The Unknown Primary

1
The Unknown Primary

• Vanessa S. Rothholtz, M.D., M.Sc.
• University of California, Irvine
• Department of Otolaryngology - Head and Neck
  Surgery

2

• 30 year old male presents with a two month
  history of non-tender neck mass. He states that
  its growth has accelerated in the past two weeks.

3
History
4
History

• No prior masses or other concurrent masses noted
• No discharge
• No erythema
• No otalgia
• No eustachian tube dysfunction
• No nasal congestion
• No epistaxis
• No cough
• No shortness of breath
• No hoarseness or change in voice

No dysphagia No trismus No fevers / sweats /
chills No weight loss / weight gain No recent
travel No smoking or ETOH history Grew up in
Southern California Married and has an 8 month
old baby Works as a 3rd grade teacher
5
Physical Exam
6
Physical Exam

• Cranial Nerves II-XII intact bilaterally
• Ears TMs clear, intact and mobile bilaterally
• Nares Patent without masses or lesions,
  turbinate hypertrophy bilaterally
• OC/OP Clear, no tonsillar hypertrophy or
  asymmetry, tongue midline / mobile, FOM/BOT soft
• Neck 3cm deep mobile, non-tender,
  non-erythematous left neck mass anterior to the
  SCM at level II, no other lymphadenopathy, no
  thyromegaly
• FFL Nasopharynx / oropharynx clear, base of
  tongue / vallecula / epiglottis clear, pyriform
  sinuses / arytenoids / TVC mobile and clear
  bilaterally, no masses or lesions noted

7
Work Up
8
Work Up
ANA 160 (borderline) Urine metanephrine
negative VMA negative EBV - negative FNA
benign lymphocytes, no evidence of
carcinoma Culture aerobic / anaerobic / fungal
/ TB AFB negative Determine if course of
antibiotics affects size / presence of mass

• CBC WBC 5.9
• Hgb / Hct 12.1 / 25.7, Plt 243
• CMP wnl
• ESR 15
• RF negative
• RPR negative
• Coccidiomycosis Ag negative
• Cryptococcus Ag negative
• Histoplasmosis negative
• Lyme Ab negative (0.58)
• TSH 2.01
• Toxoplasmosis Ab negative

9
Indications for FNA

• Progressively enlarging nodes
• Single asymmetric nodal mass
• Persistent nodal mass without signs of infection
• Infection that does not respond to antibiotics
  and in which routine bacteriologic determinations
  are unsuccessful
• Send FNA for
• Pathology
• Flow cytometry for lymphoma diagnosis
• Polymerase chain reaction (PCR) -Epstein-Barr
  virus (EBV) - nasopharyngeal carcinoma

10
Differential Diagnosis
11
Differential Diagnosis

• Carotid Body Tumor, Hemangioma, jugular vein
  thrombosis, Carotid bulb, Kawasakis Disease,
  Vascular Malformation
• Bartonella Henselae, Staph Aureus, Group A
  Streptococcus, Atypical Mycobacterium,
  Tuberculosis, Mononucleosis, Abscess, Syphilis,
  Bacterial / Viral lymphadenitis, CMV, HSV,
  Adenovirus, Roseola, Rubella, HIV, Enterovirus,
  Kawasakis Disease, Toxoplasmosis, Sarcoid,
  Fungal
• Expanding Neck Hematoma, Foreign Body, IVDA,
  tracheal trauma, aneurysm
• Granulomatous disease, Autoimmune thyroiditis,
  HIV
• Thyroid Nodules, Multinodular Goiters, Ectopic
  thyroid, Parathyroid cyst
• Fibrosis from prior surgery, idiopathic, sarcoid,
  Castlemans disease
• Neurofibroma, Schwanomma, Lymphoma, Metastatic
  SCCA, Metastatic Adenocarcinoma, Thyroid
  neoplasia, Hemangioma, Salivary gland (parotid,
  submandibular) tumor, Vascular tumor, Lipoma,
  Rhabdomyosarcoma, Hodgkins Lymphoma, Carotid
  Body Tumor, Angioma
• Epidermoid cyst, Dermoid Cyst, Teratoma,
  Lymphangioma, Cystic Hygroma, Branchial Cleft
  Cyst, Thyroglossal Duct cyst, external
  laryngocele, Thymic cyst, Pharyngeal
  diverticulum, sebaceous cyst

12
Imaging

• CXR negative
• Ultrasound -not performed
• CT neck / thorax / abdomen
• MRI - CT is enough
• Fluorodeoxyglucose positron emission tomography
  (FDG-PET) - not yet

13
CT Scan
14
Excisional Biopsy
Cummings
15
Excisional Biopsy

• Metastatic squamous cell carcinoma with basaloid
  features
• Multiple matted lymph nodes
• Largest measuring 2cm
• Extranodal extension is not present

16
What nodal stage is this patient?
17
What nodal stage is this patient?

• N2b multiple ipsilateral nodes, none greater
  than 6cm in size
• N1 - Single ipsilateral node 3 cm
• N2a - Single ipsilateral node 3 cm 6 cm
• N2b - Multiple ipsilateral nodes 6 cm
• N2c - Bilateral or contralateral nodes 6 cm
• N3 - Node 6 cm

18
Location of Nodes Involved and their relationship
to primary site

• Supraclavicular nodes primary site below level
  of clavicles (breast / lung)
• Jugulodigastric nodes (Level IIA/IIB)
  oropharynx, soft palate, tonsil, base of tongue,
  pyriform sinus and supraglottic larynx

19
Location of Nodes Involved and their relationship
to primary site

• Submental (Level IA) Mentum, middle 2/3 lower
  lip, anterior gingiva, anterior tongue
• Submandibular (Level IB) Ipsilateral lower and
  upper lip, cheek, nose, medial canthus, oral
  cavity up to anterior tonsillar pillar
• Middle jugular nodes (Level III) larynx,
  nasopharynx, hypopharynx, inferior pyriform sinus
  and postcricoid region
• Lower jugular nodes (Level IV) thyroid,
  hypopharynx, trachea, cervical esophagus
• Posterior triangle nodes (Level VA/VB)
  Nasopharynx, skin of posterior scalp / neck

20
Location of Nodes Involved and their relationship
to primary site

• Central nodes (Level VI) Thyroid, glottic and
  subglottic larynx, apex of pyriform sinus,
  cervical esophagus
• Occipital nodes Posterior scalp
• Postauricular nodes Posterior scalp, mastoid,
  posterior auricle
• Retropharyngeal nodes - Posterior nasal cavity,
  sphenoid and ethmoid sinuses, hard and soft
  palate, nasopharynx, posterior pharyngeal wall

21
PET-FDG / CT

• Focal area of increased uptake at anterior
  pharyngeal mucosa space of oropharynx centered
  at epiglottis immediately superior to hyoid
  (11.9)
• Subcentimeter level IIA lymph node (4.8)

22
Fluorodeoxyglucose positron emission tomography
(FDG-PET)

• FDG uptake reflects cellular metabolism and
  cellular processes such as infection, neoplasm or
  inflammation
• FDG-PET detected primary tumor in 24 of patients
  with metastatic cervical adenopathy and otherwise
  negative clinical and radiologic evaluation
• Limitations of PET
• Size of detectable tumor 1cm (newer is 5mm)
• Anatomically nonspecific / inaccuracy - regarding
  size or localization (but now there is PET / CT)

Johansen J, Eigtved A, Buchwald C, et al.
Laryngoscope 2002112200914
23
Fluorodeoxyglucose positron emission tomography
(FDG-PET)

• FDG-PET revealed an unknown primary -
• 7 of 27 patients (26)
• Occult primary tumor was removed surgically - 4
  out of 7 patients
• Therapeutic strategy changed as a result of the
  18-FDG-PET findings - 8 of 27 patients

Jungehulsing M et. al. Otolaryngol Head Neck
Surg. 2000 Sep123(3)294-301.
24
False negative 1/42 (2)
Johansen J, Eigtved A, Buchwald C, et al.
Laryngoscope 2002112200914.
25
What Next?
26
What Next?

• Direct laryngoscopy
• Rigid cervical esophagoscopy
• Bronchoscopy
• Examination of the nasopharynx by palpation or an
  endoscope

27
Directed Biopsies
28
Directed biopsies

• Nasopharynx
• Tonsils
• Pyriform sinus
• Hypopharynx
• Postcricoid region
• Base of tongue

29
Unilateral / Bilateral Tonsillectomy vs.
Directed Tonsil Biopsies
30
Unilateral / Bilateral Tonsillectomy vs.
Directed Tonsil Biopsies

• Detection rate of occult tonsillar carcinoma -
  increased with tonsillectomy vs. focal tonsillar
  biopsy
• 13 of tonsillar biopsy specimens positive
• 39 of bilateral tonsillectomy - positive (1)
• Bilateral
• Practical (doesnt increase morbidity and
  eliminates asymmetry )
• 10 rate of contralateral tonsillar spread from
  occult tonsillar lesion

McQuone S, Eisele D, Lee D, et al. Laryngoscope
1998108160510.
31
Etiology

• Unknown primary tumor site - 2 to 5
• Primary tumor detected 40 of patients
• Tonsillar fossa.- 43
• Base of the tongue - 39
• Pyriform sinus 9
• Posterior pharyngeal wall 3
• Lateral pharyngeal wall / vallecula / suprahyoid
  epiglottis 2

Mendenhall W et. al.. Am J Otolaryngology 22(4)
2001 261-267
32
Treatment

• Radiation alone vs. Radiation and Neck
  Dissection?
• Ipsilateral or bilateral radiation?
• Pre-operative or post-operative radiation?
• Role of Chemotherapy?

33
Treatment

• Single-modality therapy - N1 or N2a disease
• Neck dissection alone
• Extracapsular extension not present
• 5-year disease-specific survival rates
• 85 - patients with a solitary node
• 58 - patients with multiple nodes
• Radiation alone after biopsy
• 88 - 95 - neck control after excisional biopsy
  of solitary node
• Neck dissection plus radiation - extracapsular
  spread, multiple nodes N2b, N2c, N3

Colletier PJ et. al.. Head Neck. 20 (8) Jan
1998 674- 681
Mendenhall W et. al.. Am J Otolaryngology 22(4)
2001 261-267
34
Biopsy vs. Neck Dissection
Aslani M et al. Head Neck. 29(6) Feb 2007
585 590.
35
Radiation to ipsilateral vs. bilateral vs.
bilateral plus potential mucosal primary sites

• Treatment limited to the involved side of the
  neck alone
• Compromise further radiation therapy should a
  primary mucosal site emerge
• Identification of mucosal primary lesion is
  higher
• Bilateral radiation to the neck and mucosal sites
  has significantly better control
• Base of tongue (39) midline structure
• Ipsilateral neck irradiation local control 53
• Bilateral neck irradiation local control 90

Carlson L, Fletcher G, Oswald M. Int J Radiat
Oncol Biol Phys 198612210110.
Reddy SP and Marks JP. Int. J. Radiation Oncology
Biol. Phys. 37(4) 1997 797-802.
36
Ipsilateral vs. Bilateral Radiation
Reddy SP and Marks JP. Int. J. Radiation Oncology
Biol. Phys. 37(4) 1997 797-802
37
Ipsilateral vs. Bilateral Radiation
Reddy SP and Marks JP. Int. J. Radiation Oncology
Biol. Phys. 37(4) 1997 797-802
38
Ipsilateral vs. Bilateral Radiation
Reddy SP and Marks JP. Int. J. Radiation Oncology
Biol. Phys. 37(4) 1997 797-802
39
Field of Radiation
Colletier PJ et. al. Head Neck. 20 (8) Jan
1998 674- 681.
40
Pre-operative vs. Post-operative Radiation

• Pre-operative radiation
• Potential surgical complications do not delay the
  initiation of radiotherapy
• Target tissues are theoretically better
  oxygenated in the preoperative state
• Radioresistant primary tumors may become evident
  over the course of radiation therapy - removed
  with one definitive surgical procedure
• Post-operative radiation therapy
• Improved delineation of disease extent
• Better staging through pathologic evaluation of
  the neck dissection specimen

41
Role of Chemotherapy

• Adjuvant chemotherapy - mixed results Most
  evaluated in RTC for advanced HN carcinoma
• Recommended in cases of inoperable disease or
  with distant metastases
• Concurrent chemotherapy and radiotherapy in the
  postoperative setting may improve locoregional
  control rates but not overall survival
• Increases morbidity of treatment
• Ongoing trials
• European Organization for Research on Treatment
  of Cancer (EORTC), Radiation Therapy Oncology
  Group

42
Prognosis

• Lymph nodal stage ? outcome
• Poorer prognosis
• Supraclavicular lymph node metastases
• Advanced Nodal disease
• Histologic extracapsular spread
• Extent of irradiation field
• Discovery of a primary tumor worsens prognosis
  (controversial)

Wang RC, Goepfert H, Barber A. Arch Otolaryngol
Head Neck Surg 1990116138893.
43
Prognosis

• Overall 5-year survival 50
• Disease-specific survival rates - 2-, 5-, and
  10-year - 82, 74 (66), and 68 (52)
• Overall survival rates - 2-, 5-, and 10-year -
  75, 60, and 41

Strojan P and Aniin A. Radiotherapy and
Oncology. 49(1) Oct 1998 33-40.
Colletier PJ et. al. Head Neck. 20 (8) Jan
1998 674- 681.
44
Colletier PJ et. al. Head Neck. 20 (8) Jan
1998 674- 681.
45
Prognosis
46
Prognosis
47
Prognosis
48
Prognosis
49
References

• 1) Iganej et al. Metastatic Squamous cell
  carcinoma of the neck from an unknown primary
  Management options and patterns of relapse. Head
  Neck 24(3) Jan 2002 236-246.
• 2) Mahoney EJ, Spiegel JH. Evaluation and
  Management of Malignant Cervical Lymphadenopathy
  with an Unknown Primary Tumor. Otolaryng Clin No
  Amer. 38 (2005) 87-97.
• 3) Aslani M et al. Metastatic carcinoma to the
  cervical nodes from an unknown head and neck
  primary site Is there a need for neck
  dissection?. Head Neck. 29(6) Feb 2007 585
  590.
• 4) Medini E et al. The Management of Metastatic
  Squamous Cell Carcinoma in Cervical Lymph Nodes
  From an Unknown Primary. Am J Clin Onc. 21(2)
  Apr 1998 121-125.
• 5) Colletier PJ et. al. Postoperative radiation
  for squamous cell carcinoma metastatic to
  cervical lymph nodes from an unknown primary
  site outcomes and patterns of failure. Head
  Neck. 20 (8) Jan 1998 674- 681.
• 6) Simo R and Leslie A. Differential Diagnosis
  and Management of Neck Lumps. Head Neck. 2006
  312-322.
• 7) Miller FR et al. Positron Emission Tomography
  in the Management of Unknown Primary Head and
  Neck Carcinoma. Arch Otolaryngol Head Neck Surg.
  2005131626-629.
• 8) Strojan P and Aniin A. Combined surgery and
  postoperative radiotherapy for cervical lymph
  node metastases from an unknown primary tumour.
  Radiotherapy and Oncology. 49(1) Oct 1998
  33-40.
• 9) Mendenhall W et. al. Squamous Cell Carcinoma
  Metastatic to the Neck from an Unknown Head and
  Neck Primary Site. Am J Otolaryngology 22(4)
  2001 261-267.

50
References

• 10) Jereczek-Fossa BA et al. Cervical lymph node
  metastases of squamous cell carcinoma from an
  unknown primary. Cancer Treatment Reviews. 30
  2004 153164.
• 11) Reddy SP and Marks JP. 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. Radiation Oncology Biol.
  Phys. 37(4) 1997 797-802.
• 12) Johansen J, Eigtved A, Buchwald C, et al.
  Implication of 18F-fluoro-2-deoxy-D-glucose
  positron emission tomography on management of
  carcinoma of unknown primary in the head and
  neck a Danish cohort study. Laryngoscope
  2002112200914.
• 13) McQuone S, Eisele D, Lee D, et al. Occult
  tonsillar carcinoma in the unknown primary.
  Laryngoscope 1998108160510.
• 14) Wang RC, Goepfert H, Barber A. Unknown
  primary squamous cell carcinoma metastatic to the
  neck. Arch Otolaryngol Head Neck Surg
  1990116138893
• 15) Carlson L, Fletcher G, Oswald M. Guidelines
  for radiotherapeutic techniques for cervical
  metastases from an unknown primary. Int J Radiat
  Oncol Biol Phys 198612210110.
• 16) Nieder C, Gregoire V, Ang KK. Cervical lymph
  node metastases from occult squamous cell
  carcinoma cut down a tree to get apple. Int J
  Radiat Oncol Biol Phys 20015072733.
• 17) Jungehulsing M et. al. 2F-fluoro-2-deoxy-D-
  glucose positron emission tomography is a
  sensitive tool for the detection of occult
  primary cancer (carcinoma of unknown primary
  syndrome) with head and neck lymph node
  manifestation. Otolaryngol Head Neck Surg. 2000
  Sep123(3)294-301.