Issue: June 2016
June 30, 2016
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Advanced imaging and genomics may foster better musculoskeletal tumor diagnoses

Characterizing the heterogeneity of tumors may help classify patients for clinical trials, aid development of targeted therapies.

Issue: June 2016
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Recent research has led to meaningful advances in the diagnosis of primary musculoskeletal tumors. From information about tumor-specific phenotypes to improved imaging sequences, sources told Orthopaedics Today Europe they have seen slow, but steady progress in this area.

“The way in which tumors are diagnosed is firstly by awareness of the condition,” Stephen R. Cannon, MD, MCh Orth, FRCS, MRCOG, of BMI The Clementine Churchill Hospital, in Middlesex, United Kingdom, told Orthopaedics Today Europe.

Orthopaedic surgeons need a body of medical knowledge to be able to decide whether, from the patient’s symptoms, a primary tumor is a possibility and to appropriately investigate the patient, he said.

Stephen R. Cannon, MD, MCh Orth, FRCS, MRCOG
Stephen R. Cannon

“Education is of paramount importance. In fact, not only the study, but also the experience plays a major role for a proper and an early diagnosis,” Pietro Ruggieri, MD, PhD, chairman of the Department of Orthopaedics and Orthopaedic Oncology at University of Padova, in Padova, Italy, said.

Lesion differentiation, grades

Sources for this Cover Story said accurate and rapid diagnoses require cooperation among orthopaedic, oncology, radiography and pathology specialists. According to Sander D.S. Dijkstra, MD, of Leiden University Medical Center, which is one of four referral centers for bone tumors and one of eight referral centers for soft tissue sarcoma in The Netherlands, in order to state the diagnosis of primary bone cancer, benign lesions must be differentiated from malignant ones. Within malignant lesions, it must then be determined which grade and stage. This is essential to plan the treatment strategy, he said.

One recent improvement in sarcoma grading has been for cartilaginous tumors and liposarcoma, according to Ruggieri.

Sander D.S. Dijkstra, MD
Sander D.S. Dijkstra

“In fact, the new WHO classification defines as atypical cartilaginous tumors the previously called grade 1 chondrosarcomas (CS), and as atypical lipomas, the low-grade liposarcomas. This is related to the virtually absent risk of distal metastasis of these entities and has, therefore, a remarkable role in defining the type of treatment,” he told Orthopaedics Today Europe.

More complete imaging

Dijkstra, Cannon and Ruggieri agreed more complete imaging will advance how musculoskeletal tumors are diagnosed.

“Imaging, and imaging regarding more detailed reports on grading, matrix and monitoring of the tumor, I think that will be the way to go,” Dijkstra told Orthopaedics Today Europe.

“Although there are some interesting advances in hematological testing, blood testing, looking for specific markers for some cancers, the vast majority are done by imaging,” Cannon said.

He noted radiographs are fairly ineffective for a diagnosis because the tumors and resultant bone destruction usually must be extensive before it can be seen on radiographs.

Among current imaging techniques that are fairly accurate at detecting bone pathology, according to Cannon, are technetium bone scanning, which is a scintigraphic study that uses Technetium 99m as the active agent, MRI and non-radiation MRI.

Pietro Ruggieri, MD, PhD
Pietro Ruggieri

“The MRI will give you specificity and the extent” of the tumor, Cannon said.

Ruggieri said the advanced imaging he uses for primary musculoskeletal tumors are MRI, dynamic contrast MRI, total body MRI and positron emission tomography (PET) CT.

“Specifically, MRI is the best tool in the diagnosis of soft tissue tumors and in defining the extent of a resection needed to get white margins,” he said, noting he typically explores a new imaging method or sequence when it is introduced and usually ends up using it almost routinely.

Specialized MRI

“In our center, we use MRI and dynamic contrast enhancement (DCE),” Dijkstra said.

DCE enables images to be made every 3 seconds when gadolinium contrast is administered, he said. “If a lesion is enhanced within 10 seconds, it tends to be malignant,” he said.

A lesion that takes longer to be enhanced on MRI DCE is more likely to be benign, such as an endochondroma compared to a CS lesion, Dijkstra said.

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Frequency encode gradient MRI is a newer type of imaging that can be used for a lesion suspected of being a musculoskeletal tumor. Although little is published on the method now, he said it has potential.

“In those [images] you have, I think, from both worlds, the best. You have the complete body and you have the MRI of the regions of interest. You are better able to have involvement assessment,” Dijkstra said.

DWI MRI looks at cellularity

Diffuse weighted imaging (DWI) is based on cellularity of an involved lesion and shows promise as an imaging modality, Dijkstra said.

“Because the cellularity is important, you could monitor the patients and you can follow the local recurrence or the recurrence, for instance, of fibrous tissue or necrosis, and you can discriminate between tumor recurrence or one of those diagnoses. With DWI MRIs, you are able to have a better monitoring compared to the routine T1 or T2 MRI,” he said.

Better information about the tumor involvement in bone or soft tissue can help clinicians better anticipate treatment response, chemotherapy timing and any recurrence, Dijkstra noted.

Rapidly diagnosing a musculoskeletal tumor, such as an osteosarcoma (OS), which is the most common type of primary bone cancer, or Ewing sarcoma (ES), in a young adult or child who is growing is helpful to oncologists and orthopaedists. However, the time that it takes to definitive diagnosis based on imaging and to obtain pathology reports is often too long.

With a recent grant from the cancer society in The Netherlands for fast-lane diagnosis of cancer, Dijkstra’s outpatient clinic and others drastically cut the time from a patient’s first appointment to diagnosis.

Shorter time to diagnosis

“We were able to reduce the diagnosis time from 10 days to 5 working days,” Dijkstra said. “We proved and we have been, I think, successfully reducing the waiting time because waiting for the definitive diagnosis is something cumbersome. Everybody, including the patient, I think, will have benefit from early diagnosis.”

A same day MRI and biopsy, as well as a PET scan done within the next 1 [day] or 2 days, is involved, as well as the involvement of a fast-lane pathologist. It is not possible to shorten the diagnosis time after biopsy to fewer than 5 days, because the pathology — which Dijkstra said is the gold standard in bone tumors — is the limiting factor, since it takes time to get rid of the bone and to analyze the tumor.

Dijkstra said pathologists today are skilled in the types of cells to study and which parts of the biopsy can be analyzed for specific mutations, and orthopaedic surgeons must collaborate with them closely.

Patient stratification

Dominique Heymann, PhD, professor of bone oncology at The Medical School, in Sheffield, United Kingdom has authored nearly 200 publications on bone cancer and osteoclast differentiation in peer-reviewed journals. The challenge in diagnosing bone cancer, by any method, he said, is related to the heterogeneity of the tumors.

In OS, for example, the number of mutations found are impressive and the disease is complex at the molecular level.

Dominique Heymann, PhD
Dominique Heymann

“The problem is there is not one OS. There is one OS corresponding to each patient,” Heymann told Orthopaedics Today Europe.

Although it is challenging to characterize the heterogeneity of OS, he said it is necessary to stratify patients for clinical trials and, using that patient stratification, to develop like-targeted therapies.

“This is like personalized medicine,” he said.

From a biopsy, next generation sequencing (NGS) sequencing or genome sequencing can now be done to better analyze the cell subtypes in a tumor mass, in bulk. A newer technique — DEPArray System (Silicon Biosystems) — can also be used to isolate cancer cells from the tumor so these can be studied with NGS or other sequencing, at the single-cell level. However, because it is new and costly, DEPArray equipment is not yet widely available throughout Europe, Heymann said.

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Isolated circulating DNA

The objective from a single biopsy, regardless of the patient’s age or whether the biopsy sample is fresh or paraffin-embedded, according to Heymann, “is to isolate the different cell populations; to determine more in detail the percentage of population, 1%, 2% or 3%, with specific mutation, for instance; [and] to adapt the treatment,” according to Heymann.

Ruggieri said genomic analysis, which is widely used at his center, is critical for the management of musculoskeletal tumors because it allows a better and safer diagnosis of the histotype, particularly for soft tissue sarcomas.

“Also, because it is the key that can lead to successful target therapies, we do expect this area to expand further in the future,” he said.

Regardless of the analysis being done, the biopsy sample should be analyzed as soon as possible after resection because modifications of the transcriptomes in tumor cells have been observed within a few minutes of sampling, according to Heymann.

“The proximity between the orthopaedic theater and the pathology lab is also a key point to decrease the time between the sampling and the analysis,” he said.

Ruggieri said imaging is important for performing transcutaneous biopsies and guiding interventional radiology procedures.

“All of the imaging tools need to be integrated and widely used in musculoskeletal oncology,” he said.

Identification of cancer markers

Upcoming improvements in tumor diagnosis are expected in the area of genetic analysis. However, Heymann said, “For most sarcomas, the main problem is we do not have any markers to identify cancer cells.”

One advance in diagnosing bone cancer that Heymann discussed, which can now be done within the subtype of high-grade OS, is isolating circulating DNA (cDNA) from blood. This is the “signature of the disease,” he said, because there is either an increase or decrease of cDNA from the cancer cells based on tumor progression.

“This may be used as a biomarker for the follow-up of the treatment efficacy, for instance, or the tumor development,” he said.

Heymann noted, however, bone sarcoma diagnosis must be associated with the bone imaging. The diagnosis all bone sarcomas ultimately must be established by histological assessment, as well as complementary molecular analysis, such as for ES with the detection of a gene fusion. Bone imaging has other advantages, Heymann said, such as a being useful for planning the surgery and for informing the orthopaedic surgeon if the tumor is resorptive or able to form bone tissue.

Ruggieri noted intraoperative navigation techniques are being used increasingly in musculoskeletal oncology procedures.

“Reconstruction will be hopefully soon enriched by the introduction of robotics,” he said.

Origins of the disease

All bone sarcomas originate from mesenchymal stem cells. Therefore, in the future, Heymann thinks work should be done to better define the origin of the disease. It should focus on identifying the original cells responsible for the disease, which would allow earlier, more efficient interventions to fight the disease, he said.

“If we were able to isolate these cancer-initiating cells, to characterize the cells which are probably responsible for the recurrence and metastases, it should be a great advance of the cancer understanding and also for the therapeutic development,” Heymann said.

The microenvironment of tumor growth and the role of immunoregulators in tumor development, such as the role of microphages in OS development, also need to be better understood, he noted.

For primary, rather than metastatic tumors, Cannon said, “You are beginning to get an individual map of what the tumor characteristics are, and can then, we hope, begin to identify specific treatment against it. Again, people are becoming more interested in immunotherapy as a direction.” – by Susan M. Rapp

Disclosures: Cannon, Dijkstra and Heymann report no relevant financial disclosures. Ruggieri reports he is a paid consultant to Exactech Inc. and Stryker.