# Radiation Oncology/Head & Neck/Unknown primary

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## Epidemiology

* SCC of unknown primary represents 3-5% of cancers of head and neck.

## Natural History

* Likely a result from subclinical primary malignancy in upper aerodigestive tract.
* Primary identified in approximately 40% of cases (80% of identified primary cancers are from either tonsil or base of tongue).
* Most commonly affect jugulodigastric and upper jugular nodes.

## Diagnostic Workup

* Clinical examination
** Complete head and neck exam.
** Examination of the skin of the head and neck region.
* CT or MRI
** Imaging should extend from base of skull to thoracic inlet.
* Panendoscopy with directed biopsies
** Endoscopic evaluation should include direct laryngoscopy and nasopharynx survey.
** For Level II node, directed biopsies should include base of tongue, nasopharynx, pyriform sinus, tonsil.
* Tonsillectomy
** Tonsillectomy improves yield over focally directed biopsy.
** Question ipsilateral vs bilateral tonsillectomy is controversial.
** Johns Hopkins, 1998 PMID 9818813 -- McQuone S "Occult tonsillar carcinoma in the unknown primary." Laryngoscope. 1998 Nov;108(11 Pt 1):1605-10.
* PET
** NCCN recommends only if other workup does not identify the primary.
** After FNA of the neck mass, can increase diagnostic yield by 20-30%
** However, after negative PET, pan-endoscopy with directed biopsies can detect primary in 10-20% cases.
** Therefore, combination of PET and pan-endoscopy with directed biopsies is probably best, with a yield of almost 50%
** UT San Antonio, 2008 PMID 17657782 -- Miller FR, "Management of the unknown primary carcinoma: long-term follow-up on a negative PET scan and negative panendoscopy." Head Neck. 2008 Jan;30(1):28-34.
** Emory Review, 2004 PMID 15517576 -- Rusthoven KE "The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor." Cancer. 2004 Dec 1;101(11):2641-9.
*** PET detected previously unidentified primary in 24.5% of patients
* Level IV/V LNs
** Also perform bronchoscopy, esophagoscopy and CT of chest/abdomen/pelvis

## Staging

AJCC 8th edition (2017): To be used for staging beginning Jan 1, 2018.
* Cervical Lymph Nodes and Unknown Primary Tumors of the Head and Neck
** Used for squamous cell carcinoma and salivary gland carcinoma of all head and neck sites except HPV-related oropharynx cancer, nasopharyx cancer, melanoma, thyroid carcinoma, and sarcoma.
** New staging chapter for 8th edition
Occult primary tumor: Staging is T0 and the N category is according to the respective anatomic site based on EBV and HPV status:
* EBV-related cervical adenopathy -> Staged according to Nasopharynx
* HPV-related cervical adenopathy -> Staged according to HPV-mediated oropharyngeal cancer
* All other pts with EBV-unrelated and HPV-unrelated -> Staged according to main H&N staging listed here
For non-EBV and non-HPV related:
Clinical (cN)
* NX - Cannot be assessed
* N0 - No regional lymph nodes metastasis
* N1 - Single ipsilateral lymph node, <= 3 cm in greatest dimension, and ENE(-)
* N2
** N2a - Single ipsilateral lymph node, 3-6 cm in greatest dimension, and ENE(-)
** N2b - Multiple ipsilateral lymph nodes, <= 6 cm in greatest dimension, and ENE(-)
** N2c - Bilateral or contralateral lymph nodes, <= 6cm in greatest dimension, and ENE(-)
* N3
** N3a - Lymph node > 6 cm, and ENE(-)
** N3b - Clinically overt ENE(+) (ENE$_c$) (defined as invasion of skin, infiltration of muscle, dense tethering or fixation to adjacent structures, cranial nerve, brachial plexus, sympathetic trunk, or phrenic nerve invasion with dysfunction)
Pathological (pN)
* NX - Cannot be assessed
* N0 - No regional lymph nodes metastasis
* N1 - Single ipsilateral lymph node, <= 3cm in greatest dimension, and ENE(-)
* N2
** N2a - Single node (ipsi or contralateral), <= 3cm, and ENE(+); or single ipsilateral node, 3-6 cm, and ENE(-)
** N2b - Multiple ipsilateral nodes, <= 6 cm, and ENE(-)
** N2c - Bilateral or contralateral nodes, <= 6 cm, and ENE(-)
* N3
** N3a - Lymph node > 6 cm, and ENE(-)
** N3b - Single ipsilateral node, > 3 cm, and ECE(+); or multiple LNs and any with ENE(+)
Overall Stage:
* EBV-related cervical adenopathy -> Staged according to Nasopharynx
* HPV-related cervical adenopathy -> Staged according to HPV-mediated oropharyngeal cancer
* All other pts with EBV-unrelated and HPV-unrelated -> Staged as below
For non-EBV and non-HPV related:
* III - T0 N1
* IVA - T0 N2
* IVB - T0 N3
* IVC - T0 Any N M1

## Treatment Overview

Stage
* N1 disease can be treated with neck dissection alone.
* Patients w/ an excisional biopsy should be tx'd w/ definitive xrt.
* N2A-C and N3 disease can be treated with definitive xrt alone.
** Planned neck dissection following xrt if persistent disease
** Some institutions consider planned neck dissection standard after definitive xrt for N2 disease
University of Florida algorithm (in Gunderson, 2nd ed, 2007)
* cN1: neck dissection
** If pN1, no ECE - observe
** If pN2+ or ECE - adjuvant RT
** If excisional biopsy done - definitive RT
* cN2:
** If early N2: definitive RT
** If advanced N2-3: definitive chemo-RT
** For both, CT scan 1 month after RT, if residual disease, adjuvant neck dissection
Volume
* Classically, RT fields would include bilateral neck nodes and mucosal sites of putative origin (nasopharynx, oropharynx, hypopharynx, larynx)
* Modified mucosal volume may include only nasopharynx and oropharynx, since University of Florida data shows that hypopharynx and larynx primaries are rare. Nevertheless, for isolated Level III-IV LN, these should probably still be covered
* Modified neck volume may include ipsilateral Level Ib-V + RP nodes and contralateral low Level II-V lymph nodes.
* Treatment of bilateral neck + mucosal sites of risk appears to improve rate of neck control and even overall survival in some series as compared to unilateral neck irradiation. This issue is considered somewhat controversial and must be weighed against the added toxicity of comprehensive irradiation

## Surgery Alone

* Mayo Clinic; 1992 PMID 1618667 -- "Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy." (Coster JR, Int J Radiat Oncol Biol Phys. 1992;23(4):743-9.)
** Retrospective. 24 patients, unknown primary, unilateral neck disease, curative resection by neck dissection or excisional biopsy. N1 (n=14), N2a (n=6), N2b (n=3), N3 (n=1). ECE (n=8). Median F/U alive patients 8.5 years
** Outcome: Primary developed in 4%. Neck recurrence 25%, median TTF 3 months. In 5/6 patients with recurrence ECE+. Both N1 patients who recurred had ECE. 5-year CSS 74%, OS 66%
** Conclusion: In pN1 and no ECE, surgery alone sufficient. If pN2+ or ECE, consider adjuvant RT

## Definitive Radiation

* Gainesville, 2001 (1964-97) PMID 11316546 -- Erkal HS 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. 2001 May 1;50(1):55-63.
** 126 pts w/ SCC of cervical neck from unknown primary. >90% tx'd w/ comprehensive nodal/mucosal site irradiation.
** 5yr neck control 78% (10% persistent dz, 12% nodal failure.
** 5yr OS 47%
** Factors that affected OS on multi-variate analysis were ECE, N stage, RT dose to mucosal sites.
* Danish, 2000 (1975-95) PMID 10799723 -- Grau C 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 May;55(2):121-9.
** 277 pts tx'd radically for unknown primary of H&N. 81% tx'd with comprehensive fields (b/l neck, nasopharynx, hypopharynx, oropharynx and larynx).
** 5yr OS 37%
** Mucosal primary emergence rate 16% (50% of emerging primaries in lung or esophagus).
** Comprehensive xrt fields appeared to decrease neck relapse and development of distant mets. Comprehensive xrt fields also improved median overall survival.

### Volume

Larynx/Hypopharynx Sparing
* University of Florida; 2005 (1997-2002) PMID 16199981 -- "Larynx-sparing radiotherapy for squamous cell carcinoma from an unknown head and neck primary site." (Barker CA, Am J Clin Oncol. 2005 Oct;28(5):445-8.)
** Retrospective. 17 patients, curative intent. RT 64.8/36 parallel opposed fields to nasopharynx, oropharynx, and upper cervical LN. Matched anterior neck field at thyroid notch 50/25. Majority had >2 year follow-up
** Outcome: No SCC in H&N mucosa. 1/17 (6%) persistent nodal disease, 1/17 (6%) recurrent nodal disease. No distant mets. 5-year CSS 88%, 5-year OS 82%
** Conclusion: Larynx-sparing Rt appears effective, and likely reduces toxicity
Unilateral vs Bilateral Neck
* Princess Margaret; 1995 (1970-86) PMID 7480823 -- Weir L et al. "Radiation treatment of cervical lymph node metastases from an unknown primary: an analysis of outcome by treatment volume and other prognostic factors." Radiother Oncol. 1995 Jun;35(3):206-11.
** 144 pts tx'd for unknown primary H&N CA. 85 tx'd to involved nodes; 59 tx'd to both nodes and potential primary sites.
** 5yr OS 41%
** Nodal control 51% (94% neck failures failed within initial tx volume).
** Trend towards improved survival for treatment of both potential primary and nodes.
* Loyola; 1997 PMID 9128954 -- Reddy SP et al. "Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation." Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):797-802.
** 36 pts irradiated to b/l neck + mucosal sites, 16 pts tx'd to unilateral nodes (electrons).
** Contralateral nodal failure 44% (unilateral xrt) vs 14% (bilateral xrt)
** Mucosal primary emergence rate 44% (unilateral xrt) vs 8% (bilateral xrt)
** No difference in 5yr OS.

### IMRT

* Memorial Sloan Kettering; 2008 (2000-2005) PMID 17980501 -- "Intensity-modulated radiotherapy for head and neck cancer of unknown primary: toxicity and preliminary efficacy." (Klem ML, Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1100-7. Epub 2007 Nov 5.)
** Retrospective. 21 patients treated with IMRT (5 definitive, 16 postoperative). Target volume bilateral neck and mucosal surface. Median dose 66 Gy. Median F/U 2.0 years
** Outcome: 2-year PFS 90%, OS 85%
** Toxicity: PEG required in 72% combined chemo-RT and 43% IMRT alone. Acute Grade 1 57%, Grade 2 43%. Three esophageal strictures
** Conclusion: Acceptable toxicity and encouraging efficacy

## Reviews

* Nieder, C et al. PMID 11395241 "Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple?" Int J Radiat Oncol Biol Phys. 2001 Jul 1;50(3):727-33.
* Coster, J et al. PMID 1618667 "Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy" Int J Radiat Oncol Biol Phys. 1992; 23(4)743-9