PET/CT in carcinoma of unknown primary site

Combining these imaging modalities can be an important tool for diagnosis and follow-up.

Issue: April 10, 2008

ByMunir Ghesani, MD, FACNM

BySumina Goel, MD

ByGabriel Sara, MD

ByCarrie Wasserman, MD

A 36-year-old healthy woman presented after several months of right hip pain not improved with physical therapy. Magnetic resonance image of the lumbar spine and pelvis revealed a compression fracture of the L2 vertebrae and abnormal signal enhancement of L4 and L5. Biopsy of the right iliac crest showed carcinoma of epithelial origin. Immunostains were not helpful in further characterizing the tumor. Full staging workup revealed bone only disease of the axial skeleton without a primary site of origin. The patient was treated with two cycles of chemotherapy for carcinoma of unknown primary site and palliative radiation to several painful bony lesions.

On follow-up imaging, positron emission tomography identified the bony metastases, but also two hypermetabolic liver foci (figure 1, 2 and 3). The corresponding computed tomography images did not reveal these lesions (figure 1). Biopsy of a laryngeal mass confirmed adenocarcinoma, although this lesion was not considered to be the site of origin. The patient began second line chemotherapy.

A restaging PET/CT six months later showed discordant PET and CT images. The PET displayed interval improvement in the liver lesions, with evidence of corresponding photopenia (figure 1, arrow), whereas the CT visualized the liver lesions for the first time (figure 1, arrow). The bony lesions on the PET showed improvement in some areas — thoracic spine, left hip, left shoulder and right arm — (figure 2 and 3, follow-up arrows) and progression in others — right hip and elbows (figure 2 and 3 follow-up arrow).

The patient was started on third-line chemotherapy without success and required further palliative radiation to the bone. Fourth-line chemotherapy was initiated, which the patient tolerated well for four months, demonstrating interval improvement in the bone and liver metastases on follow-up PET/CT. Unfortunately, the patient expired four months later.

Figure 1: PET identified the bony metastases, but also two two hypermetabolic liver foci
Figure 1

Figure 2: PET showed improvement in thoracic spine, left hip, left shoulder and right arm
Figure 2

Figure 3: PET showed improvement in thoracic spine, left hip, left shoulder and right arm
Figure 3

Source: M Ghesani

For more information:

Kolesnikov-Gauthier H, Levy E, Merlet P, et al. FDG PET in patients with cancer of an unknown primary. Nuclear Medicine Communications. 2005;26:1059-1066.
Hogan BA, Thornton FJ, Brannigan M, et al. Hepatic metastases from an unknown primary neoplasm (UPN): survival, prognostic indicators and value of extensive investigations. Clin Radiol. 2002;57:1073-1077.
Hainsworth J, Greco FA. Adenocarcinoma of unknown primary site. Uptodate. 2008;xx:6-7.
Delgado-Bolton RC, Frenandez-Perez C, Gonzalez-Mate A, et al. Meta-analysis of the performance of 18F-FDG PET in primary detection of unknown primary tumors. J Nucl Med. 2003;44:1301-1314.

DISCUSSION
Between 0.5% and 5% of newly-diagnosed patients with cancer have an occult primary tumor, depending on the thoroughness of the diagnostic work-up. This includes physical examination and laboratory and imaging studies that fail to identify a primary site. In most cases, the primary tumor will not be found during the patient’s lifetime. Light microscopy can divide cancer of unknown primary site into five histologic categories, which further guide evaluation: adenocarcinoma (70%), poorly differentiated carcinoma (25%), poorly differentiated neoplasm (<5%) and squamous cell carcinoma and neuroendocrine carcinoma, the last two of which are rare.
Patients with adenocarcinoma of unknown primary site carry a dismal prognosis, and no prognostic factors, including knowledge of the primary tumor, are significant for patient survival. They often present with symptoms referable to the liver, lung, lymph node or bone. Many have widespread metastases and a poor performance status at presentation. These patients in particular are difficult to treat and have a median survival of four to six months. Some patients, with less advanced disease and a good performance status, can be classified into a few clinically defined subgroups for which specific therapy is available, like patients with peritoneal carcinomatosis or axillary lymph node metastases. Unfortunately, our patient did not fall into any of these categories and was therefore a candidate for empiric chemotherapy.
Retrospective analyses have identified clinical and pathologic features associated with a favorable response to empiric chemotherapy, including lymph node or soft tissue disease, fewer metastatic sites, being a woman, poorly differentiated carcinoma, good performance status, normal L-lactate dehydrogenase, normal albumin and a normal lymphocyte count. Patients with liver or bone involvement, both of which our patient had, have a particularly poor prognosis.
Little data are available on the use of PET/CT in this clinical setting. PET identified the metastatic lesions in the liver much earlier than the CT. By the time the lesions were present on CT, they were improved on the PET images. PET/CT also documented a mixed pattern of improvement and progression in the bone lesions after treatment; this would have gone unnoticed if a single imaging modality had been used alone.
This case illustrates the paradoxical CT demonstration of worsening hepatic metastatic disease when in fact the disease is responding to chemotherapy, as evidence with PET imaging. This phenomenon can occur when the metastatic lesions are initially isointense to the liver and not detectable on a single-phase contrast CT examination. When the metastatic disease responds to chemotherapy, resultant necrosis makes the lesions hypodense relative to the liver, thus becoming evident on the follow-up CT scan, but mimicking development of new metastatic lesions. Availability of PET images identified the metastatic lesions on the initial examination and appropriately classified them as responding to therapy on the follow-up images.

Sumina Goel, MD, is a Nuclear Medicine Resident at St. Luke’s-Roosevelt Hospital Center, New York.

Carrie Wasserman, MD, is a Fellow in the Department of Medicine at St. Luke’s-Roosevelt Hospital Center.

Munir Ghesani, MD, is Associate Clinical Professor of Radiology at Columbia University College of Physicians and Surgeons.

Gabriel Sara, MD, is a Senior Attending Physician in the Division of Hematology/Oncology at St. Luke’s-Roosevelt Hospital Center and Assistant Clinical Professor of Medicine, College of Physicians & Surgeons at Columbia University