Navigating the Unknown of Rare Cancers

When Arianne Missimer, a doctor of physical therapy, a dietitian and the founder of the Pennsylvania-based integrated health center The Movement Paradigm, discovered a mass behind her right knee after feeling nerve pain in her leg, she quickly scheduled an ultrasound.

“The pain wasn’t anything that was really limiting me,” Missimer says. “It was just an unusual symptom. If I didn’t know my body so well, it was something I could have easily ignored.”

After the ultrasound confirmed the mass was solid, she underwent an MRI. The results were startling. In March 2015, at age 34, Missimer received a diagnosis of stage 3 liposarcoma, a rare type of cancer that develops in the fatty tissue.

“I remember looking up ‘sarcoma’ and seeing that there are so many different types,” she says. “Then I looked up ‘liposarcoma,’... but there wasn’t a ton of information out there.”

This isn’t that uncommon, according to Dr. Melissa Burgess, a medical oncologist at UPMC Hillman Cancer Center in Pittsburgh. “Unfortunately, for some of these diseases, there is no clear standard next step,” she explains. “There’s a lack of data because it’s a difficult disease to treat. It’s also rare, so it’s hard to do large studies.”

“Sarcoma” is the general term for a broad group of cancers in the bones and connective tissues. Out of the approximately 1.9 million people who received a cancer diagnosis in the United States in 2020, only 17,000 — less than 1% — had a sarcoma, according to Dr. Robert Maki, a medical oncologist and professor of medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia.

There are two general categories of sarcoma. Soft-tissue sarcomas affect tissues that connect, support or surround the organs and include sarcomas that are present in the muscles, tendons, fat, blood vessels, nerves, fibrous tissues and synovial tissues. Bone sarcomas grow in the bone or cartilage. Between these two categories, sarcomas span 70 subtypes, often making a precise diagnosis difficult.

Brenda Kennedy, a yoga instructor and personal trainer in El Paso, Texas, experienced this difficulty after visiting the doctor for a pain that she describes as a “dull toothache in the knee.” After undergoing an X-ray, a bone scan, a PET scan and an MRI, she was found to have a grade 2 chondrosarcoma in 2009 at age 31.

“But the most frustrating thing was how long the imaging took. I couldn’t get a referral to an orthopedic oncologist until they ruled out everything else,” Kennedy says.

‘BAD LUCK TUMORS’

“In terms of the frequency, about 3,000 people in the United States develop liposarcoma each year; for chondrosarcoma, it’s around 1,000 people a year,” Maki says. “But even the terms ‘liposarcoma’ (and) ‘chondrosarcoma’ represent a family of tumors with further subtypes.”

Liposarcoma subtypes include well differentiated/ dedifferentiated, myxoid/round cell and pleomorphic. For chondrosarcoma, approximately 90% are conventional chondrosarcomas, and the other 10% are subtypes, which can include dedifferentiated, clear cell, mesenchymal and myxoid.

In addition to being both rare and highly specific with their subtypes, liposarcoma and chondrosarcoma also have few risk factors and often-vague symptoms, increasing the difficulty and timeliness of diagnosis. Maki notes that certain genetic syndromes, exposure to radiation for treat- ment of another cancer, exposure to certain chemicals or a damaged lymph system could increase a person’s risk for a sarcoma. For chondrosarcoma specifically, a family history of developing multiple benign cartilage tumors is one factor that could increase a person’s risk.

“We consider them bad luck tumors,” Maki explains. “There’s nothing people did to get them. There’s no association with eating, drinking, smoking ... nothing like that.”

“Over 80% of these cases are spontaneous,” Burgess emphasizes. “That’s what makes it so challenging. We don’t know what causes them, we can’t really screen for them and they are so rare.”

Both Missimer and Kennedy led healthy lives as athletes prior to their diagnoses. Other than the leg pain that brought them both to the doctor, neither of them exhibited any serious symptoms.

“I remember being so angry because I had done everything right,” Kennedy says. “They say, ‘You need to eat right. You need to exercise.’ I taught fitness classes. ... I did everything you are supposed to do, and I was (still) dealing with a cancer diagnosis.”

THE SYMPTOMS OF SARCOMAS

Liposarcoma is most common in adults ages 40 to 60 and presents in the extremities (60%), abdomen (10%), and head and neck (10%). Chondrosarcoma, most common in adults who are 30 to 70 years old, can present in any part of the skeleton. When it comes to symptoms, the type and severity can largely depend on where the tumor is located as well as the stage and grade.

“Liposarcomas mostly show up as a painless lump, like most cancers,” says Dr. Atrayee Basu-Mallick, director of Sidney Kimmel Cancer Center’s Multidisciplinary Bone and Sarcoma Center. “That is why in certain locations — for example, within the abdomen — diagnosis can be delayed. Symptoms happen only when the tumor is pressing on another organ, nerves or blood vessels.”

For Missimer, her pinpoint nerve pain likely occurred once the tumor grew large enough to press against her sciatic nerve. She noticed it most when sitting down and crossing her legs. A majority of patients may have a similar experience, but others could experience symptoms earlier.

Liposarcoma in the head and neck, for example, usually causes a noticeable fullness; in the abdomen, one may experience difficulty eating and going to the bathroom and swelling or distention due to growth of the tumor. As with most other cancers, it can also present with nonspecific symptoms, such as weight loss, chills, fever, fatigue and night sweats. For some, the tumor never exhibits symptoms at all and is found incidentally.

Chondrosarcoma symptoms, on the other hand, usually appear before a lump is noticed.

“(These) can include a sense of pain, stiffness and a change in the range of motion in the joints close to where the tumor (is) growing,” Basu-Mallick explains. “If you have worsening symptoms, swelling or a lump you can feel, it is always good to get it evaluated.”

A MULTIDISCIPLINARY APPROACH

According to Basu-Mallick, the best course of treatment for each patient typically depends on five factors: exact type of tumor or histology, grade, stage, location and the patient’s overall clinical picture, which is determined by any other health issues.

“For sarcomas, ‘grade’ is the most important factor for long-term prognosis,” she says.

Grade refers to how the tumor cells look under the micro- scope, whereas stage refers to the tumor size, and local and distant spread. To determine grade, factors such as how many cells are actively dividing, the number of cells that are dead and how the cells look in general compared to the primary tissue of origin are all taken into consideration.

In a grade 1 tumor, for example, a patient could have surgery for removal. However, for grades 2 and 3, treatment gets more complicated — sometimes including a combination of chemotherapy and radiation — and the surgery is often expanded to remove areas around the tumor itself.

“Sarcomas are like a mound of salt,” Basu-Mallick says. “The mound is the tumor, but there are little grains all around it.

We have to get that microscopic disease out ... so to be safe, we have to take out a bigger section.”

When putting together a treatment plan, Burgess, Maki and Basu-Mallick agree that taking a multidisciplinary approach is best.

“I always preach that it’s helpful to have your case reviewed by multiple doctors in different disciplines who understand the disease and can help come up with the plan,” Burgess says. “Getting to a center that has experience in sarcomas is also really important.”

For Kennedy, treatment involved removing 15 centimeters of her femur and inserting a metal allograft. She then underwent three more surgeries — including a total knee replacement, megaprosthesis and, due to her active lifestyle, repairing cracks in the polycarbonate structure — over the course of five years. Because she had relocated, Kennedy had surgery at different locations.

“Movement and being outside has always been my form of relieving stress,” Kennedy says. “I was dealing with the most stressful thing in my entire life, and my one way of coping with it had been taken away from me.”

Missimer, on the other hand, underwent fertility preservation, six rounds of chemotherapy, radiation, proton therapy and a limb-sparing surgery that removed the tumor and part of her hamstring. “I felt really good during the proton therapy, mentally, emotionally and physically,” says Missimer, who started training for American Ninja Warrior, a sports entertainment competition based on tough obstacle courses, while
still in treatment. “Then I got the surgery, and that was emotionally tough.”

THE FUTURE OF TREATMENT

Despite the complications that rare cancers such as these can bring, medical professionals are optimistic about where the future is headed.

“Since these tumors represent multiple types of cancers, there’s an interest in breaking each one down and finding specific treatments,” Maki explains. “For example, half of regular chondrosarcomas have a mutation in a gene called IDH1 or IDH2, which lead to hyperactivation of the encoded enzyme isocitrate dehydrogenase, and there are now drugs that target those mutations. There are hints of benefit for people who receive those medications, though it’s still very early in the development of those drugs.”

Maki also notes a clinical trial that is looking at a different way to trigger the death of the chondrosarcoma cell without having to use chemotherapy.

“The big problem with chemo for chondrosarcoma is that chondrosarcoma is in the cartilage, where there are no blood vessels. You can’t just inject a drug into the veins and expect it to get to the tumor,” he says. “But by using a monoclonal antibody that sticks around the body for weeks, you can achieve a level of medication in the body to kill off those tumor cells.”

Finally, although sarcomas are broadly thought to be a cancer that haven’t proved responsive to immunotherapy, oncologists including Burgess are dedicating their time to looking at certain genes that are expressed in the tumor and then identifying unique characteristics within subtypes that will be responsive to immune treatments.

Today, both Missimer and Kennedy are cancer-free. Kennedy’s fourth and final surgery took place in March 2014, and she has maintained her active lifestyle by walking three half-marathons, teaching yoga, camping and keeping up with her four kids. As for Missimer, three months after her surgery, she went on to compete on “American Ninja Warrior” in May 2016.

“Physically, I have limitations, but I was able to manage my pain and do my physical therapy, and I attribute that to now being as functional as I am,” Kennedy says. “I would tell patients to mentally prepare for pain; mentally prepare for keeping up with the physical therapy and be as active as you can, within reason, to keep your body going.”

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.