Hodgkin Lymphoma (HL) vs Non-Hodgkin Lymphoma (NHL) — Focus on ENT/Head & Neck

1. What they are

• Hodgkin lymphoma: a B-cell derived malignancy defined by the presence of Reed-Sternberg (RS) cells (large binucleate/multinucleate cells with prominent "owl-eye" nucleoli) sitting in a background of reactive inflammatory cells (lymphocytes, eosinophils, plasma cells, histiocytes). Only 1-2% of the tumor mass is actually malignant cells - most of the mass is the reactive infiltrate.
• Non-Hodgkin lymphoma: a heterogeneous group (>60 subtypes) of B-cell, T-cell, or NK-cell neoplasms without RS cells, composed predominantly of the malignant clone itself.

2. Relevance to ENT / Head and Neck

• HL: presents almost exclusively as cervical/supraclavicular lymphadenopathy; classic HL spreads in a contiguous nodal fashion and rarely involves Waldeyer ring, tonsils, sinuses, or preauricular/occipital nodes. Extranodal H&N presentation of HL is rare.
• NHL: extranodal head and neck involvement is common (15-20% of oropharyngeal tumors in some series are NHL, mostly B-cell, MALT-type - Bailey & Love). NHL commonly involves Waldeyer ring (tonsil, base of tongue, nasopharynx), salivary glands, thyroid, nasal cavity/paranasal sinuses (extranodal NK/T-cell lymphoma, nasal type - classically associated with EBV), and preauricular/occipital nodes - sites HL rarely touches.

3. Pathophysiology

• HL: RS cells are derived from germinal-center B cells that have lost normal B-cell gene expression; EBV infects the malignant clone in a large proportion of cases (especially mixed cellularity subtype). RS cells secrete cytokines (IL-5, TNF, TGF-β) that recruit the massive reactive infiltrate responsible for systemic "B symptoms."
• NHL: results from genetic alterations (translocations, e.g., t(14;18) BCL2 in follicular lymphoma, t(8;14) MYC in Burkitt, t(11;14) cyclin D1 in mantle cell) causing uncontrolled clonal lymphocyte proliferation with loss of apoptosis/differentiation arrest. Chronic antigenic stimulation (H. pylori for gastric MALT, EBV for NK/T-cell nasal lymphoma, HIV) also drives many subtypes.

4. Etiology / Risk factors

5. Types / Classification (WHO)

• Nodular lymphocyte-predominant HL (NLPHL) - ~5%, usually solitary node (cervical/axillary/inguinal), mediastinum spared, non-contiguous spread
• Classical HL (~95%): Nodular sclerosis (most common, especially young women, mediastinal), Mixed cellularity (strongest EBV association), Lymphocyte-rich, Lymphocyte-depleted (rare, elderly/HIV, aggressive)

• B-cell: Diffuse large B-cell lymphoma (DLBCL, most common NHL overall, aggressive), Follicular lymphoma (indolent), Chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL, indolent), MALT lymphoma (salivary gland, thyroid), Mantle cell, Burkitt lymphoma (highly aggressive, jaw/facial masses in endemic form)
• T/NK-cell: Extranodal NK/T-cell lymphoma, nasal type (classically midline destructive nasal/palatal lesion, EBV-driven - important ENT entity), Angioimmunoblastic T-cell lymphoma, Anaplastic large-cell lymphoma
• AIDS-related NHL: aggressive, often extranodal (H&N, CNS, GI)
• Post-transplant lymphoproliferative disorder (PTLD)

6. Clinical Features

7. Appearance

• Gross/clinical: firm, rubbery, painless, mobile (early) or matted/fixed (advanced) lymph nodes; NK/T-cell nasal lymphoma shows necrotic, ulcerative, midline destructive palatal/nasal lesions.
• Histology: HL shows scattered RS cells (large, binucleate, "owl-eye" nucleoli, CD30+/CD15+) in a mixed inflammatory background, often with fibrous bands (nodular sclerosis). NHL shows a monomorphic sheet of malignant lymphocytes replacing normal nodal architecture (loss of follicular pattern), immunophenotype-specific markers (CD20 for B-cell, CD3 for T-cell).
• Imaging: CT/PET show bulky, sometimes matted nodal conglomerates (HL) or variable single/multiple nodal and extranodal masses (NHL); PET-CT is central to staging and response assessment in both.

8. Complications

9. Diagnostic Differentiation Workup

10. Management / Treatment Regimens

• Early stage (I-II, favorable): ABVD chemotherapy (Adriamycin/doxorubicin, Bleomycin, Vinblastine, Dacarbazine), 2-4 cycles + involved-site radiotherapy (ISRT)
• Advanced stage (III-IV): ABVD x 6 cycles, or escalated BEACOPP in high-risk/bulky disease
• Relapsed/refractory: high-dose chemotherapy + autologous stem cell transplant; brentuximab vedotin (anti-CD30 antibody-drug conjugate); checkpoint inhibitors (nivolumab, pembrolizumab) for relapsed classical HL
• NLPHL: often managed with radiotherapy alone if localized, or rituximab (CD20+) based regimens

• Aggressive B-cell (DLBCL): R-CHOP (Rituximab, Cyclophosphamide, doxorubicin/Hydroxydaunorubicin, Vincristine/Oncovin, Prednisone), typically 6 cycles +/- radiotherapy for bulky/localized nodal disease
• Indolent (follicular, SLL): watch-and-wait if asymptomatic; rituximab-based chemoimmunotherapy (R-CHOP, R-Bendamustine) when treatment indicated; radiotherapy alone for truly localized disease
• Burkitt lymphoma: intensive short-cycle regimens (e.g., CODOX-M/IVAC, hyper-CVAD) plus tumor lysis prophylaxis (aggressive hydration, rasburicase/allopurinol)
• Extranodal NK/T-cell lymphoma, nasal type: concurrent radiotherapy + chemotherapy (asparaginase-based regimens, e.g., SMILE), since it is relatively radioresistant to standard CHOP but radiosensitive at higher doses
• MALT lymphoma (salivary/thyroid): localized radiotherapy is often curative; H. pylori eradication for gastric variants
• Relapsed/refractory NHL: autologous/allogeneic stem cell transplant, CAR-T cell therapy (axicabtagene, tisagenlecleucel) for relapsed DLBCL, bispecific antibodies

11. Overall Comparison Summary

Extranodal NK/T-Cell Lymphoma, Nasal Type — Deep Dive

Overview

Pathophysiology / Pathogenesis

• Nearly 100% EBV-associated - the tumor cells harbor clonal episomal EBV, most often the LMP1-deletion variant strain.
• Malignant cells express cytotoxic granule proteins (perforin, granzyme B, TIA-1), consistent with an NK/cytotoxic-T origin.
• The defining biological feature is angiocentricity and angioinvasion: tumor cells infiltrate and destroy vessel walls, causing thrombosis and ischemic necrosis. This vascular destruction, not direct tumor bulk alone, drives the characteristic tissue destruction and explains why biopsies are so often non-diagnostic (necrotic tissue predominates over viable tumor).
• T-cell receptor (TCR) genes are typically in germline configuration (true NK lineage) but can be clonally rearranged in the rarer cytotoxic T-cell-derived cases.
• Circulating plasma EBV DNA correlates with tumor burden and is used as a biomarker for disease monitoring and prognosis.

Pathology

Clinical Features

• Nasal obstruction, epistaxis, foul-smelling discharge
• Progressive midfacial destructive ulceration - palatal perforation, septal perforation, facial swelling/erythema
• Can extend to paranasal sinuses, orbit, nasopharynx, skin
• Clinical course may be complicated by a hemophagocytic syndrome with pancytopenia and fever - an aggressive, sometimes fatal complication
• Systemic B symptoms and disseminated disease occur in advanced stages

Imaging

• CT: best for delineating bone destruction - septal/palatal erosion, sinus wall destruction, extent of midfacial bony involvement. Shows a soft-tissue infiltrative mass centered on the nasal cavity with variable degrees of osteolysis.
• MRI: better for soft-tissue extent - defines invasion into orbit, pterygopalatine fossa, skull base, and perineural spread; lesions are typically iso- to hypointense on T1, variable T2 signal, with heterogeneous enhancement due to necrosis.
• PET-CT: essential for accurate staging (differentiating localized stage I/IIE from disseminated stage III/IV disease) and for post-treatment response assessment.
• MRI of the nasopharynx specifically is recommended at diagnosis given the propensity for deep extension along this route.
• Plasma EBV DNA PCR is a required adjunct at diagnosis and during follow-up, complementing imaging in disease monitoring.

Staging and Workup

Surgical Management (ENT-specific role)

1. Diagnostic: endoscopic nasal/nasopharyngeal biopsy — often requiring multiple deep biopsies (image-guided or repeated endoscopic sampling) because of the necrotic tumor core, plus biopsy of any skin lesions if present.
2. Staging endoscopy: assessing extent of mucosal/bony involvement for radiotherapy planning and to define resectable necrotic/infected tissue.
3. Debridement of necrotic tissue: endoscopic debridement can be needed to control secondary infection, foul discharge, or crusting from the necrotic ulcerated mass, and to relieve nasal obstruction — this is palliative/supportive, not oncologic.
4. Management of complications: control of epistaxis (which can be significant given the angioinvasive, vessel-destructive biology), airway management if there is significant obstruction, and treatment of secondary sinus infection.
5. Reconstruction after treatment-related tissue loss: a growing surgical literature (e.g., Ueda et al., Cureus 2025, PMID 41561241) addresses external nasal reconstruction in patients left with saddle-nose deformity, septal/palatal perforation, or significant soft-tissue and cartilage loss after the disease process and/or radiotherapy — using local flaps, cartilage grafts, or free flaps once the disease is in remission. This is reconstructive/rehabilitative surgery performed after oncologic treatment, not primary treatment.
6. There is no role for radical surgical resection or wide local excision as primary curative therapy — attempting this delays definitive chemoradiotherapy and does not improve outcomes, unlike squamous cell carcinoma of the sinonasal tract.

Definitive (Non-Surgical) Management — for context

• Stage I/II (localized): Radiotherapy is the backbone (minimum dose 50-56 Gy). Low-risk stage I can sometimes be treated with RT alone; high-risk stage I/II (per criteria above) requires combined chemoradiotherapy (concurrent platinum-based or sequential regimens).
• Chemotherapy regimen of choice: non-P-glycoprotein (non-MDR)-based regimens, since ENKTL cells frequently over-express multidrug-resistance proteins that confer resistance to anthracycline-based regimens like CHOP. L-asparaginase-based regimens are preferred:
  • SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) — response rates 80%+ in trials
• Stage III/IV (disseminated): chemotherapy (e.g., 3 cycles) followed by autologous hematopoietic stem cell transplant; allogeneic transplant reserved for relapsed/refractory disease.
• Monitoring: serial plasma EBV DNA levels track tumor burden and relapse risk during and after treatment.

Prognosis