The Devil You Don’t Know: Cancer of Unknown Primary Origin

AONN+ 2020 Conference Highlights Special Feature —January 4, 2021

A 55-year-old woman with liver disease received a liver transplant. In the removed liver, doctors found a grade 1 well-differentiated neuroendocrine tumor. Because primary neuroendocrine tumors in the liver are largely unheard of, pathologists delved deeper to deduce the originating site of the patient’s malignancy. The histology of the tumor pointed to an origin in the small bowel, or more specifically, the terminal ileum. Doctors took a closer look at the patient’s imaging and confirmed the presence of a lesion in that area. Soon after, they removed from the patient’s terminal ileum the small primary tumor that had metastasized to her liver.

“If the primary [tumor] had been kept in there, it would have continued to shed malignant cells that would have continued to spread through the body and particularly go into her new liver,” said Emma Furth, MD, Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, Philadelphia, who identified the primary site in this patient. “By our ability to not only diagnose that the tumor is a neuroendocrine tumor but even to further refine what the primary site was, we were able then to help in terms of subsequent treatment that will hopefully extend the life of this particular patient.”

Although pathologists are typically able to determine a primary malignancy, in rare cases, tumors cannot be traced to their site of origin, Dr Furth explained during a session on the topic. Making such a determination is vital, as the originating site of a cancer determines its prognosis and treatment.

“We do still have cancers of unknown primary, but they represent a truly small percentage of malignancies with which we deal,” she said. “Even in those situations where we can’t say with absolute certainty where it started, we can tell you pretty much in a probabilistic manner what we think the odds are of the primary site.”

A first step in understanding cancers of unknown primary is comprehending pathology. Composed of a multitude of professionals with a variety of skill sets, pathology departments are staffed by much more than pathologists. In addition, Dr Furth pointed out, many people do not realize that pathologists are physicians, and although they work with specimens taken from patients, they indeed are part of the multidisciplinary team providing patient care.

“Most people think of pathology as … a big black box, and they think we put the specimen into this black box and out spits an answer,” she said.

Pathology involves histology, or the examination of specimens under a microscope, but includes much more. Ancillary predictive and prognostic marker testing help to determine the best treatments for a patient.

For example, not all adenocarcinomas are treated the same. The origin of the carcinoma determines which chemotherapeutic options will be employed in fighting the cancer. Fortunately, some underlying mechanisms can help to tease out a diagnosis.

In neoplastic progression, genetic or epigenetic changes drive benign cells to develop the malignant phenotype. Although such cells change in appearance, they retain some characteristics from when they were benign.

“We try then to work backwards, given a malignant cell, what do we think it most looks like in terms of its benign counterpart,” Dr Furth said, adding that the process is not as straightforward as it sounds.

As a cell undergoes genetic mutations or changes on the road to becoming malignant, it may no longer resemble the benign cell it once was, complicating matters further. Also, these changes in the cell affect its behavior. Fortunately, pathologists have the ability to establish what changes have occurred in the cell’s progression toward malignancy, thereby providing insight into the pathway of the malignancy. Sometimes, however, molecular changes in the nucleus of a cell can make it so dedifferentiated that it is unrecognizable.

“That might be a situation where we truly have a carcinoma or malignancy of unknown primary,” Dr Furth said, adding that in such cases, pathologists are able to examine the proteins or antigens expressed on a cell through immunohistochemistry to provide insight into its pathway.

Pathologists do not work in a vacuum, however. Tumor boards and multidisciplinary team meetings help them to make their determinations.

“Not any one piece of data may yield the diagnosis,” she said. “One has to integrate and put all the pieces of the information together.”

Because of this, communication is crucial, according to Dr Furth, who said she regularly communicates with nurse navigators and other members of the clinical team, along with patients and families, with the latter being relatively unique among pathologists.

“I am a true believer in that the more we know, the better we are and knowledge is indeed power,” she said, adding, “Communication and teamwork are absolutely paramount. We can’t render great patient care without that.”

When pathologists provide a diagnosis by composing a report, its contents may not be easily understood by the clinician reading it.

“If in reading the report, one doesn’t fully understand what is being said, calling the pathologist of record would be the next step,” Dr Furth advised. “Don’t think the report is the end of the road at all.”

In spite of the many tools available to pathologists, some malignancies remain a mystery in terms of their origin.

“In this day and age, it’s really actually rare to have a malignancy of unknown primary,” Dr Furth said. “It does happen for sure, and in those situations we do our best. We can say where it’s not and we can say what it might be. And sometimes, that is the best we can do.”

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Last modified: August 10, 2023

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