Carcinoma of unknown primary is a diagnosis given when doctors aren't able to locate where a cancer began. Most often, cancer is diagnosed when doctors discover the spot where the cancer began (primary tumor). If the cancer has spread (metastasized), those sites might be discovered, too. In carcinoma of unknown primary, also known as occult primary cancer, doctors find the cancer cells that spread in the body, but they can't find the primary tumor. In carcinoma of unknown primary, also known as occult primary cancer, doctors find the cancer cells that spread in the body, but they can't find the primary tumor. Doctors consider the location of the primary tumor when choosing the most appropriate treatments.So if carcinoma of unknown primary is found, doctors work to try to identify the primary tumor site. Your doctor might consider your risk factors, symptoms, and results from exams, imaging tests and pathology tests when trying to determine where your cancer began.

1. HEAD AND NECK OCCULT PRIMARY
CANCERS
PRESENTERS;
1.Dr. Samuel Thuo
2.Dr. Richard Lunyonga
FACILITATOR:
DR. HENRY SWAI.
27.07.2021
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2. Objectives
Introduction
• Definition
• Overview
Epidemiology
Risk factors and etiology
pathophysiology
Clinical presentation and staging.
Diagnostic evaluation
 Management options
 Treatment outcomes
 Prognosis 2

3. 1.OBJECTIVES.
By the end of this presentation one should be able to:
a) Define head and neck occult primary cancer/malignancy.
b) Discuss the pathology of occult primary cancer.
c) Identify the clinical presentation.
d) Describe the diagnostic evaluation.
e) Understand the management options.
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4. 2.INTRODUCTION
Definition
• Occult primary tumors, or cancers of unknown primary (CUP),
are defined as histologically proven metastatic malignant tumors
whose during pretreatment
evaluation (
).
: Histologic dx of malignant neoplasm metastatic to
cervical LN without identifiable 1o tumor following comprehensive
evaluation.
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5. These heterogeneous tumors have a wide range of clinical
presentations and a poor prognosis in most patients.
Early dissemination, and of
metastatic pattern are characteristic of these tumors.
They have poor prognosis in most patients.
Life expectancy is generally very short.
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6. 3.EPIDEMIOLOGY
Cancers with no known primary lesion site estimated to
account for of all tumors.
Metastases in the upper and middle neck generally are
attributed to head and neck cancers
Lower neck (supraclavicular area) involvement is often
associated with pimary malignancy below the clavicle.
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7. Epidemiology....
Incidence of cervical CUP varies between 2-9% of all head and neck
malignancies and approximately 90% are SSC with the remainder being
Most common histologic type is squamous cell carcinoma (SCC) followed
by , , other malignancies -
lymphoma and melanom and other rare histologic variants
CUPs occur roughly equally in both men and women.
L.Calabrese et al, 2005,Milan-Italy
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8. Epidemiology.....
 Swedish Family-Cancer Database analysis between 1958 to
2008 showed 2.8% of occult primary cases were familial
(i.e., a parent and offspring were both diagnosed with occult
primary cancer).
8

9. A primary tumor site is found in fewer than 30% of patients
who present initially with an occult primary tumor.
In 20% to 50% of patients, the primary tumor is not identified
.
Average diagnosis of CUPs is at 60 year of age
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10. Epidemiology.....
A study in Ibadan-Nigeria among 18 patients with CUPs between
2010 and 2012 by John E et al
Prevalence of cervical nodal metastasis (CUP) was 9.7%.
There was
Majority were in the third decade of life.
CUPs of the NPC accounted for 50%.
Most common histologic subtype was SCC.
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11. Genetic factors
 First degree relatives and siblings
with CUP.
 Chromosomal abnomalities and
over expression of genes such as;
 EGFR
Bcl-2
HER2
P53
RAS
Environmental facors
 Upper aerodigestive tract .
 Smoking cigarretes
 Alcohol
 Betel nut
Viral
HPV in SCC, EBV
Other Potential risk factors - poor oral
hygiene, LPR, GERD,
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12.  Location of the primary tumor
 Histologic differentiation
 Size of the lesion
 Recurrent Vs untreated lesions.
 Density of capillary lymphatics
 - Profuse capillary lymphatic
network is present in
nasopharynx & pyriform sinus.
 - PNS, middle ear and true
vocal cords have sparse
capillary lymphatics
12

13. Etiologies
 The etiology depends on the potential site of the unknown primary
cancer.
 Nasopharynx -Environmental factors - Nitrosamines, polycyclic
hydrocarbons, wood dust, and nickel exposure.
- Epstein-Barr virus
 Sinonasal - Nickel, wood dust.
 Cutaneous Ultraviolet light exposure
Genetic disorder xeroderma pigmentosum
13

14. 5.PATHOPHYSIOLOGY
The biology of CUP is poorly understood.However the are hypotheses;
postulates that CUP does not undergo type 1
progression (from a premalignant lesion to malignant) but instead it
follows a type 2 progression without forming a primary site.
A second hypothesis supports that CUP follows the parallel
progression model, where metastases can arise early in the
development of a malignant process.
Tumor expansion is attributed to cancer stem cells which a
characterized by high intrinsic migration and dissemination potential.
14

15. Pathophysiology....
15

16. Pathogenesis...
CUP is characterized by;
Early metastatic spread
Regression of primary site
Aggressive course of disease
E.Rassy et al 2020,France.
S
Chromosomal
alteration(4q31,6q15,11q22)
Evasion of apoptosis and immune
destruction(anti-apoptotic ptn Bcl-2,
MIF).
Limitless replicative potential(TP53
alteration).
Sustained angiogenesis(VEGF-A)
Self sufficiency in growth signals
Resistance to growth inhibitory
signals(p21 prtn inh cyclin-CDK
complexes). 16

17. Pathophysiology.....
• The pathophysiology of the unknown primary carcinoma is
the same as that of known carcinoma of the head and neck.
• Either metastasizes early to the cervical lymphatics or
• Develops in an
.
17

18. NCCN 2016 guidelines
• Well or mod. diff’d AdenoCA-
60%
• Poorly diff’d or undifferentiated
AdenoCA- 29%
• SCC- 5%
• Other poorly differentiated
malignant neoplasm- 5%
• Neuroendocrine tumors of
unknown primary- 1%
• Good-mod differentiated
AdenoCA- 50%
• Poorly undiff. AdenoCA- 30%
• SCC- 15%
• Undifferentiated neoplasms- 5%
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19. • CUP can mets to any site.
• Presentation depends on site involved.
• More than 50% of patients show multiple site
of involvement Common sites involved in
the mets of the primary cancer are LNs,
liver, lung, bones.
• Patients generally present with a painless,
solitary neck mass, most often discovered by
the patient.
19

20. • Enlarged cervical LN is often the of a
neoplastic process in the H & N.
• 25%-oral and oropharynx CA
• 60-90%-NPC
• 23%- Thyroid CA
• Pts may have anorexia and weight loss.
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21. Possible sites of the CUP
Symptom Possible Source
 Otalgia/aural fullness Pharynx, larynx
 Dysphagia/odynophagia Pharynx, esophagus, or oral cavity
 Hoarseness Larynx
 Trismus, dysarthria Oral cavity or oropharynx
 Nasal congestion ,epistaxis Sinonasal tract,NP
 Aspiration Oropharynx or larynx
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22. Relationship of Node involvement to likely
primary disease site.
22

23. STAGING OF CUP (AJCC 8TH EDITION)
T-primary Tumor
T0-No evidence of primary tumour
N-Regional LN(clinical)
N1-Metastasis in a single ipsilateral LN ≤3cms in greatest dimension ,ENE(-
)
N2a-Metastasis in a single ipsilateral LN >3cms but ≤ 6cms in greatest
dimension, ENE(-)
N2b- Metastasis in mx ipsilateral LNs ≤ 6cms in greatest dimension,
ENE(-)
N2c- Metastasis in bil/contalateral LNs ≤ 6cms in greatest dimension,
ENE(-) 23

24. • N3a- Metastasis in a LN >6cms in
greatest dimension, ENE(-)
• N3b- Metastasis in a LN >6cms in
greatest dimension, ENE(+)
M- Distant Metastasis
M0- No distant metastasis
M1- Distant metastasis
STAGE
- T0 N1 M0
T0 N2 M0
- T0 N3 M0
STAGE IVC- T0 (N1/N2/N3) M1
24

25. • In upper and mid-cervical region 80% are usually due
to SCC.
• In lower cervical and supraclavicular region, 40% are
due to adenocarcinomas.
• Common sites of the primary for adenocarcinomas are
thyroid, breast, GIT, salivary glands, lungs, prostate and
kidneys.
25

26. 7. DIAGNOSTIC EVALUATION
 Diagnosis procedures should be aimed at clarifying the
histology of the nodal metastases and detecting the primary.
 Complete history: including detailed review of systems.
• Previous H/o – Malignancy, radiation, skin lesions and surgeries
: Head and Neck and Other
sys(GIT+ rectal exam, GUS, RESP+breast, axilla, groins,
testicles, pelvic exam).
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27.  Mucosal palpation of the oropharynx-tongue base and oral
cavity.
 Palpate for Lymph nodes – axillary, inguinal and supra-
clavicular nodes
 –lymphoma and leukemia.
– carcinoma
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28.  Indirect laryngoscopy / fiber-optic
 Biopsy samples should be obtained
(NPC, tonsils, pyriform sinus, postcricoid
area, the base of the tongue) and any other suspicious sites
such us oral mucosa, thyroid gland, breast, GIT, salivary
glands, prostate and kidneys.
 Pan-endoscopy – , laryngoscopy ,
bronchoscopy , Esophagoscopy and colonoscopy
28

29. Diagnosis....
Lab investigation
Complete blood cell count
Liver function test
Renal function test
Thyroid function tests
Urinalysis
Stool for occult blood
Serum prostate-specific antigen
Tumor markers
Viral tests for EBV and HPV
29

30. • FNAC and core biopsy.
• Incisional /excisional biopsy.
Excisional if inconclusive repeated FNA, ulcerated, lymphoma
• Direct laryngoscope with biopsies nasopharynx, tonsils ,base of the
tongue and pyriform sinuses.
• Also review of previous biopsies is important.
• Immunohistochemistry markers and molecular profiling help to define
tumor lineage.
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31. Immunohistochemistry- 67% accuracy
• Epithelial origin
• cytokeratins
• Melanoma
• S100
• HMB45
• Germ Cell Tumour
• Neuroendocrine
• chromogranin
• Synaptophysin
• CD56
• Lymphoma
• CD45
• CD20
• CD10
• CD3
• Thyroid
• Prostate
• PSA
• Sarcoma
• AML
• CD31 31

32. Screening tonsillectomy
 Most common site for primary is the tonsil.
Tonsillectomy is done if primary has not been discovered and unilateral
or is usually performed.
Primary can be found in 10-25% of cases. Small tumors may originate in
deep crypts and not to be detected by superficial biopsy.(Calabrese et al
2005).
 Contralateral spread from occult tonsil was seen in approximately 10%
of cases.
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33. 33

34. 8. IMAGING
Imaging studies provide an assessment of LN size and shape as well as
information about the internal architecture.
Suspicious LNs are spherical and greater than 1.0 to 1.5 cm. LNs that
demonstrate , or
irregular borders or groups of two or more LNs leads to suspicion for
metastases.
CT followed by an MRI if inconclusive
Head and neck, chest, abdomen and pelvis.
PET scan or PET/CT or MRI
Bone scans
34

35. Imaging....
 CT scan of the head and neck with I/V contrast.
Evaluation of cervical lymphadenopathy and the
identification of occult primary lesions.
 Assessing the involvement of vital structures.
 To determine .
35

36. CT and MRI scans
36

37. Positron emission tomography
• PET scan with the radiolabeled glucose analog
fluorodeoxyglucose (FDG) provides information about the
metabolic activity of tissues.
• Squamous cell carcinoma cells have increased metabolic and
proliferative rates. Consequently FDG accumulates in cancer
cells at increased rates relative to normal tissues.
• Has upto 25% accuracy in detecting primary when used alone
but when combined wit CT/MRI it increases upto 43%- 75%.
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38. PET
38

39. 9. TREATMENT MODALITIES.
• Despite aggressive diagnostic approach, the primary site is not found in the
majority of patients.
• Treatment of CUP is the same as for the primary.
Depends on Nodal stage and histological diagnosis.
• Squamous cell carcinoma and adenocarcinomas respond to cisplatin-based
combination chemotherapy.
• Tonsillectomy is often performed since the primary can be found in 10 to
25% of cases - Small tumors may originate in the deep crypts and not be
detected by superficial biopsy.
• Treat as locally advanced head and neck cancer.
39

40. • N1 – neck dissection(MRND) Or radiation if positive margins or capsular
invasion.
• N2, N3 - combined neck dissection and radiation
• N2a &2b mobile - RND followed by radiotherapy, fixed node RT followed by
RND
• N2c Bilateral - RND followed by RT.
• N3 Resectable - RND followed by RT +CHEMO.
• N3 Unresectable - RT followed by RND when it is resectable
40

41. N1 with a history of excisional or incisional biopsy
- neck dissection and radiation.
N2a with no persistent tumor after radiation may
undergo neck dissection.
41

42. Purpose is to decrease dose to the parotid gland so as to
decrease the grade of xerostomia can also prevent
radiations to other organs e.g. larynx.
 It uses linear accelerators to safely deliver
to a tumor while minimizing the dose to
surrounding normal tissue.
42

43. Radiation controversies
Ipsilateral neck vs. bilateral neck, Bilateral favored
Some studies show increase risk of neck disease or
emergence of primary with ipsilateral treatment compared to
bilateral , without overall survival being affected
 Alternate studies show extensive radiation of mucosa
and bilateral neck improve survival compared to
ipsilateral neck radiation.
43

44. Radiation by levels
 Radiation fields need to i
(decreased subsequent incidence of primary tumor).
 Level I: no mucosal radiation recommended due to potential
extensive morbidity.
Levels II and V: radiation field should include Nasopharynx
and oropharynx.
44

45. Radiation by levels....
: radiation field should include nasopharynx
and oropharynx.
It is generally not recommended to include
hypopharynx and larynx as well, since these are of low
probability as primary site, and have an increased
probability of complications
45

46. Platinum-based chemotherapy in combination with
radiation recommended for N3 patients by European
Society of Medical Oncology (ESMO).
 Consider concurrent chemo/RT with supraclavicular
LN or undifferentiated tumors.
 Chemo/ RT is an option for palliation in unresectable
local disease and distant metastatic spread.
46

47. Treatments outcomes
69 patients were enrolled ,the median time of follow-up was (4.5) years. The
2-year loco-regional control rate of all the patients was .
N3 stage, extracapsular spread, distant metastasis and treatment modality
were significantly associated with neck recurrence.
The actuarial 5-year disease-specific survival rates of
 Neck dissection - 80.0%.
 Neck dissection plus adjuvant therapy - 61.7%.
 Radiotherapy alone - 33.3%.
 Combined therapy - 68.8%.
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48. Treatment outcomes...
• The 5-year disease-specific survival rates of
 N1/N2a (83.9%) , N2b/N2c (64.3%), and N3 (36.7%).
• Neck recurrence, supraclavicular node involvement, distant
metastasis, N3 stage, and unhealthy lifestyle habits were
correlated with disease-specific mortality, especially the first
three parameters.
• Patient’s occupation and comorbidity were not significantly
correlated with survival.
48

49. Recurrence
• Comparing subsequent mucosal primary lesions in patients with
unknown primaries to head and neck cancer with a known
primary site shows the incidence of a subsequent mucosal recurrence
was similar for both groups.
49

50.  The best indicator of prognosis is N stage at presentation.
 Histological type of the metastatic neoplasm
 Also, the presence of extracapsular extension is associated with a poorer
prognosis.
 Prognosis is similar between patients with a known vs. an unknown
primary with the same nodal stage.
 Significant difference in survival when occult metastases with ECS are
present.
50

51. Prognosis....
• Data from another study suggests that ECS in occult nodes
has the same impact as ECS in palpable nodes does.
• The number of pathologically positive occult LNs also
correlates with survival.
• Patients with two or more positive nodes have significantly
worse survival compared to those with less than two positive
nodes.
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52. FOLLOW UP
Should be individualized.
• Year 1 : Every 1-3 months
• Year 2 : Every 2-4 months
• Years 3-5 : Every 4-6 months
• 5+ years : Every 6-12 months
• For pt with active and incurable diseases, psychosocial support,
symptom mgt, end of life discussion, palliative and hospice care
should be considered.
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53. CONCLUSION.
• CUP is a devastating diagnosis with previously poor treatment
options and prognoses.
• Detailed history and comprehensive physical exam is key.
• Investigations should be focused as it is an expensive endeavor.
• Wide-field radiation therapy causes significant morbidity.
• Finding primary site leads to much better survival outcomes.
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54. References
• Surgical Pathology of the Head and Neck vol 2, 3rd Edition by Leon Barnes
• Treatment of unknown primary of head and necksquamous cell carcinoma- Primary surgery versus primary
radiotherapy - Nuwan S. et al . 2019
• Daiagnosis and management of neck metastasis fron unknown primary by L.Calabrese et al ,milan Italy, 2005.
• Strojan P et al. Contemporary management of lymph node metastases from an unknown primary to the neck,2013.
• The currently declining incidence of cancer of unkown primary by E.rassy et al France,2019
• AJCC staging manual,Eighth edition.
• Medscape, Neck cancer with unkown primary site.
• National Comprhensive cancer network guidelines Version 2 . 2016 - Occult Primary.
• Bailey, Byron J.; Johnson, Jonas T.; Newlands, Shawn D.
• Title: Head & Neck Surgery - Otolaryngology, 4th Edition Controversies in Management of the N0 Neck in Squamous
Cell Carcinoma of the Upper Aerodigestive Tract.
• Differential diagnosis of neck mass cummings 5th edition by Amy chen , Kristten j otto doi: 10.1186/1758-3284-4-34
• Dentomaxillofac Radiol. 2012 Jul; 41(5): 396–404.doi: 10.1259/dmfr/57281042 published online 2018 Oct
18. doi: 10.1371/journal.pone.0205365
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55. THANK YOU
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