Carcinoma of Unknown Primary

Todd M. Blodgett, MD

Alex Ryan, MD

Hesham Amr, MD

Key Facts

Terminology

Metastatic cancer without known site of origin; histology inconsistent with known tumors from organ biopsied

Imaging Findings

Most common site: Upper aerodigestive tract, specifically lung
Gastrointestinal and urogenital tract also common
Squamous cell: Primary most often in tonsils, nasopharynx
Adenocarcinoma: Primary most often in thorax, GI tract, urogenital tract
Likelihood of primary detection with PET/CT: 25-40%; CT: 25%
FDG PET provides whole-body survey
PET may commonly reveal “missed primary” rather than unknown primary in true sense, i.e., following complete work-up
Small study showed PET/CT more sensitive than PET alone, with 53% detection rate for occult cancers missed by other techniques

Top Differential Diagnoses

Physiologic Activity
Inflammation
Infection

Diagnostic Checklist

In patient with CUP, perform conventional laboratory workup and combination of imaging studies, with consideration of PET/CT

Axial CECT shows a complex cystic left renal mass suggestive of renal cell carcinoma

in this patient with a brain metastasis and no primary.

Axial fused PET/CT shows mildly increased FDG activity corresponding to the mural nodularity

, confirmed to be renal cell carcinoma.

TERMINOLOGY

Abbreviations and Synonyms

Carcinoma of unknown primary (CUP)
Includes undifferentiated carcinomas in addition to adenocarcinoma

Definitions

Metastatic cancer without known site of origin
- Histology inconsistent with known tumors from organ biopsied
Also defined as presence of metastatic disease for which site of primary lesion remains unidentified
- Remains unknown despite review of
  - Medical history
  - Physical exam
  - Lab work (CBC, kidney/liver/pancreas function tests, PSA, U/A)
- Imaging evaluation usually includes CXR, abdominopelvic CT, mammography
- After common imaging investigation, 20-27% of primaries remain unidentified

IMAGING FINDINGS

General Features

Best diagnostic clue: Detection of focal intense FDG activity in potential primary organ or site in patient with biopsy-proven carcinoma of unknown primary
Location
- Most common site: Upper aerodigestive tract, specifically lung
  - May also have abnormal mediastinal nodes
  - Consider accessible areas for subsequent confirmatory biopsy
- Gastrointestinal and urogenital tract also common
  - Appear as focal areas of intense FDG activity in bowel rather than linear areas of physiologic activity
  - Look carefully at kidneys as a small renal cell carcinoma may be missed or obscured by physiologic excretory FDG activity
- Frequency of metastases by location
  - Lymph node (LN) 46.3%
  - Liver 12%
  - Brain 11%
  - Bone 11%
  - Lung 6%
  - Pleura 4%
  - Peritoneum 4%
  - Other 10%
- Involvement of supraclavicular and low cervical lymph nodes may be suspicious for primary in chest or abdomen
  - Associated with poorer prognosis than metastases of upper neck levels
- Squamous cell
  - Primary most often in tonsils &/or nasopharynx
  - Look for asymmetrical focal intense FDG activity on PET and PET/CT
- Adenocarcinoma
  - Primary most often in thorax, GI tract, or urogenital tract
Size: Varies from small (< 1 cm) to several centimeters
Morphology: Range of morphologies, including no obvious findings on CT to a several centimeter mass

Imaging Recommendations

Best imaging tool
- Likelihood of primary detection with PET/CT: 25-40%; CT: 25%
- FDG PET provides whole-body survey
- Patients with head/neck mets of non-SCCA histology should not be limited to imaging of head/neck area only
  - Whole-body imaging has been proven beneficial
- Typical workup for patients with SCCA lymph node mets
  - Thorough physical exam including transnasal fibre-endoscopy of nasal cavity, nasopharynx, oropharynx, hypopharynx, larynx
  - CECT or CEMR of neck and PA/Lat CXR
  - Panendoscopy includes rigid esophagoscopy, tracheobronchoscopy, hypopharyngoscopy, laryngoscopy
  - Inspection/palpation of oropharynx and oral cavity, with biopsies taken from suspicious mucosal areas
  - Ipsilateral tonsillectomy if no primary detected during panendoscopic random biopsies
  - FDG PET often used when all of the above approaches have failed; may also direct biopsies
  - Non-SCCA histology has similar workup, with CT of chest and abdomen along with pelvic/prostate examinations
- Mammography very low yield; rarely do patients with CUP have primary mass in breast
Protocol advice
- Consider PET/CT evaluation, although currently not routinely used for CUP
- Contrast-enhanced CT may provide additional benefit
  - Better characterization of focal areas of FDG activity
  - Differentiation of potential bowel lesion from those adjacent to bowel

CT Findings

CT typically used to help identify primary
- Low sensitivity (˜ 25%)
CT scanning is the imaging modality of choice in terms of availability, cost effectiveness, quickness, and patient compliance
- Especially for evaluation of cervical lymphadenopathy and identification of occult primary lesions
Newer technology and methods of acquisition
- Better image quality and resolution
- Better reconstructive capabilities
- Quicker scans
- Decreased artifact
Quicker scans also allow dynamic maneuvers to be used
- Puffed cheek and modified Valsalva techniques can help open opposed mucosal surfaces in the oral cavity, oropharynx, and hypopharynx
  - May allow easier detection of unknown mucosal primaries
- Nonetheless, critical evaluation of the CT scan helps direct biopsies during panendoscopy in the workup of the unknown primary tumor
For evaluation of cervical lymphadenopathy, a CT scan of the neck is helpful to assess the involvement of vital structures
- Also provides the clinician with useful data regarding surgical resectability
CT scan can also be used to evaluate clinically negative cervical lymph node zones
Radiographic criteria of potential pathological lymph nodes
- Rounding of the lymph node
- Size > 1.5 cm in the jugulodigastric region or > 1 cm in other regions
- Hypodense fluid center of the lymph node that signifies necrosis
- Mass effect

Nuclear Medicine Findings

PET
- FDG PET shown to identify lesion in ˜ 25-40% of patients with negative conventional imaging investigations
- PET may commonly reveal “missed primary”
  - Rather than unknown primary in true sense, i.e., following complete workup
- False negative may result from
  - Low tumor uptake (e.g., carcinoid) or high background uptake (e.g., liver, high serum glucose level)
- PET has high specificity for tumors in lung, breast, and pancreas
Possibly low clinical impact of FDG PET in patients who have already undergone extensive workup with panendoscopy
Small study showed PET/CT more sensitive than PET alone, with 53% detection rate for occult cancers missed by other techniques
Criteria for malignancy on FDG PET or PET/CT
- FDG hypermetabolism at site of pathological changes on CT
- Marked focal hypermetabolism at sites suggestive of malignancy (liver parenchyma, bone marrow)
  - Despite absence of signs of pathology at those sites on CT
Identification of primary is more complex than identification of metastatic lesions
- Patient’s history is often helpful
- Distribution of pathological lesion may be helpful
  - Knowledge of the pattern of spread of different tumors
- More difficult in cases of generalized disease with many foci in different organs
- If unable to identify a lesion as the site of primary, may conclude that CUP syndrome was generalized
- Rate of detection of malignancy in general will be higher than that of primary

DIFFERENTIAL DIAGNOSIS

Physiologic Activity

Following structures commonly have increased physiologic activity that may mimic that of malignancy
- Colon: Can be focal, short segment, or linear
- Cardiac: Usually left ventricular, though all chambers may have increased wall activity in pathologic states
- Thymus: Seen in younger patients, usually linear if physiologic
- Glands: Look for symmetry to differentiate physiologic from pathologic activity
- Lymphoid tissue: May be asymmetrical or symmetrical
- Muscle: Often linear, helping to establish as physiologic; when focal can look like malignancy; correlate with CT
- Brown fat: CT showing fat attenuation is diagnostic
PET/CT helps facilitate differentiation of pathologic from physiologic FDG activity

Inflammation

Several inflammatory or granulomatous conditions, such as sarcoidosis, may cause focal FDG activity and mimic malignancy

Infection

Infectious processes such as underlying fungal infection or TB may cause focal activity
Dental abscesses may cause focal intense FDG activity, mimicking head and neck cancer

Benign Lesion

Colonic adenomas and thyroid adenomas may have focal FDG activity
Benign osseous lesions include fibrous cortical defect, osteoradionecrosis, and Paget

Iatrogenic