Solitary Thyroid Nodule

Differential Diagnosis

• Colloid nodule / multinodular goiter (MNG)
• Follicular adenoma
• Simple cyst
• Focal thyroiditis
• Carcinoma (papillary, follicular, medullary, anaplastic)
• Status post hemithyroidectomy
• Hemiagenesis
• Metastasis to thyroid

• Thyroglossal duct cyst
• Lymph node
• Parathyroid cyst
• Cystic hygroma, dermoid, teratoma
• Laryngocele

History - Red Flags for Malignancy

• Radiation history: Low-dose therapeutic radiation (for tinea capitis, acne, tonsillar hypertrophy) confers ~40% risk of malignancy in any resulting nodule. Risk peaks 20-30 years after exposure. After Chernobyl, children showed a marked surge in papillary thyroid cancer within 4 years.
• Pain is usually hemorrhage into a benign nodule or thyroiditis; aching in the neck can also occur with medullary thyroid carcinoma (MTC).
• Hoarseness suggests possible recurrent laryngeal nerve (RLN) involvement by malignancy.
• Family history: MEN2 syndromes (medullary carcinoma + pheochromocytoma + hyperparathyroidism), Cowden disease (PTEN mutation - follicular thyroid carcinoma), Gardner syndrome (polyposis coli + papillary thyroid carcinoma).

Physical Examination

• Nodules are palpable when ≥1 cm; smaller ones are found incidentally on imaging.
• Firmness of the nodule increases the risk of malignancy 2-3 fold.
• Nodules >2 cm and solid lesions have higher incidence of carcinoma.
• Fixation to surrounding structures is strongly suspicious.
• Cervical lymphadenopathy adjacent to the nodule raises suspicion; it can be the only presenting sign of thyroid carcinoma.
• Check if the nodule moves with swallowing (thyroid origin) vs. non-thyroid.
• Assess for substernal extension: inferior aspect below the clavicle; Pemberton's maneuver (arms raised above head eliciting facial flushing + venous engorgement = thoracic inlet obstruction).

Investigations

1. Serum TSH (First-Line)

• Suppressed TSH (hyperthyroid): Perform radionuclide scan - risk of malignancy is only ~1% in hot nodules.
• Elevated TSH (hypothyroid): Treat appropriately, then perform FNAC.
• Normal TSH (euthyroid): Most patients - proceed directly to ultrasound + FNAC.

2. Ultrasound (US) - Most Important Imaging

• Differentiates solid vs. cystic nodules.
• Identifies sonographic features raising malignancy risk: microcalcifications, hypoechoic solid nodule, irregular margins, taller-than-wide shape, absent halo, abnormal regional nodes.
• Guides FNAC for difficult-to-palpate nodules.
• Preferred for surveillance of benign nodules.
• Elastography: malignant nodules are stiffer (less deformable) than benign; newer technique, still being validated.
• Contrast-enhanced ultrasound (CEUS): A 2026 meta-analysis (Huo et al., PMID 42262145) shows emerging diagnostic utility for nodule characterization.

3. Fine Needle Aspiration Biopsy (FNAB) - Gold Standard

• Difficult-to-palpate nodules
• Cystic/solid-cystic nodules recurring after prior aspiration
• Multinodular goiters

4. Radionuclide Scanning (¹²³I or ⁹⁹ᵐTc)

• NOT routine - use only if TSH is suppressed (to confirm hot/warm nodule) or after indeterminate FNAC.
• Cold nodules: 95% of all nodules; malignancy rate 10-15%.
• Hot nodules: malignancy rate ~4% (benign autonomous nodule usually).
• ⁹⁹ᵐTc: tests iodine transport only, faster (1 day), less radiation; cannot penetrate sternum.
• ¹²³I: tests transport AND organification; 2 days; preferred for substernal extension.

5. CT / MRI

• Not routine for thyroid nodule evaluation.
• Indicated for: substernal lesions, large/fixed tumors, suspected visceral compartment invasion, mediastinal adenopathy.
• Caution: iodinated CT contrast delays postoperative RAI therapy by 2-3 months.
• MRI superior to CT for distinguishing recurrent tumor vs. postoperative fibrosis.

6. Laboratory Tests

• Serum TSH - always
• Serum calcitonin - if MTC or MEN2 suspected (family history, FNAB suspicious for MTC)
• Serum thyroglobulin (Tg) - cannot differentiate benign from malignant preoperatively; used for post-thyroidectomy surveillance
• RET oncogene mutation testing - all patients with confirmed MTC; 24-hr urine VMA/metanephrines to rule out pheochromocytoma

Bethesda Classification of FNAB Results + Management

• Benign (II): Most common result. Includes colloid nodule, follicular adenoma, Hashimoto's, granulomatous thyroiditis. Cysts are aspirated; if they reaccumulate 3 times, thyroidectomy is recommended. Colloid nodules are observed; thyroidectomy if continued growth or compressive symptoms.
• FN/Suspicious for FN (IV): Up to 35% of Bethesda IV lesions are actually hyperplastic follicular proliferations, not true neoplasms. Lobectomy is preferred as it is both diagnostic and potentially therapeutic.
• Malignant (VI): Near-total or total thyroidectomy.

Molecular Marker Testing (for Indeterminate FNAB)

Management Algorithm Summary

1. History + Physical Exam - identify high-risk features
2. Serum TSH
   • Suppressed → Radionuclide scan → hot nodule = treat medically; cold nodule = FNAB
   • Normal/elevated → Ultrasound + FNAB
3. FNAB result guides surgical vs. conservative management (Bethesda criteria)
4. Surgery for: malignant/suspicious cytology, follicular neoplasm, cyst reaccumulating ×3, symptomatic growth, history of radiation exposure, high-risk clinical features

Special Situations

• Radiation-exposed patients: Even a nodule showing benign FNAB cytology may harbor cancer in a separate nodule in 40% of cases - near-total thyroidectomy may be warranted.
• Children (<20 years): 20-50% malignancy rate with STN - aggressive workup mandatory.
• Elderly males: Higher incidence of nodular disease; malignancy if found has worse prognosis.
• MEN2 / Medullary thyroid carcinoma: Confirm RET mutation, rule out pheochromocytoma before surgery.

Recent evidence update: A 2025 systematic review (Lim et al., PMID 40658618) confirms efficacy and safety of thermal ablation (radiofrequency, microwave, laser) as a non-surgical option for indeterminate benign thyroid nodules, offering volume reduction while preserving thyroid function.

1. Definition & epidemiology - present in ~4% of the US population
2. Differential diagnosis - 95% benign (colloid nodule, adenoma, cyst, focal thyroiditis, carcinoma)
3. History & red flags for malignancy (age <30/>60, male sex, radiation exposure, rapid growth, hoarseness, lymphadenopathy, fixation)
4. Physical examination findings
5. Investigations - TSH, ultrasound, FNAB (gold standard), radionuclide scan, CT/MRI, lab tests
6. Bethesda classification (I-VI) with malignancy risk and management per category
7. Molecular marker testing (Afirma, ThyroSeq, ThyGenX) for indeterminate FNAC
8. Management algorithm flowchart
9. Special situations (radiation exposure, children, MEN2)

Hodgkin Lymphoma (HL)

Definition

1. Classic Hodgkin lymphoma (cHL) - characterized by the pathognomonic Hodgkin-Reed-Sternberg (HRS) cell
2. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) - ~10% of cases; characterized by predominance of small lymphocytes and "popcorn cells"

Epidemiology

• Incidence: ~2.7 per 100,000; ~30,000 new cases annually in North America and Europe
• Bimodal age distribution: early peak at age 25-30 years (young adults), later peak at >50 years
• Slightly more common in males and in White populations
• Higher incidence in higher socioeconomic classes
• Lifetime cumulative risk: approximately 1 in 250-300 in North America
• In the Indian subcontinent, the age distribution is strongly shifted into childhood

Pathogenesis & Etiology

• RS cells arise from germinal center B cells (proven by single-cell microdissection showing clonal immunoglobulin gene rearrangements with somatic hypermutation in all RS cells)
• Epstein-Barr virus (EBV): Present in RS cells in up to 70% of mixed-cellularity subtype and smaller fractions of other classic forms. The EBV genome is clonally integrated - infection precedes transformation
• Immune evasion: RS cells express high levels of PD-L1 and PD-L2, which antagonize T-cell responses. Many tumors amplify the chromosome 9 region encoding these ligands - explaining why anti-PD-1 antibodies (checkpoint inhibitors) are so effective even in resistant disease
• RS cells also cause loss of β2-microglobulin function → failure to express Class I MHC molecules → hidden from cytotoxic T cells
• Cytokine-driven inflammation:
  • IL-5 (from RS cells) → eosinophil chemoattraction
  • TGF-β (from RS cells) → fibrosis (nodular sclerosis pattern)
  • IL-13 (from RS cells) → autocrine RS cell growth stimulation

WHO Classification of Subtypes

Pathology: Reed-Sternberg Cell

• Very large cell: 15-45 μm in diameter
• Enormous multilobate nucleus with exceptionally prominent nucleoli
• Characteristic "owl-eye" appearance - two mirror-image nuclei/lobes, each with a large acidophilic nucleolus surrounded by a clear halo
• Abundant, slightly eosinophilic cytoplasm
• Tumor cells are typically a minor fraction of the total tumor mass; most cells are reactive host inflammatory cells

• CD30+ (90-100%) ← most reliable marker
• CD15+ (75-85%)
• CD45- (leukocyte common antigen negative)
• B and T cell markers usually negative
• CD20+ in ~40% (weak, minority of cells)
• PAX5/BSAP+ (>90%)

• CD20+ (strongly, unlike cHL)
• CD45+, CD79a+
• CD30-, CD15-

Clinical Features

Presentation

• Asymptomatic peripheral lymphadenopathy is the most common presentation - most commonly cervical and supraclavicular nodes
• Incidence peaks between 15-40 years
• Nodular sclerosis particularly involves lower cervical, supraclavicular, and mediastinal lymph nodes

B Symptoms (present in ~25% at diagnosis, uncommon in early-stage disease)

• Persistent fever >38°C
• Drenching night sweats
• Unexplained weight loss >10% body weight in 6 months

Other Symptoms

• Generalized pruritus - common in HL (rare in NHL); often precedes diagnosis by months; related to RS cell cytokine production
• Pel-Ebstein fever - characteristic cyclic fever pattern
• Alcohol-induced pain at lymph node sites (pathognomonic but rare)
• Mediastinal involvement → cough, dyspnea, SVC syndrome
• Bone pain if skeletal involvement

Spread Pattern

• HL spreads in a contiguous, stepwise fashion from one lymph node region to the anatomically adjacent one (unlike NHL, which spreads unpredictably) - this has important therapeutic implications for radiation field planning

Staging: Ann Arbor System with Cotswolds Modification

• A = no B symptoms; B = B symptoms present
• E = limited, contiguous extranodal extension
• X = bulky disease (>1/3 mediastinal width or >10 cm nodal mass)

Investigations / Staging Workup

1. Complete history - B symptoms, bone pain, pruritus
2. Physical examination - lymphadenopathy, organomegaly
3. CBC - may show leukocytosis, lymphocytopenia, eosinophilia, thrombocytosis
4. Serum biochemistry - albumin (<4 g/dL is a poor prognostic factor), LDH, alkaline phosphatase, bilirubin, creatinine, ESR
5. Mediastinal Mass Ratio (MMR) - calculated on chest X-ray; MMR >0.33 (CXR) or >0.35 (CT) = bulky disease, worse prognosis
6. CT neck/chest/abdomen/pelvis - standard staging; widely available
7. ¹⁸F-FDG PET/CT - investigation of choice for staging; sensitivity 97%, specificity 100% for HL; changes management in 10-20% of HL cases vs CT alone; HL is FDG-avid
8. Bone marrow biopsy - no longer routine if PET/CT performed
9. Biopsy - excisional node biopsy preferred; RS cells + immunophenotyping required for diagnosis

International Prognostic Score (IPS) - Advanced HL

• IPS 0-2 (low risk): ~80% cure rate
• IPS ≥3 (high risk): ~60% cure rate (Goldman-Cecil Medicine; Cummings Otolaryngology)

Treatment

• Nonbulky Stage I-II: 90-95%
• Bulky Stage I-II: ~80%
• Stage III-IV: ~70%
• Overall 5-year survival (SEER): 86.4%

Treatment by Stage

ABVD Regimen (cornerstone of HL treatment)

• A - Adriamycin (doxorubicin)
• B - Bleomycin
• V - Vinblastine
• D - Dacarbazine

BEACOPP (escalated, for high-risk advanced HL)

• Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin (vincristine), Procarbazine, Prednisolone

Special Considerations

• Women aged 15-30 receiving mediastinal/axillary RT: high risk of secondary breast cancer - chemotherapy alone preferred
• Smokers: marked risk of lung cancer after mediastinal RT
• PET-adapted therapy: Interim PET scan after 2 cycles guides escalation or de-escalation of therapy

Relapsed/Refractory Disease

• Autologous HSCT: Standard of care for primary refractory or relapsed HL sensitive to salvage chemotherapy
• Brentuximab vedotin (anti-CD30 antibody-drug conjugate): Effective in relapsed/refractory cHL
• Anti-PD-1 checkpoint inhibitors (nivolumab, pembrolizumab): Highly effective even in multiply relapsed disease, leveraging the PD-L1 overexpression mechanism of RS cells
• Allogeneic HSCT: Option for patients relapsing after autologous HSCT

Long-Term Treatment Complications

• Cardiopulmonary toxicity - anthracycline cardiomyopathy, bleomycin pulmonary toxicity, radiation pericarditis/coronary artery disease
• Secondary malignancies - breast cancer (mediastinal RT in young women), lung cancer (mediastinal RT + smoking), therapy-related AML/MDS (alkylating agents)
• Infertility / premature menopause (alkylating agents)
• Hypothyroidism (neck irradiation)

Differential Diagnosis

• Non-Hodgkin lymphoma
• Primary mediastinal B-cell lymphoma
• Mediastinal gray zone lymphoma
• Germ cell tumors
• Thymoma
• Sarcoidosis
• Tuberculosis
• Reactive lymphadenopathy (EBV infectious mononucleosis)