Carcinoma of Unknown Primary

Carcinoma of Unknown Primary

Todd M. Blodgett, MD

Alex Ryan, MD

Hesham Amr, MD

Axial CECT shows a complex cystic left renal mass suggestive of renal cell carcinoma image in this patient with a brain metastasis and no primary.

Axial fused PET/CT shows mildly increased FDG activity corresponding to the mural nodularity image, confirmed to be renal cell carcinoma.


Abbreviations and Synonyms

  • Carcinoma of unknown primary (CUP)

  • Includes undifferentiated carcinomas in addition to adenocarcinoma


  • 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


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


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


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


  • 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

Sep 22, 2016 | Posted by in MAGNETIC RESONANCE IMAGING | Comments Off on Carcinoma of Unknown Primary

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