Mr. Sunil, a 72-year-old male, presented with a 3-month history of a left neck swelling. Further examinations revealed metastatic squamous cell carcinoma in the left neck lymph nodes. He was diagnosed with carcinoma of unknown primary (CUP) and underwent radical neck dissection, followed by chemotherapy and radiotherapy. CUP describes metastatic cancers where the primary site cannot be identified despite various examinations and evaluations. Treatment options for CUP include surgery, radiation therapy, chemotherapy, or concurrent chemoradiation depending on the lymph node involvement and other factors. Prognosis depends on the stage and presence of extracapsular extension, with 5-year survival rates ranging from 30% for upper cervical nodes to 5%

1. Presenter:
Dr. Mohammed Shaiful Hassan Shameem
MD (Radiation Oncology) Thesis part
Radiation Oncology Department, NICRH
NICRH

2. Mr. sunil, 72 years old male hailing from Tangail presented with
a swelling of left side of neck for 3 months.
 FNAC (Left sided neck mass)(7.2.18): metastatic Squamous
cell ca.
 Fibreoptic videolaryngoscopy(FOL)(7.2.18): Normal.
 USG whole abdomen(15.02.2018): suggestive of cystitis.
Otherwise normal study.
 CT scan of neck(17.02.2018) : Left sided neck mass (3.4
cmX3.1 cm)- possibily Lymphadenopathy. B/L maxillary
sinusitis.
 Chest x-ray(19.02.2018): normal.
 CT scan of chest(01.03.18): unremarkable CT scan of chest.

3.  He was diagnosed as a case Carcinoma of
Unknown primary(CUP) with metastatic neck
node.
 He underwent Radical neck node
dissection(RND) outside NICRH on 09.03.18.
 Histopathology report revealed Metastatic
Squamous cell ca.
 He visited tumor board NICRH on 19.03.18
and tumor board decision was 3 cycle
chemotherapy followed by CCRT.
 Patient received 3 cycle CT with Cisplatin+5-
FU. And now patient is receiving Radiotherapy
with weekly CPL under Radiation
oncology Dept.

4. CUP are metastatic solid tumors (hematopoietic and
lymphomas are excluded) for which the site of origin is
not identified despite-
➢ History
➢ Physical examination
➢ Imaging
➢ Routine blood & urine studies
➢ Thorough histological evaluation

6. The main limitation of FDG-PET appears to be low
specificity, with suggested reasons including
physiological uptake in the tonsils, reactive lymph nodes,
or the muscles of mastication

7. 1. Submental (sublevel IA)
2. Submandibular(Sublevel IB)
3. Upper Jugular(Sublevel
IIA&IIB)
4. Middle Jugular (Level III)
5. Lower jugular (Level IV)
6. Posterior triangle (Sublevel VA &
VB)
7. Anterior compartment (Level VI)
8. Superior Mediastinal (Level VII)

8. Other groups not included in this levels are
 Suboccipital
 Retropharyngeal
 Parapharyngeal
 Buccinator (facial)
 Preauricular
 Periparotid and intraparotid
 Source: AJCC 8th edition

9.  3% to 9% of all head neck cancers.
 Male female ratio 6:1.
 Usually heavy smoker and heavy drinkers who have
noted the mass for several months.
 According to Hospital based cancer Registry 2014 of
NICRH the incidence is1.4% among all solid tumors.

10.  Located in upper jugular chain in most patients.
 Histological type varies according to anatomical location
 Most are Squamous cell carcinoma or poorly Differentiated
Carcinoma.
 Adenocarcinoma in the neck almost always associated with
a primary lesion below clavicles. But must rule out salivary
gland, thyroid & parathyroid primary tumors.

11.  Involved nodes are single in 75% patients, multiple
but ipsilateral in 15% patients and bilateral in 10%.
 Multiplicity is associated with Adenocarcinoma or
metastases from Nasopharynx or infraclavicular sites.
 Most likely head neck primary site-
Tonsil 45%> base of tongue 40%> Pyriform sinus
10%.

12. Metastatic neck node level Potential primary site
Level I Oral cavity(Including lip)
Level II Oropharyngeal cancer
Level III & IV Larynx & Hypopharynx
Level V NPC & Cuteneous primary
Supra clavicular LN Infraclavicular sites: Lungs,
Oesophagus, Breasts, Pancreas,
GIT, Genitourinary sources.
Most cases specially with level II lymphadenopathy are p16-
positive/HPV associated oropharyngeal cancer but p16 positivity
in a level II node does not rule out cutaneous primary

13. Three explanations have been proposed for the inability to
detect the occult primary tumor, despite modern pathology
and radiographic techniques:
 The primary tumor may have involuted spontaneously and
is no longer detectable, despite the presence of metastatic
disease.
 The malignant phenotype of the primary tumor favors
metastatic biologic behavior over local tumor growth.
 Current imaging technology lacks the resolution to detect
tumors smaller than 5–10 mm in size.

14. ❑ T – Primary Tumour
T0 No evidence of primary tumour
❑ N – Regional Lymph Nodes
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in
greatest dimension without extranodal extension
N2 Metastasis described as:
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm
but not more than 6 cm in greatest dimension without extranodal
extension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than
6 cm in Greatest dimension, without extranodal extension
N2c Metastasis in bilateral or contralateral lymph nodes, none more
than 6 cm in greatest dimension, without extranodal extension

15. N3a Metastasis in a lymph node more than 6 cm in greatest
dimension without extranodal extension
N3b Metastasis in a single or multiple lymph nodes with
clinical extranodal extension*
❑ M – Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
❑ Stage
Stage III T0 N1 M0
Stage IVA T0 N2 M0
Stage IVB T0 N3 M0
Stage IVC T0 N1, N2, N3 M1

16.  Specialist examination, imaging, and panendoscopy identify
primary site >50% of the time
 H&P including in-office nasopharyngolaryngoscopy with
examination of oral cavity, pharynx, and larynx
 . Imaging:
➢ Chest X-ray
➢ CT and/or MRI of head and neck
➢ PET/CT useful in prebiopsy setting as it increases primary site
detection rate by approximately 25%.
➢ Chest CT for N stage ≥N2b, or low neck or bulky
lymphadenopathy to evaluate for pulmonary metastases

17.  Laboratory studies:
➢ CBC
➢ Chemistries including electrolytes,
➢ BUN/Cr,
➢ LFTs
➢ EBV and HPV testing
 EUA with panendoscopy (sometimes called “triple
endoscopy”) and biopsies of nasopharynx, both tonsils, base
of tongue, both pyriform sinuses, and any other suspicious
areas seen during examination.
➢ Identifies 40% of primaries (but only 25% if no CT or MRI)

18.  Ipsilateral or bilateral tonsillectomy may also be
performed in those with adequate lymphoid tissue in
tonsillar fossae.
➢ Evaluate tumor samples for EBV DNA in patients who
have ethnicity from regions where nasopharyngeal
carcinoma is endemic.
➢ Detects 30% of primaries.
➢ Bilateral tonsillectomy identifies contralateral tonsillar
primary in 10%; may make surveillance exam easier.

19.  If lymphoma is suspected: core needle or excisional
biopsy of node preferred; staging and treatment per
lymphoma guidelines.
 Dental examination and cleaning; extractions done
beforeany RT.

21. ❑ Excisional biopsy of cervical node should not be performed
because-
➢ It distorts surgical plane
➢ May result in poor outcome if it is proved to be a SCC originating in
an occult site in H&N.
❑ On the other hand ,Supraclavicular LN rarely represent curable
disease, these node may be excised directly for histological
examination.
❑ Biopsy of the suspected node should only be done when
➢ Thorough physical examination fail to reveal a primary tumor
➢ CT/MRI Scan is not conclusive
➢ FNA & Panendoscopy fail to reveal diagnosis
➢ Suspected Lymphoma.

22. Disease related
Advanced N classification
Extracapsular spread
Poorly differentiated disease
Low-neck or supraclavicular nodes
Subsequent emergence of primary tumor.
Treatment related
Single modality treatment versus combined modality
(i.e., surgery and radiotherapy)
Unilateral neck versus pan-mucosal comprehensive RT

23. 1. Surgery
2. Radiation therapy
3. Chemotherapy/ Concurrent
Chemoradiation

24. Goals for treatment:
➢Control disease in the neck.
➢Prevent posttreatment primary tumor
emergence.

25. If only 1 cN+
 RT alone
 Alternatively,
➢ Selective or modified radical neck dissection first
(benefit = directs pathology and post-op RT dose is
lower, but disadvantage is more surgical morbidity)
➢ If no additional lymphadenopathy or extracapsular
extension (ECE), may observe.
➢ If ≥2 LN or ECE on pathology: post-op RT or chemo-
RT

26. If ≥2 cN+
 Selective or modified radical neck dissection first
➢ N2A: RT
➢ N2–N3 or ECE: RT or chemo-RT
 Alternative: Definitive RT or chemo-RT with
surveillance PET/CT in 12 weeks with salvage surgery
reserved for persistence/recurrence

27. If Squamous cell carcinoma of lower cervical or
supraclavicular nodes or Adenocarcinoma then
➢ RT alone.
➢ Survival rates are poor no matter what is done; the goal
of treatment is control of local disease

29.  Neck control rates with primary RT
➢ N1–N2a: 90–100%
➢ N2b–N2c: 80%
➢ N3: 50–60%
 Rate of Distant Metastasis
➢ N1–N2a: <10%
➢ N2b–N2c: 15%
➢ N3: 25%

30.  Indications
➢ Definitive treatment or adjuvant to surgery
➢ Salvage of locoregional failure after surgery
➢ Palliative treatment to locoregional or distant
metastatic sites

31. ➢ Typically irradiate nasopharynx, oropharynx, and both
sides of neck (Comprehensive RT).
➢ Hypopharynx and larynx were irradiated historically;
eliminated more recently because they are rarely the
primary site and including these sites greatly increases
morbidity of treatment.
➢ Consider hypopharyngeal and laryngeal irradiation for
adenopathy centered in level III/IV.

32. ➢ Oral cavity is not irradiated unless submandibular
lymphadenopathy is present.
➢ If submandibular lymphadenopathy: perform neck
dissection and observe or irradiate oral cavity and
oropharynx but not nasopharynx.
➢ Comprehensive RT achieves high rate of local control
in the neck.
➢ Limited locoregional treatment to ipsilateral neck.

33.  Dose Prescription:
➢ UCSF definitive IMRT doses
GTV 2.12/69.96 Gy, high-risk CTV 2/66 Gy, intermediate-risk
CTV 1.8/59.4 Gy, low-risk CTV 1.64/54 Gy in 33 fractions.
➢ Conventional definitive = 42–45 Gy followed by off-cord
boost to 70 Gy, or if using concomitant boost, 72 Gy.
➢ Postoperative
With no adverse features = 50–54 Gy to potential primary
mucosal sites and bilateral neck
Boost high-risk areas to 60–66 Gy (e.g., for perineural
invasion, ECE, close/+ margin)

34.  DOSE LIMITATIONS
IMRT limits
Mandible <70 Gy,
spinal cord <45 Gy,
brainstem <54 Gy,
mean parotid dose <26 Gy,
optic nerves and chiasm 54 Gy,
retina 45 Gy

35. Acute Toxicity Late Toxicity
•Mucositis
•Dermatitis
•xerostomia
•loss of taste
•Hypothyroidism
• neck fibrosis
• xerostomia
• dysphagia
• strictures
• Aspiration pneumonia
• impaired lymphatic
drainage
• second cancers
• psychosocial Problems

36.  Outcome of treatment depends on
➢ Clinical stage at the time of diagnosis
➢ Presence of ECE.
 85–90% of recurrences occur within 3 years.
 If recurrence suspected but biopsy negative, follow-up
every 1 month until resolved.
 No significant 5 year survival difference between
Patients treated with CT with RT alone compared to
patients who also received Surgical treatment.

37.  Upper cervical LN metastasis:
5 year survival 30% if primary tumor is found and 60% if
primary never found.
➢ N1 or N2A
- The 5 year and 10 year survival rate are both 70% to 80%.
- At 10 years of treatment the risk of finding of primary site
is about 30%.
➢ N2B
Survival rates variable
Result of Treatment.
➢ N3
5 year survival 20%.

38.  Patients with low cervical or supraclavicular LN
metastasis:
-5 year survival rate is 5%.
-Median survival time 7 months.

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41. Department of Radiation Oncology
National Institute of Cancer Research &Hospital