“Carcinoma” of Unknown Primary: Understanding the Role of Pathology

March 2021 Vol 12, No 3



When a person has a malignancy, but it is unknown where that cancer originated, it is up to pathologists to connect the dots. Carcinomas or malignancies of unknown primary are rare, but when the pathology team cannot determine the primary site of malignancy with certainty, they can still employ methods to further refine the probable site of origin, according to Emma Elizabeth Furth, MD, who spoke at the Academy of Oncology Nurse & Patient Navigators 11th Annual Navigation & Survivorship Conference.

She said the central issue pathologists face is understanding that the biology of the origin of the malignancy—be it a brain tumor, colon cancer, liver cancer, or a hematopoietic disorder—will drive the treatment and prognosis of a person’s cancer. For example, not all adenocarcinomas are treated the same: adenocarcinoma of the colon will be treated with one set of chemotherapeutic agents, depending on the stage, whereas adenocarcinoma of the pancreas will be treated with a different set of chemotherapeutic options. It is the pathologist’s job to help dissect and further refine the potential origin of the malignancy, because the chemotherapeutic options are dependent upon the site of origin.

“Most people think of pathology as a big black box. They think we put the specimen into this box and out comes an answer. But pathology is not a black box; we do receive specimens, and we do try to give ‘answers,’ but it’s a little bit more refined than that,” said Dr Furth, professor of pathology and laboratory medicine at the University of Pennsylvania. “The pathology team encompasses many individuals, including clinical chemists, cytopathologists, molecular pathologists, and ancillary staff. I am a pathologist, but I’m also a physician; as a physician I often interact with patients directly, but I also act in multidisciplinary teams to best refine the diagnosis, the treatment options, and the prognosis for patients.”

What Type of Specimen Are We Talking About?

A number of different types of specimens—like blood, fluid, cells, and tissue—require analysis by a pathologist, but some are more important in terms of diagnosing cancer, and particularly when it comes to determining the primary site of cancer. Dr Furth specializes in surgical pathology, so she examines tissues.

Examining a specimen typically leads to a diagnosis, and that diagnosis determines what will happen to the patient in terms of treatment and prognosis. For example, if a patient has a diagnosis of colon cancer, the stage and presence of lymph node metastasis or further metastases will drive what type of chemotherapy, radiation therapy, and/or immunoregulatory therapy the patient will receive. For many malignancies, the specimen will also undergo further ancillary testing to determine treatment modality.

“All of this is dependent upon the evaluation of the specimen made by a pathologist,” she said. “We not only give a diagnosis, but we also help to render patient care in terms of predictive markers that may tell us whether or not various immunotherapies will be of use (eg, through PD-L1 immunohistochemistry). So it’s a very complex system that helps to give a diagnosis and prognosis, which then drives treatment.”

Determining the Site of Origin

As a cancer develops during the process of neoplastic progression, the malignant cells begin to look different from the benign cells, but they still maintain some of the phenotype, or “look,” of their benign counterparts. So essentially, pathologists try to work backwards and determine what type of benign cell a malignant cell resembles.

“That’s how we can look at a malignant cell and surmise that it’s a colon cancer, because it retains some of the features that it had in a benign state,” she explained.

But, unfortunately, it’s not always that easy. Depending on the types of genetic and epigenetic changes and mutations that occur during neoplastic progression, the cells may also correspondingly change their phenotype (eg, a colon cancer may begin to look more like a lung cancer, even though it did not come from the lung). These genetic changes not only drive the way a cell looks, but also the way it behaves in terms of its malignant properties. So even when the origin of the tumor is unclear, the type of mutation present may help to guide treatment, since tumors with certain types of mutations or translocations tend to respond to certain types of treatment.

The Pathologist’s Toolbox

According to Dr Furth, sometimes tumors become so malignant that they’re unrecognizable. Although carcinomas or malignancies of unknown primary are rare, when this happens, certain tools in the pathologist’s toolbox can help them go backwards and figure out what genetic changes that tumor has undergone, and also what proteins or antigens are expressed on the cell.

Vital tools in that toolbox include communication with other members of the care team (including navigators) and critical thinking. “If something looks like a lung cancer and the patient doesn’t have a lung mass, I’m going to have to rethink my diagnosis, because that doesn’t fit clinically,” she said.

Other crucial tools include an understanding of histology (eg, looking at proteins on the surface of the cell) and immunohistochemistry (eg, identifying expression of PD-L1 and HER2). She noted that the results of immunohistochemical staining on a pathology report might look like “alphabet soup,” but this is where the importance of communication comes into play. “Part of my job is communication; if someone doesn’t understand my report, they can call me, and if I need more clinical information, I can call them,” she said. “So don’t think that the report is the end of the road; communication is paramount.”

At her institution, Dr Furth has run a unique program for more than 10 years in which she actually meets with patients in the clinic. “I have a conversation with the patients who want to talk to me, and I go over a presentation that I made specifically for them. I sit with them and often their families, and I explain their process and what’s going on with them,” she said. “It’s certainly been an incredibly enriching experience for me, but the patients I’ve met have also benefited from this education. I’m a true believer that knowledge is indeed power.”

The final tools in the pathologist’s toolbox include informatics, particularly advances in laboratory information systems technology (but Dr Furth noted that although artificial intelligence is a helpful tool, particularly in terms of quantitative analysis, it does not provide diagnostic answers), and molecular testing, including next-generation sequencing and methylation assays.

“Immunohistochemistry, our ability to look at the proteins expressed on a malignant cell, is incredibly powerful because the proteins expressed on or in the cell are also reflective of the cell lineage, ie, the cell of origin,” she said. “But at the end of the day, tumors do what tumors want to do. Although it’s not very common, sometimes we just don’t know. But even though we may not be able to determine where the tumor site of origin is, a lot of times we can tell you where it’s not. And that is really, really important.”

Last modified: August 10, 2023

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