Delving into

the Occult

Introduction

Occult • From the Latin

word occultus meaning clandestine, hidden or secret

Occult Cancer• Carcinoma of

unknown primary (CUP)

Introduction

• Case Study

• Diagnostic Work-Up of CUP

• Role of Pathology

• Future Advances

Case Study

• Mr X

• Presented to his GP with a 3-week history of left-sided neck swelling

• Referred to ENT for diagnostic work-up

Past History:• None of note• Non-smoker

Case Study

History of Presenting Complaint•Noticed swelling in left neck

no increase in size, non-painful

•No other symptoms no dysphagia, hoarseness, weight loss,

fevers, night sweats etc.

Case Study

Diagnostic Work-up

Case Study

Clinical Examination• Neck:

Palpable enlarged node in the left neck at Level IV

Firm and mobile Non-fluctuant

• No other significant findings

Case Study

Biopsy• Fine Needle Aspirate

Cytology• Malignant epithelial

cells with keratinisation and necrosis

• Consistent with metastatic squamous cell carcinoma

Case Study

Biopsy•Fine Needle Aspirate

Histology•Malignant epithelial cells with keratinisation and necrosis•Consistent with metastatic squamous cell carcinoma

Case Study

Biopsy•Fine Needle Aspirate

Histology•Malignant epithelial cells with keratinisation and necrosis•Consistent with metastatic squamous cell carcinoma

Where is the primary?

Case Study

CT Scan of Neck, Thorax, Abdomen & Pelvis•2 lesions in left neck behind sternocleidomastoid muscle, 2cm each•Most likely necrotic lymph nodes

•No other abnormality identified

Case Study

Whole Body PET-CT •FDG avid left-sided cervical lymphadenopathy

•Small focus of increased FDG uptake at left base of tongue

•No other abnormality identified

Case Study

Whole Body PET-CT •FDG avid left-sided cervical lymphadenopathy

•Small focus of increased FDG uptake at left base of tongue

•No other abnormality identified

Case Study

Panendoscopy with Left Tonsillectomy & Tongue Biopsies• Panendoscopy revealed no obvious

tumour

• Left Tonsillectomy: Reactive lymphoid hyperplasia

• Biopsy Left Base of Tongue Biopsy: No evidence of malignancy

Case Study

Case Summary• Metastatic SCC• No known primary despite extensive

clinical work-up

CUP

CUP

Definition• Metastatic tumour detected when

the site of the primary origin cannot be identified despite a detailed work-up

• Accounts for 3 - 5% off all cancers• 7th – 8th most frequent malignant

tumour• 4th most common cause of cancer

death

CUP

• Incidence in Ireland 10 – 13 cases per 100,000 per year

• Up to 4.7% of all cancer deaths

• Males > Females• Median age at presentation is 65 – 70

years• Average survival of 4 – 12 months

CUP with Cervical Nodes

• Location of the positive node can indicate the location of the primary tumour

Upper & Middle Neck LN• Head & neck primary

Lower Neck LN• Primary below the clavicles

CUP with Cervical Nodes

• Primary tumours tend to be small 65% less than 1.0 cm 30% less than 0.5 cm May be deep in tonsil

• Why do we get early nodal metastatic disease from a small primary tumour?

Characteristics of CUP

• Early metastases

• Absence of symptoms of the primary

tumour

• Unpredictable pattern of metastases

• Undifferentiated metastases

• Aggressive clinical course

Diagnostic Work-Up

• History & physical examination• Routine laboratory studies• Serum tumour markers• Chest X-ray• Symptom-directed endoscopy• CT thorax, abdomen & pelvis

Further imaging: PET-CT, Mammogram

• Biopsy

Role of Pathologist

• Determine the histopathological subtype to aid in Locating the primary tumour Optimising treatment options

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Histopathological Subtype

• Carcinoma Adenocarcinoma Squamous Cell

Carcinoma

• Melanoma

• Lymphoma

• Sarcoma

Determining Primary Site

Immunohistochemistry

•AE1/3, CAM5.2

•S100, MelanA, HMB45

•CD45

•Vimentin

Tumour Subtype

•Carcinoma

•Melanoma

•Lymphoma

•Sarcoma

Immunohistochemistry

CK7 / CK20

CK7 + / CK20 +

CK7 + / CK20 -

CK7 - / CK20 +

CK7 - / CK20 -

Immunohistochemistry

CK7 / CK20

CK7 + / CK20 +

Upper GIT

Pancreas

CK7 + / CK20 -

CK7 - / CK20 +

CK7 - / CK20 -

Immunohistochemistry

CK7 / CK20

CK7 + / CK20 +

Upper GIT

Pancreas

CK7 + / CK20 -

Thyroid Lung

BreastEndometrium

CK7 - / CK20 +

CK7 - / CK20 -

Immunohistochemistry

CK7 / CK20

CK7 + / CK20 +

Upper GIT

Pancreas

CK7 + / CK20 -

Thyroid Lung

BreastEndometrium

CK7 - / CK20 +

Colon

CK7 - / CK20 -

Immunohistochemistry

CK7 / CK20

CK7 + / CK20 +

Upper GIT

Pancreas

CK7 + / CK20 -

Thyroid Lung

BreastEndometrium

CK7 - / CK20 +

Colon

CK7 - / CK20 -

Prostate

KidneyAdrenal

Adenocarcinoma

Primary Site Immunohistochemistry

Lung TTF-1

Pancreas CK19

Upper GIT CDX2, CK7

Colon CDX2, CK20

Liver Hepar-1

Thyroid TTF-1

Breast ER, GCDFP-15

Prostate PSA

Kidney RCC, PAX8

Squamous Cell Carcinoma

Primary Site Immunohistochemistry

Lung p63, CK5/6

Head & Neck:

-Oropharyngeal

-Nasopharyngeal

-Oral (Mouth)

CK5/6

p16 (HPV)

EBV

p16 and EBV negative

Future Advances

Molecular Profiling•Gene expression profiling to identify the genetic signature of the CUP

•Uses RT-PCR and microRNA assays to identify the tissue of origin of the tumour

•Prediction accuracies of 80 – 90%

Case Study

Case Study

• Left modified radical neck dissection

Case Study

Histology

• Forty lymph nodes • 2 lymph nodes

positive for metastatic SCC

Case Study

Histology

• Forty lymph nodes • 2 lymph nodes

positive for metastatic SCC

Case Study

Histology

•Forty lymph nodes •2 lymph nodes positive for metastatic SCC

•p16 positive

Case Study

Histology

•Forty lymph nodes •2 lymph nodes positive for metastatic SCC

•p16 positive

Possible oropharyngeal origin

Case Study

Staging•N2b

Ipsilateral nodes < 6 cm in greatest dimension

Conclusion

• CUP accounts for 3 – 5% of all cancers and has a poor prognosis.

• Diagnostic work-up includes: Careful clinical history & thorough

examination Routine laboratory tests and tumour

markers Imaging Biopsy

• IHC is an essential part of histopathological assessment in determining the primary site.

Take Home MessagesCUP in Neck Node

• Cystic neck node in male > 40 years is metastatic malignancy until proven otherwise

• Inadequate/negative aspiration must be followed up with further tissue evaluation

• p16 (HPV) positive carcinoma in cervical node may be an oropharyngeal primary Tonsil and base of tongue are primary suspects

• EBV positive carcinoma in cervical node may be a nasopharyngeal primary

Future Model for CUP

Thank you