Management of

Cancer of Unknown Primary (Neck)

Moderator : Dr. Mushtaq sir

Presenter : Dr. Musaib Mushtaq

  Definition

Cancer of Unknown Primary  Epidemiology

 Mechanism

 Suggested Hypothesis

 Prognostic Factors

 Clinical Presentation

 Diagnostic Evaluation
(CUP)

 Management

 Clinical Scenario
 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.

 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.

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.
 Mechanism clonal proliferation
invasion and intravasation
widespread dissemination via circulation
extravasation

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

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

Complete History
Physical Examination

Skin Examination
[Head to Toe]
Sub-mucosal lesions are not usually evident
on inspection
Palpation
Cranial Nerve Examination
 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
 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.
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
Performing a Biopsy

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

T0 Oropharynx:
TNM
Role of PET-CT
• 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.
 Management of Carcinoma
Unknown Primary Presenting
as Metastatic Cervical
Adenopathy
 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.
Radiation Therapy
RT-associated toxicities :
Xerostomia
Dysphagia
Odynophagia
Neck stiffness
Trismus
 Regional Lymph NodesAJCC Cancer Staging Manual, 8 th ed.

N Clinical N criteria (cN) Pathological N criteria (pN)

category
Nx Regional lymph nodes cannot be Regional lymph nodes cannot be
assessed as

N0 No regional lymph node No regional lymph node metastasis

metastasis

N1 Metastasis in a single ipsilateral Metastasis in a single ipsilateral lymph

lymph node, 3 cm or smaller in node, 3 cm or smaller in greatest
greatest dimension and ENE (-) dimension and ENE (-)

N2a Metastasis in a single ipsilateral Metastasis in a single ipsilateral lymph

lymph node, larger than 3 cm but not
larger than 6 cm in greatest
dimension and ENE (-)
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 (+)
N Clinical N criteria (cN) Pathological N criteria (pN)
category
N2b Metastasis in multiple ipsilateral Metastasis in multiple ipsilateral lymph
lymph nodes, none more than 6 nodes, none more than 6 cm in greatest
cm in greatest dimension and ENE dimension and ENE (-)
(-)

N2c Metastasis in bilateral or Metastasis in bilateral or contralateral

contralateral lymph nodes, none lymph nodes, none more than 6 cm in
more than 6 cm in greatest greatest dimension and ENE (-)
dimension and ENE (-)

N3a Metastasis in a lymph node, larger Metastasis in a lymph node, larger than
than 6 cm in greatest dimension 6 cm in greatest dimension and ENE (-)
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 (+)
 N1, N2a Disease N2b, N2c, N3 Disease
Upfront Surgery alone? N2b : Primary chemo-
Initial RT f/b Salvage radiotherapy.
Surgery N2c/N3 : Induction
Surgery f/b PORT chemotherapy.
[A loco-regional failure rate of 13-
32% for patients treated with surgery
alone versus 0-18% with surgery +
PORT]

PET Scan based Response Assessment

Chemotherapy Regimens
• Choice of the regimen should be based on the histologic type
of cancer.

1. Paclitaxel and Carboplatin: Choice for first-line

based on the relatively therapy, large experience
Combination. with this
• 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.
Chemothrapy Regimens
 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
Clinical Scenario

Presented with right

Young lady XYZ
submandibular neck swelling *
32 years of age
3 months.
No underlying co Evaluated for same at periphery.
morbidities USG Neck : Right Lv. Ib-II (+)
Married with 2 kids FNA : Inconclusive
Hailing from J&K

Q. What you will do next?

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 diagnosis.
Thank You