inhibitors (nivolumab or pembrolizumab), which exploit the overexpression of PD-L1 on RS cells.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on Hodgkin lymphoma questions is by selecting FNA instead of excisional biopsy as the diagnostic test. Test-writers consistently use this as a trap: FNA may suggest lymphoma but cannot provide the architectural context needed to identify RS cells within their reactive background. If the question asks for the "next best step" in a patient with suspected lymphoma, excisional biopsy is almost always the answer.

Another frequent trap involves confusing classical Hodgkin lymphoma with NLPHL. The immunophenotype is reversed: classical HL is CD15+/CD30+/CD20-, while NLPHL is CD20+/CD15-/CD30-. This distinction has direct treatment implications because NLPHL responds to rituximab (anti-CD20), whereas classical HL does not.

Students also commonly miss the significance of bleomycin pulmonary toxicity. If a vignette describes a patient on ABVD who develops a new cough with decreased DLCO on pulmonary function testing, the answer is to discontinue bleomycin. Conversely, if a patient is about to undergo surgery and has a history of bleomycin exposure, the key teaching point is to avoid high concentrations of supplemental oxygen during anesthesia, as it can precipitate fatal pulmonary toxicity.

The concept of contiguous spread is another testable feature. If a vignette describes lymphadenopathy that has spread to nonadjacent lymph node groups or extranodal organs early in the disease course, this pattern favors NHL over Hodgkin lymphoma.

Finally, remember the long-term survivorship complications. A young woman treated with mediastinal radiation for Hodgkin lymphoma is at increased risk for secondary breast cancer and should begin screening mammography earlier than the general population (typically starting 8-10 years after radiation or at age 40, whichever comes first). Secondary acute myeloid leukemia and myelodysplastic syndrome are also risks, particularly with alkylating agents and topoisomerase II inhibitors.

The core competency being tested across all Hodgkin lymphoma questions is the ability to recognize the classic presentation (young patient, painless rubbery lymphadenopathy, mediastinal mass, B symptoms), order the correct diagnostic test (excisional biopsy, not FNA), interpret the pathology (RS cells, CD15+/CD30+), and understand the treatment framework (ABVD, PET-adapted therapy, and management of treatment toxicities).