Cancer of unknown primary is a disease that has metastasized (spread) from another part of the body. The place where it began, also called the primary site, is unknown. These cases make up about 2% to 5% of cancers diagnosed in the United States. Thanks to better diagnostic tests, though, they are becoming less common.
About four of every five cases that are first diagnosed as cancer of unknown primary eventually are confirmed to be specific types of cancer. CUP most often is found in the lymph nodes, liver, lung, peritoneum (lining of the bowel) or bone.
Cancer of unknown primary often is challenging because it tends to be aggressive and has often spread to many parts of the body before it is found. In addition, because origin of cancer is unknown, it may be more challenging to choose the best treatment.
Cancer of Unknown Primary Types
Although doctors are at first unable to determine where CUP began, they study the cancer to find out as much as possible about them. After looking at the cancer cells under a microscope, they usually decide the cancer belongs in one of the following categories:
Adenocarcinomas: About six of every 10 cancer of unknown primary cases are adenocarcinomas, meaning they began in gland cells. Most frequently, the primary sites are the lung, pancreas, breast, prostate, stomach, liver or colon.
Poorly differentiated carcinoma: Cancer cells are present, but they do not have enough detail for doctors to decide the type of cancer. Around 10% of these CUP cases are found to be lymphoma, melanoma or sarcoma.
Squamous cell cancer: The cells are flat, similar to cells on the skin or linings of some organs.
Poorly differentiated malignant neoplasm: Cells are definitely cancer, but they are so abnormal it cannot be determined what type of cell or part of the body they began in. Sometimes they are lymphomas, sarcomas or melanomas.
Neuroendocrine carcinoma: This type of CUP begins in the neuroendocrine system, making the cells like nerve cells and hormone-making cells. They are scattered in organs including the esophagus, stomach, pancreas, intestines and lungs.
CUP Risk Factors
Because the primary site of many cancer of unknown primary cases is never found, it is difficult to say what causes them. In the cases in which the primary site is determined, possible risk factors are based on that type of cancer.
- Smoking tobacco is a risk factor in cancers of the pancreas, lungs, kidney, throat, larynx and esophagus. More than half of people with CUP have used tobacco.
- Diet and being overweight are linked to cancers that begin in the stomach, colon or rectum.
- Too much sun exposure causes some melanomas.
However, it has not been proven that any of these factors make a person more likely to develop cancer of unknown primary.
Learn more about cancer of unknown primary:
- Cancer of unknown primary symptoms
- Cancer of unknown primary diagnosis
- Cancer of unknown primary treatment
Learn more about clinical trials for cancer of the unknown primary.
Cancer of unknown primary (CUP) survivor grateful for UT MD Anderson
When John Clark III was diagnosed with cancer of unknown primary (CUP) in April 2023, he was shocked and scared. CUP is a rare cancer that spreads from another part of the body, but the original cancer site is not known.
“It’s usually not good to have a rare cancer, but it worked out OK for me,” says John, who was diagnosed at age 65. “I was very blessed to get connected with some really good people at UT MD Anderson.”
Getting a second opinion at UT MD Anderson
CUP can be complex to diagnose and treat. The type of CUP John had was poorly differentiated carcinoma with squamous features involving one right inguinal lymph node. After getting his diagnosis, John had surgery close to home in Killeen, Texas, to remove the cancerous lymph node in his right groin.
Friends and family encouraged him to get a second opinion at UT MD Anderson. John’s from Houston originally, so he knew of UT MD Anderson’s reputation for cancer care. With a rare cancer like CUP, he knew he needed to seek treatment at a specialized center.
“I’d been assigned to a wonderful doctor in Killeen, but I was afraid to tell her I was going to get a second opinion somewhere else. I thought she might get mad, or it would hurt her feelings,” he recalls. “Instead, she told me that she expected me to get a second opinion. I learned then how important it was to educate yourself and be your own advocate.”
When he first got to UT MD Anderson, he had scans and bloodwork. A few days later, colon and rectal surgeon Craig Messick, M.D., performed an anoscopy to see if the primary tumor was anal squamous cell carcinoma.
The results of the anoscopy were normal with no suspicious findings. He also underwent molecular profiling of the tumor and a blood test to detect microscopic cancer cells. John’s bloodwork and scans didn’t show any evidence of disease. He met with Kanwal Raghav, M.D., a gastrointestinal medical oncologist who specializes in treating CUP. Based on the results, Raghav recommended that John continue on close surveillance and come back to UT MD Anderson in three months.
“I told him, ‘That sounds good to me,’” says John. Then, he went home.
Treatment for cancer recurrence
In December 2023, a follow-up PET scan at UT MD Anderson revealed that the cancer had come back. The scan lit up in a lymph node close to where the other cancer was found. His blood test was also positive.
“A guy told me long ago to listen to my gut because the gut never lies,” says John. “Somehow, my gut told me before that appointment that something was going to come up. So, I wasn’t surprised.”
Raghav recommended that John complete two rounds of chemotherapy – carboplatin and paclitaxel – to treat the recurrence. He would receive chemotherapy near his home under Raghav’s guidance.
“As I was talking to the chemo nurse back home, I was very upset, so she got a social work counselor to speak with me,” recalls John. “I told her that I believe in positivity and not manifesting negative things, but chemotherapy seemed like the beginning of the end.”
His side effects included fatigue and nausea, but he says his anti-nausea pills helped.
“I mostly just felt sick and tired for a few weeks,” he says.
John completed chemo on Feb. 6, 2024.
His first scans after chemo yielded some good news: he’d had a complete response to chemotherapy, and there was no evidence of cancer. His blood test was also negative.
“It was a major relief,” says John. “I’d been keeping a daily journal since I was diagnosed to sort through my thoughts. But after six months, I got tired of writing about cancer every day, so I stopped. But once I got that good news, I picked my journal back up and kept writing.”
Advice for others facing rare cancer diagnoses
John’s scans have remained clear, and he is on surveillance. He has follow-ups at UT MD Anderson every six months.
“A cancer diagnosis really makes you aware of your own mortality,” says John. “I’m grateful that my treatment was successful.”
He stresses the importance of connecting with other cancer patients who know what you’re going through. He was able to do that through a local support group.
These days, John enjoys golfing and writing. He also hasn’t ruled out pole vaulting, a sport he competed in before his diagnosis.
“I encourage anyone facing a rare cancer diagnosis to do a lot of research and educate themself about the disease. This will help them make informed decisions,” he says.
He’s glad he chose to come to UT MD Anderson, where even the rarest of cancers are not rare to us.
“Back in the day, people used to think cancer was a death sentence,” he says. “But now there are so many treatment advances. You just have to have faith and believe that you’re going to be OK.”
Request an appointment at UT MD Anderson online or call 1-877-632-6789.
Why choose UT MD Anderson for cancer of unknown primary care?
At UT MD Anderson’s Gastrointestinal Center, we have the depth of expertise to provide customized treatment for each patient with cancer of unknown primary (CUP). Our pathology experts have significant experience in evaluating cancer of unknown primary. We use advanced diagnostic methods to pinpoint the origin of CUP tumors, which are then treated by a team of renowned specialists.
Our experts work together in specialized teams that focus an incredible level of knowledge on you. Using the latest, most advanced technology, UT MD Anderson’s pathologists have extraordinary skill in diagnosing the origin of cancer of unknown primary.
Advanced Treatment, Range of Support
If the site of origin of cancer of unknown primary is found, UT MD Anderson offers a full range of the most advanced treatments for every diagnosis. Depending on the type of cancer, these may include proton therapy, targeted therapies, surgery and others.
As one of the world’s leading cancer centers, we offer a range of clinical trials of new therapies. And because we know CUP can take a toll on you and your family’s quality of life, we provide a range of support and wellness services to help you live your life to the fullest. This includes specially trained psychologists and a supportive care team who know what you are going through and can help.
Cancers of unknown primary are treated in our Gastrointestinal Center.