Lung Lesions: Clues To Help Determine Benign vs Malignant

BALTIMORE--A number of factors can suggest whether a focal pulmonary lesion is malignant or benign, but no single test affords a quick answer, and biopsy is usually necessary to make the diagnosis, said Peter White, Jr., MD, assistant professor of medicine at Johns Hopkins University.

At a meeting on nuclear medicine sponsored by Johns Hopkins, two speakers outlined advances in noninvasive imaging of such lesions via PET scan and somatostatin receptor scintigraphy, while Dr. White reviewed the lesion characteristics that may suggest malignancy.

A lung cancer goes through 40 doublings of volume in its life cycle and is not visible until it reaches 1 cm in size, Dr. White said. At 3 to 4 cm, it has gone through seven eighths of its life history.

"By the time it reaches 2 cm, the tumor contains 500 million malignant cells and starts to metastasize," he said. "When there are that many cells, it's not surprising that a few will wander off and set up shop somewhere else."

Statistically, the most common sites for lung cancers are in the upper lobe and in the right lung. "But," Dr. White said, "finding a lesion in the lower left lung doesn't mean it's not malignant."

Age is another suggestive factor. Fewer than 1% of malignancies arise in patients under 30, and fewer than 5% under age 40, so Dr. White places the crossover point to suspect malignancy at age 35. Nonetheless, he said, "you can't assume the lesion is benign on the basis of age alone."

Nor does calcification rule out a tumor, since 2% of lung cancers are calcified. Lesions with a wall thickness less than 4 mm are benign 95% of the time, while those with a thickness greater than 16 mm are 84% likely to be malignant. "Anything in between," Dr. White said, "calls for a biopsy." As for size and shape, malignancy is more likely if the lesion is greater than 3 cm, round or oval, has sharply defined edges, and is surrounded by aerated lung tissue.

Computed tomography (CT) scans may offer further guidance, he said. Lower CT numbers (below 164 Hounsfield units) tend to indicate malignancy.

"Perhaps the most useful indication is any change of the lesion over time," he said, citing an interesting case (see box). Malignancy is indicated if the doubling time (of volume, not diameter) is between 30 and 490 days. "Anything longer points to pneumonia or histoplasmosis, but biopsy may still be necessary to give a clear diagnosis," Dr. White said.

"If we had better noninvasive imaging techniques, we could avoid many thoracotomies and biopsies," said Edward Patz, Jr., assistant professor of radiology, Duke University Medical Center.

Dr. Patz's current work with PET is proving "extremely valuable" in differentiating pulmonary lesions. He has tested 51 patients with solitary pulmonary nodules using F-18 fluorodeoxyglucose (FDG), which accumulates in higher than usual proportions in abnormally metabolizing tumor cells. These studies showed that lesions falling below a standardized uptake ratio of 2.5 were always benign.

Dr. Patz advised that the workup of patients with focal lesions should start by looking at old chest films if available. "If a solitary pulmonary lesion is stable (no sign of lesion growth in 2 years), the patient can be sent home without follow-up. If not, go to a CT scan with con-trast enhancement," he said. At Duke, researchers have found that if there are less than 15 Hounsfield units difference in contrast on CT scan, chances are 100% that the lesion is benign.

If x-rays and CT are inconclusive, Dr. Patz said that FDG PET imaging should be considered, if available. If uptake is low, the patient should be followed, but "you can hold off on biopsy," he said.

He suggests that an asymptomatic patient whose diagnosis is unclear on x-ray, CT scan, and PET should be sent to surgery. "If you do a biopsy," he reasons, "and get back a T1 lesion, you go to surgery. But if you get nonmalignant cells, you can't be sure you haven't missed the tumor."

He added that researchers are looking at new imaging agents for use with PET. "As knowledge of cancer cells expands," he said, "PET will become more useful as a differentiating tool."

Somatostatin Receptor Imaging

Another useful tool for detection and staging, in this case for small-cell lung cancer, is somatostatin receptor scintigraphy, said Larry K. Kvols, MD, director of Clinical Research, Mallinckrodt Medical, Inc., St. Louis.

Somatostatin, Dr. Kvols said, is a hormone that functions like an endocrine off switch, inhibiting secretion of other hormones like somatotropin, gastrin, and insulin. A synthetic version, octreotide (Sandostatin), has been used for a decade to treat several neuroendocrine cancers.

By linking indium-111 to pentetreo- tide, a somatostatin analog similar to octreotide, researchers have been able to image tumor tissues containing somatostatin receptors. A variety of tumors express somatostatin receptors, including small-cell carcinomas of the lung.

In small-cell lung cancer, whole body imaging with 111In-labeled pentetreotide (OctreoScan) may reveal distant metastases not recognized by other imaging systems, and so aids in staging the cancer. Furthermore, Dr. Kvols said, because it visualizes brain metastases sooner than other systems, OctreoScan scintigraphy permits early brain radiotherapy.

Even non-small-cell lung cancers without these receptors can be spotted by OctreoScan imaging. "The lesion is cold radiographically, but there is much activity around it," Dr. Kvols said. "Activated lymphocytes express somatostatin receptors, which may explain why tagged somatostatin congregates around the tumor. But OctreoScan imaging is not of much value for staging of NSCLC."

A 3-Year-Old X-ray Rules Out Pulmonary Cancer

In his presentation, Dr. Peter White recalled one case of a difficult to diagnose pulmonary lesion in a woman in her early 40s. "Her x-rays showed increased interstitial masses, and her CT scan was suspicious for cancer. A biopsy was inconclusive. Finally, someone found a 3-year-old x-ray, and we saw that the lesion hadn't changed. That time frame essentially rules out cancer."