Note on source: Stell & Maran's Head and Neck Surgery is not among the textbooks in this library. The information below is drawn from the closest equivalent authoritative ENT references available — Cummings Otolaryngology: Head and Neck Surgery and Goldman-Cecil Medicine — which cover this topic comprehensively and are the standard references for this content.

Lymph Nodes and Metastasis of Unknown Primary (MUP) — Head & Neck

1. Definition

2. Initial Evaluation

Clinical presentation

• Neck mass, usually painless, is the presenting feature
• Diagnosed histologically by fine needle aspiration (FNA) biopsy
• FNA tissue should be sampled for p16 immunohistochemistry or HPV testing — positivity strongly suggests an oropharyngeal (tonsillar or base of tongue) primary, and less commonly nasopharyngeal

History and examination

• A thorough head and neck examination of the entire upper aerodigestive tract is mandatory
• Smoking and alcohol history are relevant (traditional SCC risk) — but HPV-positive tumors increasingly occur in non-smokers

Endoscopy

• Operative endoscopy with directed biopsies of the most common occult primary sites:
  • Nasopharynx
  • Base of tongue
  • Palatine tonsil
  • Piriform sinus
• The primary is usually found at this step; if excisional biopsy was performed first, intraoperative directed biopsies of these sites should be done simultaneously

3. Role of Lymph Node Level in Localizing the Primary

4. Imaging

• CT and MRI are used first
• ¹⁸F-FDG PET/CT (fused) is the most useful modality: in 190 patients with unknown primary lesions, PET/CT showed a sensitivity of 62% and specificity of 81.9% in identifying the primary site
• PET/CT can identify a primary head and neck lesion in approximately 25% of endoscopy-negative patients

5. HPV-Positive Unknown Primary: Modern Surgical Workup

1. If HPV positive with no primary on exam or imaging → Direct laryngoscopy
2. If still no primary → Ipsilateral palatine tonsillectomy with frozen section
   • Positive for SCC → treat with staged TORS + neck dissection or definitive chemoradiation
3. If tonsillectomy negative → Ipsilateral base-of-tongue resection (TORS) — diagnostic and therapeutic

6. Management by Histology

Squamous Cell Carcinoma (most common)

• Neck dissection should not be undertaken until all efforts to identify the primary are exhausted (treatment depends on primary location)
• Once workup is complete:
  • Concurrent chemoradiotherapy — standard for locally advanced SCC of unknown primary
  • 5-year disease-free survival: 50–60%
• Adverse prognostic features:
  • Node >2 cm
  • Multiple involved lymph nodes

Melanoma of Unknown Primary

• Accounts for 2–3% of all melanoma presentations
• Possible mechanisms: small primary missed, immune regression, or origin from ectopic melanocytes in a lymph node
• Better prognosis than stage-matched melanoma with a known primary (improved immune response)
• Treatment: comprehensive neck dissection + adjuvant radiation and/or immunotherapy
• Ongoing dermatologic surveillance is mandatory

7. Regional Metastases from Other Sites

8. Distant Metastases to the Neck

• Lung, esophagus (supraclavicular nodes)
• Kidney, ovary, cervix, prostate

9. Cancer of Unknown Primary — Broader Subsets (Goldman-Cecil Framework)

• Cummings Otolaryngology: Head and Neck Surgery, Chapter 115 (Malignant Neoplasms of the Neck / Unknown Primary / Metastatic Lesions), pp. 2229–2231
• Goldman-Cecil Medicine, Chapter 164 (Cancer of Unknown Primary Origin) / Chapter 176 (Cervical Adenopathy), pp. 1889–1890

Lymph Nodes — Detailed Anatomy & Physiology

1. Overview and General Features

• Axillae (armpits)
• Inguinal (groin) regions
• Cervical (neck) regions
• Thorax, abdomen, and visceral mesenteries

• Filter lymph and trap microorganisms, foreign particles, and tumor cells
• Provide enclosed environments for antigen presentation
• Generate adaptive immune responses (B- and T-cell activation, antibody production)

2. Gross Anatomy

• A convex surface where multiple afferent lymphatics enter
• A concave depression (hilum) where a single efferent lymphatic exits, along with the artery, vein, and nerve

3. Supporting Framework

4. Histological Regions

A. Cortex (Superficial / Nodular Cortex)

• The outermost zone, directly beneath the capsule
• Contains lymphoid nodules — the hallmark of the cortex:
  • Primary nodules: dense, uniform small lymphocytes; no germinal center (resting state)
  • Secondary nodules: contain a germinal center (pale-staining center surrounded by a dark mantle zone) — indicate active humoral immune response
• Predominantly B-cell zone — B cells and follicular dendritic cells (FDCs) dominate
• Subcapsular (cortical) sinus: space immediately beneath the capsule; receives lymph from afferent lymphatics; lined by discontinuous endothelium perforated by reticulin fibers
• Trabecular (cortical) sinuses: branch internally from the subcapsular sinus alongside trabeculae; lymph percolates from these into surrounding lymphoid tissue

B. Paracortex (Deep Cortex)

• Zone between superficial cortex and medulla
• No lymphoid nodules — distinguishes it from the cortex
• Predominantly T-cell zone — T lymphocytes dominate, especially CD4⁺ T helper cells
• Also called thymus-dependent cortex — neonatal thymectomy causes a poorly developed paracortex
• Contains High Endothelial Venules (HEVs) — the critical entry point for circulating lymphocytes from blood (see below)
• Dendritic cells (DCs) are concentrated here to present antigens to T cells

C. Medulla

• Medullary sinuses are continuous with cortical sinuses and converge at the hilum to drain into the single efferent lymphatic vessel
• The reticular meshwork within medullary sinuses forms a final filter for particulate matter

5. Cells of the Lymph Node

6. High Endothelial Venules (HEVs)

1. HEV endothelial cells are unusually cuboidal/enlarged (unlike flat venular endothelium)
2. They express specific apical surface glycoproteins (addressins)
3. L-selectin on lymphocytes recognizes sugar-rich ligands on HEV endothelial surfaces → lymphocytes slow and tether ("rolling")
4. Integrins on lymphocytes bind adhesion molecules on HEVs → firm adhesion
5. Lymphocytes undergo diapedesis (squeeze between endothelial cells) → enter the paracortex

7. Lymph Flow Through the Node

Afferent lymphatics (multiple, convex surface)
        ↓
Subcapsular sinus (beneath capsule)
        ↓
Trabecular (cortical) sinuses (alongside trabeculae)
        ↓
Medullary sinuses (between medullary cords)
        ↓
Efferent lymphatic (single, at hilum)

8. Blood Supply

• Artery enters at the hilum → branches along trabeculae → forms capillaries around nodules → HEVs in paracortex → post-capillary venules → vein exits at hilum
• HEVs represent the critical microvascular specialization for lymphocyte homing

9. Cervical Lymph Node Classification (Head & Neck)

10. Physiological Functions

A. Filtration

• Lymph passing through the subcapsular and medullary sinuses is phagocytosed by macrophages
• Particulate matter (bacteria, debris, tumor cells) is trapped and degraded
• This prevents systemic dissemination of local infection

B. Antigen Presentation and Immune Activation

• Dendritic cells (most efficient APCs) capture antigen in peripheral tissues, migrate via afferent lymphatics, and present processed peptides on MHC II to naïve CD4⁺ T cells in the paracortex
• B-cell activation occurs when antigen in the cortex is recognized by B cells → germinal center reaction

C. Germinal Center Reaction (B-cell physiology)

1. Antigen-specific B cells encounter antigen (± T-cell help) → enter follicle
2. Clonal expansion within the germinal center
3. Somatic hypermutation of immunoglobulin V genes → generates B cells with diverse affinities
4. Affinity maturation — only high-affinity clones survive (selected by FDCs retaining antigen)
5. Class-switch recombination → IgM → IgG, IgA, IgE
6. B cells differentiate into long-lived plasma cells (migrate to medullary cords or bone marrow) or memory B cells

D. T-Cell Priming

• Naïve T cells enter via HEVs → scan paracortical DCs → if cognate antigen is found:
  • CD4⁺ cells differentiate into Th1, Th2, Th17, or T_fh (follicular helper) cells
  • CD8⁺ cells differentiate into cytotoxic T lymphocytes (CTLs)
• Activated T cells exit via the efferent lymphatic → thoracic duct → bloodstream → target tissues

E. Lymph Node Enlargement (Lymphadenopathy)

1. Reactive/Inflammatory: cellular proliferation in response to antigen (most common in children/young adults)
2. Neoplastic infiltration: primary (lymphoma) or secondary (metastatic carcinoma)
3. Deposition: foreign substances, storage diseases

• Histology: A Text and Atlas with Correlated Cell and Molecular Biology (Ross & Pawlina), pp. 1209–1220
• Junqueira's Basic Histology: Text and Atlas, 17e, pp. 704–710
• Cummings Otolaryngology: Head and Neck Surgery — Lymph Node Anatomy and Classification, pp. 183–185
• Goldman-Cecil Medicine — Lymphadenopathy, p. 1771