4Cancer IncidenceFrom Jemal, A. et al. CA Cancer J Clin 2007;57:43-66.
5Head and Neck Incidence Estimated New Cases per year, male and femaleOral cavity and pharynx, total 34,360Tongue ,800Mouth 10,680Pharynx 11,800Other oral cavity ,100Larynx 11,300Estimated Deaths per year, male and femaleOral cavity and pharynx, total 7,550Tongue 1,830Mouth 1,860Pharynx 2,180Other oral cavity ,680Larynx 3,660From Jemal, A. et al. CA Cancer J Clin 2007;57:43-66.
6Risk factorsTobacco and heavy alcohol use are the most common risk factors for head and neck cancer.This includes all tobacco products including cigarettes, cigars and chewing tobacco.Cigarette smokers have a lifetime increased risk for head and neck cancers 5-25 times over the general populationEx-smokers risk for head and neck cancer begins to approach the general population 20 years after quitting tobacco
7Additional Risk Factors Leukoplakia (1/3 develop oral cancer)M > F (2-3 times risk)Age > 40Betel nut chewingOccupational inhalant exposures including nickel refining, textile fibers and woodworking dust
8Unknown primaryA lymph node in the neck with malignant pathology without any obvious primary mucosal origin.Head and neck unknown primaries are generally squamous cell carcinomasIncidence: 2-3% of head and neck cancers are unknown primaries ( new cases/year)
10Levels of the NeckLevel I - This includes the submental and submandibular lymph nodes.The submental triangle (sublevel IA) is bounded by the anterior belly of the digastric muscles (laterally) and the hyoid (inferiorly). The submandibular triangle (sublevel IB) is bounded by the body of the mandible (superiorly), the stylohyoid (posteriorly), and the anterior belly of the digastric (anteriorly).Level II - This includes lymph nodes of the upper jugular group and is divided into sublevels IIA and IIB.Level II is bounded by the inferior border of the hyoid (inferiorly), the base of skull (superiorly), the stylohyoid muscle (anteriorly) and the posterior border of the SCM (posteriorly). Sublevel IIA nodes lie anterior to the SAN. Sublevel IIB nodes lie posterior to the SAN.Level III - This includes lymph nodes of the middle jugular group.This level is bounded by the inferior border of the hyoid (superiorly) and the inferior border of the cricoid (inferiorly), the posterior border of the sternohyoid (anteriorly) and the posterior border of the SCM (posteriorly).Level IV - This includes lymph nodes of the lower jugular group.This level is bounded by the inferior border of the cricoid (superiorly), the clavicle / sternal notch (inferiorly), the posterior border of the sternohyoid (anteriorly) and the posterior border of the SCM (posteriorly).Level V - This includes posterior compartment lymph nodes.This compartment is bounded by the clavicle (inferiorly), the anterior border of the trapezius (posteriorly), the posterior border of the SCM (anteriorly). It is divided into sublevels VA (lying above a transverse plane marking the inferior border of the anterior cricoid arch) and VB (below the aforementioned plane).Level VI - This includes the anterior compartment lymph nodes.This compartment is bounded by the common carotid arteries (laterally), the hyoid (superiorly), the suprasternal notch (inferiorly).
11Clinical Presentation Patients generally present with a painless, solitary neck mass, most often discovered by the patient.Masses are usually at least 2-3 cmPatients have usually gone through at least one course of antibioticsBenign masses are also often solitary and painless
13Differential diagnosis MalignantMetastatic carcinoma, sarcoma or melanomaLymphoma, LeukemiaCarotid body tumorPrimary major salivary gland tumorThyroid cancerParathyroid cancerHistiocytosisCarcinoid
14Relationship of Node Location to Likely Disease Nodes at certain levels more likely certain primariesUpper neck nodes are the most likely to be head and neck cancerSubdigastric node may be virtually any head and neck primary, or a non-Hodgkin’s lymphomaSubmandibular node suggests oral cavity, lip, nasal vestibule or salivary gland primarySubmental nodes are uncommon
15Relationship of Node Location to Likely Disease Mid NeckLikely primaries include larynx, hypopharynx, and less commonly esophagus, disease below clavicles or lymphoma•Lower Neck and Supraclavicular NodesMost often metastatic from chest or abdomen, possible esophagus or lymphoma. A primary head and neck node is uncommon at this levelParotid lymph nodes are more likely skin cancer than from a primary parotid tumorBenign neck masses are most common except in supraclavicular lymph nodes
16Percentage of patients presenting with neck nodes who go on to develop squamous cell carcinoma Erkal HS, Mendenhall WM et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys 2001a;50:55-63
19Diagnosis Physical exam Soft, rubbery nodules suggest lymphoma and leukemiaHard, fixed masses suggest carcinomaIndirect examination of oral cavity and oropharynx with mirror and/or fiberoptic endoscopy
20Diagnosis Biopsy Fine needle biopsy of LN Incisional or excisional biopsy before definitive treatment have increased rates of neck recurrence, distant metastasis and wound necrosis compared to patients without a biopsy.
21Diagnosis Imaging CT followed by an MRI if inconclusive If there is still no imaging data for a primary, a PET may be orderedIn a meta-analysis of 16 studies looking at the role of PET in 302 patients with cervical node metastases where a primary has yet to be discovered through the work up, 25% of primaries are identified through PET. Previously unrecognized regional or distant metastases were identified in 27% of patientsRusthoven, KE, Koshy, M, Paulino, AC, The role of fluorodeoxyglucose PET in cervical lymph node metastases from an unknown primary tumor. Cancer 2004; 101:2461
23Diagnosis Laryngoscopy Direct laryngoscopy with biopsies of nasopharynx, tonsils, base of tongue, pyriform sinuses as well as any suspicious areas seen on imaging.
24Screening Tonsillectomy DiagnosisScreening TonsillectomyIf a primary site has not been discovered by this point, an ipsilateral screening tonsillectomy may be performedThis is of greatest benefit in patients with subdigastric, submandibular or midjugulocarotid lymph nodesIn a study of 87 patients with unknown primaries, 26% were discovered to have a tonsillar primary after tonsillectomyLapeyre, M, Malissard, L, Peiffert, D et al. Cervical lymph node metastasis from an unknown primary: Is a tonsillectomy necessary? Int J Radiat Oncol Biol Phys; 39: 291
25Treatment Treat as aggressive disease Treat based on staging N1- neck dissection OR radiationN2, N3- combined neck dissection AND radiation
26TreatmentN1 with a history of excisional or incisional biopsy- neck dissection and radiationN2a with no persistent tumor after radiation may forego neck dissectionIncisional or excisional biopsy before definitive treatment have increased rates of neck recurrence, distant metastasis and wound necrosis compared to patients without a biopsy.
27Radiation- Dosing Dose to mucosa- 50 to 70 Gy Dose to the neck- 59 to 70 GyNeck 55Gy at 180 cGy fractions with addition 500 to 1000cGy in 3-5 fractions to any suspected site. Spinal cord to max 45GyLateral-opposed fields
28IMRTPart of the purpose of using IMRT is to decrease dose to the parotid, in order to decrease the grade of xerostomia and improve dose homogeneityBhide, S et al. Intensity modulated radiotherapy improves target coverage and parotid gland sparing when delivering total mucosal irradiation in patients with squamous cell carcinoma of head and neck of unknown primary site. 2007; 32(3):188-95Can also keep dose off of the larynx
29IMRT21 patients underwent IMRT for unknown primary either as initial treatment or post-op. Median dose was 66Gy. During treatment 57% patients developed grade 1 xerostomia and 43% developed grade 2 xerostomia. The researchers concluded IMRT shows acceptable toxicity and encouraging efficacy. Patients had marked improvement of xerostomia by 6 months. Three patients developed esophageal strictures, and were effectively treated with dilation. Techniques to limit esophageal dose may help further minimize this complication.Klem ML et al, Intensity-modulated radiation therapy for head and neck cancer of unknown primary ASCO Annual Meeting
30Radiation Ipsilateral neck vs. bilateral neck, Bilateral favored Some studies show increase risk of neck disease or emergence of primary with ipsilateral treatment compared to bilateral without overall survival being affectedAlternate studies show extensive radiation of mucosa and bilateral neck improve survival compared to ipsilateral neck radiationStudy of 352 patients with squamous cell or undifferentiated cancer of the cervical lymph nodes with no evident primary, the patients who received ipsilateral neck radiation compared to those receiving bilateral had a 1.9 relative risk of recurrence in the head and neck and lower 5 year disease free survivalGrau, C Johansen, LV, Jakobsen, J et al. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol 2000;55:121.
31Radiation by levelsRadiation fields need to include neck and potential primary sites (decreased subsequent incidence of primary tumor)Level I: no mucosal radiation recommended due to potential extensive morbidityLevels II and V: radiation field should include naso- and oropharynxLevel III: radiation field should include naso, oropharynx. It is generally not recommended to include hypopharynx and larynx as well, since these are of low probability as primary site, and have an increased probability of complications.
32Radiation by Node location Upper nodesNaso-, oro- and hypopharynx and supraglottic larynx. Oral cavity not includedJunctional or lateral retropharyngeal nodeNaso- and oropharynxSubmandibular- solitary nodeNeck only because of the major morbidity of irradiating the entire oral cavityMidjugularOro-, hypopharynx and supraglottic larynxSupraclavicularLarge portal to include apex of axilla
33Complications of Radiation Therapy Most common complication is xerostomia (dry mouth due to decreased saliva production)Also, fatigueMucositisAltered taste sensationsRed and irritated skinOccasional nauseaEsophageal stricture
34ChemotherapyPlatinum-based chemotherapy in combination with radiation recommended for N3 patients by European Society of Medical Oncology (ESMO)Consider concurrent chemo/RT with supraclavicular LN or undifferentiated tumors, though no strong data to supportChemo/ RT is an option for palliation, unresectable local disease, distant metastatic spread
36RecurrenceComparing subsequent mucosal primary lesions in patients with unknown primaries to head and neck cancer with a known primary site shows the incidence of a subsequent mucosal recurrence was similar for both groups.
37Percentage of unknown primaries compared to known sites to develop mucosal recurrence Erkal HS, Mendenhall WM et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys 2001a;50:55-63
38Prognosis The best indicator of prognosis is N stage at presentation Also, the presence of extracapsular extension is associated with a poorer prognosisPrognosis is similar between patients with a known vs. an unknown primary with the same nodal stage.
39Survival by N stageErkal HS, Mendenhall WM et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys 2001a;50:55-63
40Cause specific mortality Erkal HS, Mendenhall WM et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys 2001a;50:55-63
41Overall survival by nodal stage Iganej, S et al. Metastatic squamous cell carcinoma of the neck from an unknown primary: Management options and patterns of relapse. 2002; 24(3):
42Future ResearchPhase III Randomized Study of Selective Irradiation Versus Extensive Irradiation in Patients With Cervical Lymph Node Metastases of Squamous Cell Carcinoma From an Unknown Primary- Opened 2002, now closedEORTC-24001, EORTC-22005, DAHANCA-EORTC-24001, CAN-NCIC-EORTC-24001, RTOG-EORTC-24001, NCT