The document discusses the management of cancer of unknown primary presenting as neck lymph node metastases, including definitions, epidemiology, diagnostic evaluation, and treatment approaches such as chemotherapy, radiation therapy, and surgery. Identification of the primary site can help guide more targeted treatment but often remains challenging given the metastatic presentation; combined modality therapy is generally recommended.

1. Moderator : Dr. Mushtaq sir
Presenter : Dr. Musaib Mushtaq
Management of
Cancer of Unknown Primary (Neck)

2.  Definition
 Epidemiology
 Mechanism
 Suggested Hypothesis
 Prognostic Factors
 Clinical Presentation
 Diagnostic Evaluation
 Management
 Clinical Scenario
Cancerof
UnknownPrimary
(CUP)

3. Definition
Occult primary tumours or CUPs are histologically
proven metastatic tumors whose primary site cannot
be identified during standard pre-treatment
evaluation.
CUP’s (Neck) : Metastatic disease in the lymph
nodes of the neck WITHOUT any evidence of
primary tumour.
Remains a Multidisciplinary challenge.
Lack of prospective randomized studies.

4. Epidemiology
accounts 2% to 9% of all H&N tumours.
1.5-5% accuracy of the diagnostic workup. [Strogen P
et. al 2013]
Primary site is found in <30% of cases.
Q: Why CUP’s is a Diagnostic Challenge?
Unusual Presentation.
Delaying Treatments.
Therapeutic Errors.
CUP’s is a diagnosis of Exclusion.

5. Epidemiology
men = women
average age at diagnosis 60-75 years.
10 most frequently diagnosed tumours in developed
countries.
On the global scale, the CUP is ranked as 6th to 8th most
common cancer. (NCCN 2020)
SKIMS Data : Approx. 350 patients of CUP’s are registered
per annum (2015-2020) constituting 10% of all tumors.

6. Mechanism
I. The primary cancer may have shed metastases and then
undergone spontaneous regression.
II. The primary tumor may be too small to be detected, even at
autopsy.
III. The site of origin may be obscured by the extensiveness of
metastases or by the atypical pattern of dissemination.
IV. Primary acquires a metastatic phenotype soon after
transformation and remains small.
clonal proliferation
invasion and intravasation
widespread dissemination via
circulation
extravasation

7. Hypothesis
Hidden Location
Transformation
Inborn Errors
Infra-clavicular Theory

8. Head & Neck CUP’s
 Most encountered site of primary origin is oropharynx.
 CUP of the oropharynx is known for metastasis to levels II or III, in
certain cases to levels IV as well.
 Squamous cell carcinoma (55-90%) > undifferentiated
carcinoma > adenocarcinoma
 Risk factors :
smoking, alcohol, poor oral hygiene
HPV & EBV (90%).
90% correlation between HPV & squamous cell CUP (Fu TS. J Otolaryngol.2016)
GERD, Malnutrition, Plummer-Vinson Sx.

9. ClinicalPresentation
 Painless neck mass in an adult >40 years.
[94% Cl./P (Grau et.al. 2005)]
Symptoms Possible Primary Tumor
Otalgia Oral cavity/Pharynx/Larynx/Ear
Dysphagia/Odynophagia Pharynx/oesophagus
Hoarsness Larynx
Trismus, Speech alteration Oral cavity/oropharynx
Nasal congestion, Epistaxis Sino-nasal
Aspiration Orophaynx/Larynx

11. Nodal group Primary tumor sites
Level IA (submental) Anterior oral cavity, lower lip
Level IB (submandibular) Oral cavity, anterior nasal cavity,
submandibular gland, midfacial face
skin
Level II (upper jugular) Oropharynx, oral cavity, nasopharynx,
nasal cavity, larynx, hypopharynx
Level III (mid jugular) Oropharynx, oral cavity, nasopharynx,
larynx, hypopharynx
Level IV (lower jugular) Oropharynx, larynx, hypopharynx, upper
esophagus, thyroid
Level V (posterior triangle) Nasopharynx, posterior scalp skin,
thyroid
Level VI (anterior compartment) Thyroid, larynx, hypopharynx, upper
esophagus
Supraclavicular Non-head and neck, thyroid
Retropharyngeal Nasopharynx, posterior pharynx
Parotid Lateral/upper facial and scalp skin,
parotid gland

12. Complete History
Physical Examination
Skin Examination
[Head to Toe]
Sub-mucosal lesions are not usually
evident on inspection
Palpation
Cranial Nerve Examination
Diagnostic Work-up

13. Further Evaluation
 BLI
 Panendoscopy-tonsillectomy-Biopsy [preferably
after imaging]
 Narrow Band Imaging
 FNA of node [First Step], image guided.
 Trucut Biopsy [95% yield reported Novoa et. al
2012]
 Molecular studies.
 HPV DNA or RNA
 In situ Hybridization (ISH) for EBV-encoded RNA or
PCR for EBV-genomic DNA.
 CT/MRI [First Imaging Choice]
 PET/CT

14. Narrow band Imaging
Advanced endoscopic imaging techniques (AEITs)
Based on the penetration properties of light.
 Shorter wavelengths penetrate only superficially
into the mucosa, whereas longer wavelengths can
penetrate more deeply.
 NBI utilizes red-green-and-blue filters to modify WL
endoscopy (WLE): the blue light filter (400–430 nm)
highlights the capillaries in the superficial mucosa
through mean peak absorption of hemoglobin (415
nm), while the green light filter (525–555 nm)
penetrates deeper into the mucosa.
 This results in greater clarity of mucosal surface
structures due to the increased contrast between
mucosa and superficial vessels, which appear
brown/black.

15.  Detection of lesions in the digestive tract.
 Distinction between benign and malignant
lesions
 Targeting biopsies
 Prediction of the risk of invasive cancer
 Delimitation of resection margins
 Identification of residual neoplasia in a scar

17. PerformingaBiopsy
• Patients with metastases to neck lymph nodes only :
• Suspicious cervical nodes should not undergo
excisional biopsy until a complete diagnostic
evaluation of the head and neck has been performed.
• About 35% of these patients have potentially curable
cancers of the upper aerodigestive tract.
• However, supraclavicular lymph nodes may be
directly excised for histologic examination.

18. IHC
• improves diagnosis, determine lineage, determine tissue
of origin.
• Tumor biomarkers that can help with treatment
decisions: EGFR, BRAF, HER2, RAS, BCL2, c-kit, p53.
• BCL2 & p53 are over expressed in 40% and 26%-53% of
occult primary respectively.
Nowadays but not recommended by NCCN for CUPs
• Gene expression profiling assays are developed to
identify the tissue of origin in pt’s of occult primary.
• Mutational testing with Next generation sequencing
have gained interest.

20. T0 Oropharynx:
TNM
same for
EBV + : T0
Nasopharynx
90% correlation
between HPV &
SCC CUP (Fu TS.
J
Otolaryngol.2016)
.

22. • Identification of primary 24-73%.
• Modification of treatment plans 20-60%.
• Good candidates for PET/CT
• CUP Patients with cervical adenopathy.
• Patients with single metastatic focus–prior to definitive
loco regional therapy.
• Additional sites of metastases.
• Post RT neck evaluation.
• Largely necrotic nodes : -ve on PET
Caution : False Positives
Lympho-epithelial tissue of Waldeyer’s ring.
Salivary glands : physiological uptake.
RoleofPET-CT

23. Management of Carcinoma
Unknown Primary Presenting
as Metastatic Cervical
Adenopathy

24. Management
Combined-modality therapy (surgery and radiation
therapy) is better than either modality alone
Neck dissection is indicated if:
Goss disease is left behind after excisional biopsy
Single LN > 6 cm
E C E+
In squamous cell carcinoma, unilateral tonsillectomy
ipsilateral to the presenting neck mass is indicated
In unresectable squamous cell head and neck cancers
chemotherapy with cisplatin/5- fluorouracil–based and
cetuximab-based regimens has been given
Identification of the primary site help reduce morbidity by
limiting the field of radiation and would improve surveillance.

26. Radiation Therapy

30. RT-associated toxicities :
 Xerostomia
 Dysphagia
 Odynophagia
 Neck stiffness
 Trismus

31. RegionalLymphNodes
N
category
ClinicalN criteria(cN) Pathological N criteria(pN)
Nx Regional lymph nodes cannot be
assessed
Regional
as
lymph nodes cannot be
N0 No regional
metastasis
lymph node No regional lymph node metastasis
N1 Metastasis in a single ipsilateral
lymph node, 3 cm or smaller in
greatest dimension and ENE (-)
Metastasis in a single ipsilateral lymph
node, 3 cm or smaller in greatest
dimension and ENE (-)
N2a Metastasis in a single ipsilateral
lymph node, larger than 3 cm but not
larger than 6 cm in greatest
dimension and ENE (-)
Metastasis in a single ipsilateral lymph
node, larger than 3 cm but not larger than
6 cm in greatest dimension and ENE (-)
OR
Metastasis in a single ipsilateral or
contralateral node, 3 cm or smaller in
greatest dimension and ENE (+)
AJCCCancerStaging Manual, 8th ed.

32. N
category
Clinical N criteria(cN) Pathological N criteria(pN)
N2b Metastasis in multiple ipsilateral
lymph nodes, none more than 6
cm in greatest dimension and ENE
(-)
Metastasis in multiple ipsilateral lymph
nodes, none more than 6 cm in greatest
dimension and ENE (-)
N2c Metastasis in bilateral or
contralateral lymph nodes, none
more than 6 cm in greatest
dimension and ENE (-)
Metastasis in bilateral or contralateral
lymph nodes, none more than 6 cm in
greatest dimension and ENE (-)
N3a Metastasis in a lymph node, larger
than 6 cm in greatest dimension
and ENE (-)
Metastasis in a lymph node, larger than
6 cm in greatest dimension and ENE (-)
N3b Metastasis in any lymph node(s)
with clinically overt ENE (+)
Metastasis in any lymph node(s) with
clinically overt ENE (+)
OR
Metastasis in single ipsilateral node,
larger than 3 cm in greatest
dimension and ENE (+)

33. PET Scan based Response
Assessment
N1, N2a Disease N2b, N2c, N3 Disease
 Upfront Surgery
alone?
 Initial RT f/b Salvage
Surgery
 Surgery f/b PORT
[A loco-regional failure rate of 13-
32% for patients treated with
surgery alone versus 0-18% with
surgery + PORT]
 N2b : Primary chemo-
radiotherapy.
 N2c/N3 : Induction
chemotherapy.

36. Chemotherapy Regimens

37. • Choiceof the regimenshould bebasedonthe histologictype
of cancer.
1. Paclitaxel and Carboplatin:
based on the relatively
Choice for first-line therapy,
large experience with this
Combination.
• Addition of a third drug (either Etoposide or Gemcitabine) to
a taxane and platinum regimen may improve efficacy
2. Second line therapy - Single agent Gemcitabine (1000
mg/m2 weekly three of four weeks) has modest
activity.

38. ChemothrapyRegimens

39. Neuroendocrine Tumors
Neuroendocrine CUPs
 are uncommon
 clinical behaviour is dependent on the tumour grade
and level of differentiation
 represent a favourable prognostic subset of CUPs
 responsive to combination chemotherapy,
 making long-term survival a possibility in some
patients

40. Clinical Scenario
 Young lady XYZ
 32 years of age
 No underlying co
morbidities
 Married with 2 kids
 Hailing from J&K
 Presented with right
submandibular neck
swelling * 3 months.
 Evaluated for same at
periphery.
 USG Neck : Right Lv. Ib-II
(+)
 FNA : Inconclusive
Q. What you will do next?

41. Unfortunately she was operated at periphery
Submandibular gland excision with LN
Dissection..
Post-op HPR : DLBCL
 Without complete
evaluation they operated
the patient, thought there
was no need for surgery if
they would have
considered excision biopsy
rather than surgery.
 Same is true with CUP’s
do proper evaluation and
you will reach the

42. ThankYou