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Diagnostic Applications of Nuclear Medicine: Sarcomas

  • Janet F. EaryEmail author
Living reference work entry

Abstract

Sarcomas most commonly occur in the muscles, bones, fat, and connective tissues. These tumors constitute approximately 1% of cancers in adults and about 20% of pediatric cancer. The American Joint Committee on Cancer (AJCC) criteria are often used clinically for staging soft tissue sarcoma patients. Bone tumor staging follows the schemes utilized for other tumors. Adverse prognostic factors include deep tumor location, largest dimension >5 cm, locally recurrent disease, proximal lower extremity site, and presence of metastasis.

Imaging studies, including plain films, chest X-ray, CT with and without contrast, MRI, and [18F]FDG PET, are used in combination to stage and restage sarcoma patients. Serial imaging studies, especially [18F]FDG PET scans, can identify treatment response to neoadjuvant chemo- and radiation therapy. The bone scan with99mTc-MDP is still routinely used because of its sensitivity in detection of bone metastases and to occasionally identify metastatic lesions in soft tissues.18F-Fluoride is increasingly being used as a sensitive bone scanning agent for metastatic surveys.

[18F]FDG PET/CT can reliably distinguish low-grade from high-grade soft tissue sarcoma based on the SUV. Special features and [18F]FDG uptake are related to specific histologic types. Moreover, by identifying areas of increased uptake within a lesion, [18F]FDG PET can be helpful to localize a site for diagnostic biopsy. [18F]FDG PET has been used for tumor staging identifying bone and soft tissue metastases and nodal metastases. A high-resolution contrast chest CT is preferred to visualize small lung metastases.

Keywords

Sarcoma imaging Imaging in sarcoma Staging in sarcoma [18F]FDG PET in sarcoma 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

99mTc-HDP

99mTc-hydroxyethylenediphosphonate

99mTc-MDP

99mTc-methylenediphosphonate

AJCC

American Joint Committee on Cancer

CT

X-ray computed tomography

EWS-FL1

Ewing’s sarcoma fusion gene encoding for a transcriptional activator

FNCLCC

Fédération Nationale des Centres de Lutte Contre le Cancer

G

Histologic tumor grade

GIST

Gastrointestinal stromal tumor

M

Metastasis status according to the AJCC TNM staging system

MFH

Malignant fibrous histiocytoma

MRI

Magnetic resonance imaging

N

Lymph node status according to the AJCC TNM staging system

NF

Neurofibromatosis

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PET/MR

Positron emission tomography/magnetic resonance

PNET

Primitive neuroectodermal tumor/peripheral neuroepithelioma

RECIST

Response evaluation criteria in solid tumors

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC TNM staging system

Disease Overview

Sarcoma is a cancer that originates from the mesenchymal body tissues [1]. These comprise the connective, muscle, fat, bone, cartilage, peripheral nerve, and blood vessel tissues. Sarcomas most commonly occur in the muscles, bone, fat, and connective tissue. While the bone marrow is also derived from mesenchymal tissues, in clinical practice the hematologic malignancies are considered separately from the solid tumors, or sarcomas. Sarcomas are a complex group of tumors that have many different clinical manifestations, but they most often present as a mass.

Sarcomas occur in children and adults. Although the overall cancer incidence is much lower for children, sarcomas account for about one fifth of pediatric cancers. In adults, on the other hand, sarcomas constitute about 1% of cancers [2]. In the USA approximately 10,000 people are diagnosed with sarcomas each year and approximately 3,700 people per year succumb to their disease [2]. The median age of adult sarcoma patients is 59–60 years. There are approximately 30 common sarcoma subtypes that occur in both adults and younger age groups [3]. Most adult sarcomas are the soft tissue types, while bone tumors and cartilage tumors occur less frequently. Women comprise approximately 60% of sarcoma patients [3]. The majority of childhood sarcomas are bone sarcomas which have different clinical presentations, age preponderance, and outcomes compared to childhood soft tissue sarcomas.

The complexity of clinical presentations and diagnoses for sarcomas are based on their pathological characteristics. As these tumors are derived from mesenchymal elements, the tumors at presentation may have histologic and tissue marker characteristics that identify their tissue of origin. They can arise in any mesenchymal tissues. Some sarcomas appear to have no cell of origin identified in normal tissues, supporting the theory that sarcomas form and may differentiate according to surrounding tissue signals or other environmental and genetic factors. There are more than 50 histologic subtypes of sarcoma [4]. They most commonly occur in the extremities and trunk regions. Table 1 lists the mesenchymal tissues, while Table 2 lists the most common soft tissue sarcoma subtypes in adults. Table 3 lists the most common pediatric sarcomas. Bone tumors predominate in the pediatric population.
Table 1

Mesenchymal Tissues

Muscle

 Smooth muscle

 Skeletal muscle

Connective tissue

Fat tissue

Peripheral nerves

Blood vessels

Table 2

Common soft tissue sarcoma subtypes

Leiomyosarcoma

Rhabdomyosarcoma

 Subtypes

  Alveolar (pediatric)

  Embryonal (pediatric)

   Pleomorphic (adult)

Fibrosarcoma

Malignant fibrous histiocytoma (MFH)

Liposarcoma

 Subtypes

  Well differentiated

  Myxoid

   Round cell

   Pleomorphic

   De-differentiated

Malignant peripheral nerve sheath tumor

Malignant schwannoma

Angiosarcoma

 Hemangiopericytoma

 Lymphangiosarcoma

Pleomorphic sarcoma

Synovial sarcoma

Alveolar soft part sarcoma

Gastrointestinal stromal tumor

Table 3

Common pediatric sarcomas

Osteosarcoma

 Conventional types

  Chondroblastic

  Fibroblastic

  Osteoblastic

 Parosteal

 Telangiectatic (vascular)

 Small cell

 Periosteal

 High-grade surface types

 Secondary

Chondrosarcomas

 Central, primary, secondary

 Peripheral

 Mesenchymal

Clear cell

Ewing sarcoma

Extraosseous Ewing sarcoma

Askin tumor (chest wall primary tumor)

Peripheral primitive neuroectodermal tumor/peripheral neuroepithelioma (PNET)

Giant cell tumor

Malignant giant cell tumors

Notochordal tumors (i.e., chordoma)

Adults with sarcomas have approximately a 50% 5-year overall survival rate [1]. Patients with poor outcomes succumb to metastatic disease, local recurrence, or both. Local recurrence after resection occurs in 25% of patients with soft tissue sarcomas, an event that portends eventual metastatic spread [1]. Typically, pulmonary metastases are the leading site, followed by bone and other soft tissue locations. Disease prognostic factors include patient age, tumor grade (a risk assessment based on histopathological characteristics), tumor depth (superficial or deep), size, histologic subtype, surgical margin status at resection, and disease status (primary or recurrent disease) [1].

Adverse prognostic factors affecting patient survival with soft tissue sarcomas are deep tumor location, a tumor greatest dimension of 5 cm or larger, locally recurrent disease, proximal lower extremity site, and microscopic or grossly involved tumor margins at surgical resection [1]. Sixty percent of adult soft tissue sarcomas occur in the extremities. The proximal lower extremity is a common location for soft tissue sarcomas in adults, which increases risk for poor outcome because of its association with other poor risk factors. Poor risk factors include depth beneath the fascial plane and large tumor growth before diagnosis. In most patients, once metastases occur, survival time diminishes rapidly, despite salvage combination therapy regimens [4]. There are a number of treatment protocols for adults with sarcomas. Patients with low-grade, small sarcomas are likely to proceed to tumor resection with the possibility of adjuvant radiation. Those with high-grade large tumors are often treated with doxorubicin-based neoadjuvant chemotherapy with or without radiation followed by resection and adjuvant therapy. Surgical resection ranges from simple excision with wide margins to complex limb salvage procedures.

Experimental therapy clinical trials for sarcoma are now incorporating targeted therapy agents, which may influence imaging considerations in the future for clinical care. Adult bone tumors are most often cartilaginous histologic types. Usually, only high-grade tumors are metastatic. The intermediate-grade and low-grade cartilage tumors have high morbidity rates due to repeated local recurrence and poor responses to neoadjuvant chemotherapy. The bone tumors are less frequent in older adults, and osteosarcomas and Ewing’s sarcomas are typically seen in younger adults. They are rarely observed in adults over age 50. Bone sarcomas are metaphyseal tumors that primarily spread to the lungs. Risk factors for osteosarcoma include prior radiation therapy and germ line mutations [5]. There are a few soft tissue sarcoma histologic types that can also occur in the bone. Synovial sarcoma is a common example of a cancer that is more biologically consistent with its soft tissue tumor counterparts. As in the soft tissue sarcomas, prognostic factors include the presence of metastases at presentation and chemotherapy resistance. Treatment for the bone sarcomas in adults is similar to the soft tissue sarcomas. Neoadjuvant doxorubicin-based chemotherapy is given and is followed by surgical resection and additional chemotherapy. Five-year survival depends largely on the level of chemotherapy resistance, which is approximately 60%. The lower-grade osteosarcomas are treated with wide local excision and limb salvage procedures. They typically recur in about 5% of cases; however, these recurrences decrease 5-year survival significantly if the tissue recurrence degenerates into a higher-grade or undifferentiated tumor type.

Pediatric sarcomas are dominated by the osteosarcomas and Ewing’s sarcomas. The osteosarcomas have a peak incidence in patients in their second decade of life, and the age range begins at approximately 10 years. They predominately present in the extremities, and 15–20% of patients have pulmonary metastases at the time of diagnosis. In addition to prior radiation, the list of possible predisposing factors includes germ line p53 mutations, growth abnormalities, trauma, fetal and parental X-ray exposure. Metastases present at the time of diagnosis are prognostic of poor outcome. Treatment with intensive neoadjuvant chemotherapy results in 60–80% 5-year survival [5]. The treatment response rate and overall survival rate for pediatric sarcomas are significantly higher than that for adults with osteosarcomas.

Ewing’s sarcomas are also a bone tumor of adolescence with a peak incidence around the age of 15 years [5]. They most commonly present as a painful mass in the extremities and are often metastatic at presentation. Bone metastases (15–30% of patients), lung metastases, and soft tissue involvement adjacent to the primary tumor mass are common. Presumably, these tumors arise from postsynaptic neural crest precursors and are synonymous with the peripheral neuroectodermal tumors (PNETs), which occur more predominantly in soft tissues [5]. The presence of the EWS-FL1 fusion protein in the tumor confers poor prognosis. There are no known risk factors for causing these tumors, and they are rarely associated with other syndromes.

Patients with sarcoma have highly variable characteristics and clinical outcomes. Sarcomas are often multidrug resistant [6, 7]. The multidrug resistance systems are tissue transporters that remove toxins from tissues. Normally occurring in tissue epithelial linings in the intestines, kidneys, and blood-brain and placental barriers, their activity is unregulated in sarcomas [8, 9, 10]. This is a major cause of increased treatment failure and disease progression. The pathobiological basis of multidrug resistance activity and other sarcoma characteristics are complexities that are likely a result of a substantial variety of genetic abnormalities. These consist of broad categories of tumor-specific translocations that contribute to tumor diagnostic criteria and to sarcoma subtypes that have genetic and chromosomal instability [11]. Sarcomas in all body locations present unique challenges for diagnosis and management. These challenges have presented opportunities for evaluation and validation of new imaging techniques.

Approaches to Staging

Because sarcomas are difficult to risk stratify for outcome, staging systems have been devised to improve patient treatment and outcome. The American Joint Committee on Cancer (AJCC) criteria are often used clinically for staging soft tissue sarcoma patients (Tables 4 and 5). This system undergoes periodic analyses and revisions. The current AJCC soft tissue sarcoma system stratifies patient tumor by size (T1≤5 cm, T2≥5 cm). Additionally, the tumor is characterized by histologic grade (I–III), the presence or absence of nodal and distant metastasis, and special location descriptions. Revisions that have been suggested include categories for very large tumors (T3≥15 cm), specific primary tumor sites, tumor margin status, histologic subtypes, the presence or absence of tumor local recurrence, and specific markers for biologic aggressiveness.
Table 4

AJCC definition of TNM and stage grouping for soft tissue sarcoma

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor 5 cm or less in greatest dimensiona

T1a

Superficial tumor

T1b

Deep tumor

T2

Tumor more than 5 cm in greatest dimensiona

T2a

Superficial tumor

T2b

Deep tumor

Regional lymph nodes (N)

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1b

Regional lymph node metastasis

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasis

aSuperficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia

bPresence of positive nodes (N1) in M0 tumors is considered Stage III

Table 5

AJCC anatomic stage and prognostic groups for soft tissue sarcoma

Group

T category

N category

M category

 

Stage IA

T1a

N0

M0

G1,GX

 

T1b

N0

M0

Gl.GX

Stage IB

T2a

N0

M0

Gl.GX

 

T2b

N0

M0

G1,GX

Stage IIA

T1a

N0

M0

G2, G3

 

T1b

N0

M0

G2, G3

Stage IIB

T2a

N0

M0

G2

 

T2b

N0

M0

G2

Stage III

T2a, T2b

N0

M0

G3

 

Any T

Nl

M0

AnyG

Stage IV

Any T

Any N

Ml

AnyG

Sarcoma groups are incorporating these parameters in clinical practice more routinely each year. The pathologic tumor grade is an important component of any tumor staging system; however, there are pitfalls that exist in its application to individual patient tumors. The most widely used sarcoma grading system is the FNCLCC designed by the French Fédération Nationale des Centres de Lutte Contre le Cancer [12]. Even with well-defined grading systems, there are several challenges with grading soft tissue sarcomas. Tumors for which it is difficult to assign histologic grade because of their rare characteristics include tumors where the grade applied does not provide additional prognostic information beyond what is conferred from accurately determining the tumor histologic subtype. These include differentiated liposarcomas, the tumors that are considered “ungradable”; the epithelioid, clear cell, and angiosarcomas; and those where the histologic grade does not predict outcome well, such as the malignant peripheral nerve sheath tumors [13]. These findings reflect the heterogeneity of biological behavior in the sarcomas, and they provide the stimulus for incorporation of newer systems that integrate tumor characteristics from a number of different sources that identify patient risk for malignant behavior more accurately.

A comparative analysis of the AJCC, the Memorial Sloan Kettering Cancer Center system, and the Surgical Staging System of the Musculoskeletal Tumor Society soft tissue sarcoma staging systems found that schemes that include tumor depth, grade, and size are most predictive of tumor relapse in patients with extremity tumors. Wunder et al. suggest that these systems can be used to identify patients that are most likely to benefit from participation in adjuvant therapy trials [14].

Bone tumor staging follows the schemes utilized for other tumors, with a few notable exceptions. The primary tumor is assessed by whether it is confined to cortex (T1) or if it extends beyond this bone structure (T2) [15]. The tumor histologic type and grade predominate the staging criteria for prognosis. The presence or absence of distant metastases is also significant. As with soft tissue sarcoma staging, bone sarcoma staging includes a careful examination of the lungs to discover metastases, which are often present at the time of initial diagnosis. Inclusion of nomograms for improved prognosis has also been developed, and their use may help to improve selection of multimodality treatment for bone sarcoma patients [16].

Imaging plays an increasingly important role in sarcoma staging. All types of examinations – including plain films, chest X-ray, CT with and without contrast, MRI, and [18F]FDG PET – are now used routinely in combination to stage sarcoma patients and to restage patients when treatment decisions are contemplated. The bone scan is still used routinely because of its sensitivity in detection of bone metastases, although most sarcomas predominantly metastasize to the lungs. If necrosis or ossification is present in the lung metastasis, the lesion may appear as a focal region of low-level uptake in the pulmonary parenchyma. It is rare, however, to detect lung metastasis on a bone scan that is not visible on CT. Several types commonly have associated bone metastases, such as the osteosarcomas, Ewing’s sarcomas, and highly undifferentiated tumors. Imaging methods and their uses in sarcoma management are discussed more thoroughly in the following sections.

Radiopharmaceuticals

Disease staging in sarcoma involves all aspects of imaging the body with radiopharmaceuticals. Since these tumors vary considerably in their presentation, local recurrence rates, and patterns of metastatic spread, different imaging studies that provide complementary information for disease staging are used in clinical practice. These are for characterizing the extent of tumor; presence of bony, lymph node; and soft tissue metastases. Some tumor types involve multifocal primary disease presentation, synchronous tumors, and skip metastases. In most sarcoma clinics, a combination of nonspecific, highly sensitive, and tissue-specific imaging agents is used in diagnosis, staging, response, and restaging aspects of patient management.

99mTc-MDP

The bone scan is widely used in oncology for staging the skeleton for the presence of bony metastases. Sarcoma metastases generally show osteoblastic behavior and are less likely to show lytic metastases. For soft tissue masses, the bone scan is also a standard part of disease staging. Patients with bony metastases show increased uptake in typical metastatic disease patterns in the axial skeleton and extremities. The presence or absence of uptake is often diagnostic in separating benign or locally aggressive tumors from malignant types. Bone scans also have special utility in primary bone tumors. These tumors form malignant osteoid matrices that are undergoing disordered calcification; therefore, they are 99mTc-MDP avid (Fig. 1). Both the osteosarcomas and some chondrosarcomas with osteoblastic differentiation contain malignant osteoid. Ewing’s sarcomas cause bone destruction and reaction that result in bone scan positivity. Primary bone tumors have frequent bone metastases and can present with skip lesions in the affected bone. The osteosarcomas also frequently have bone metastases, but bone scan positive appearance in multiple sites is also common in Ewing’s sarcoma. In this latter group of tumors, metastases are often present at the time of diagnosis.
Fig. 1

(a) Bone of the right ankle showing a Ewing’s sarcoma. There is marked uptake in the proximal foot. (b) Plain x-ray image of the right ankle shows fibular involvement with soft tissue extension

The bone scan is a sensitive method for identifying osteosarcoma pulmonary metastases (Fig. 2). These are often highly 99mTc-MDP avid. Some clinicians use the relative decrease in 99mTc-MDP uptake in pulmonary metastases as an indicator of treatment response and suitability for wedge resection metastasectomy. In osteosarcoma patients with limited pulmonary metastasis, this procedure has been shown to increase disease-free survival [17]. The 99mTc­MDP scan has been reported to contribute to the diagnosis of bone-forming malignant tumors by revealing unusual sites and presentations. The 99mTc-MDP bone scan is also a means of monitoring treatment response. A decrease in malignant osteoid matrix calcification indicates a response to treatment in this cellular portion of the tumor. The bone scan appearance in metastatic disease, as with other tumors, can also underestimate the extent and severity of skeletal metastases. In these cases, the metastases involving the bone may only be apparent when a cortical reaction occurs. Subsequent other whole-body surveys such as CT or [18F]FDG PET may provide a complimentary picture of the extent of diseased skeleton [18].
Fig. 2

Bone scan in a patient with active osteosarcoma pulmonary metastases

201TI-Chloride

201TI-Chloride as a nonspecific tumor imaging agent has been described for use in many tumors, including sarcoma. Most often, higher uptake is noted in malignant tumors, while lower uptake more frequently signifies benign neoplasms. Soft tissue, bone, and cartilaginous tumors have all shown positivity [19]. Typical high-grade tumor features, such as central necrosis, can also be noted in 201Tl-chloride imaging; this finding is predictive of decreased survival [20].

18F-Fluoride

18F-Fluoride is increasingly being used as a sensitive bone scanning agent for metastatic surveys for many cancers. Recent imaging study results indicate that a combination of [18F]FDG and 18F-fluoride may provide a more complete visualization of bone metastases than either agent alone. This is also the case for sarcomas; however, the use of 18F-fluoride may extend beyond the detection of metastases in bone sarcomas. Since the hallmark of these tumors is new bone formation, uptake of 18F-fluoride will likely change in response to therapy. A particular use may be in evaluating activity in lung metastases since it is common practice to resect lung metastases when they are quiescent after successful chemotherapy. Figure 3 shows a whole-body 18F-fluoride bone scan.
Fig. 3

Whole Body [F18]Fluoride PET bone scan

[18F]FDG and Sarcoma Diagnosis

Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) has been evaluated for use in sarcoma imaging . Imaging in primary cancers has several critical aspects for patient treatment planning. It is used to determine the biological behavior of the tumor, often determining if the tumor is benign or malignant; however, sarcomas include numerous tumors that do not fit well with either category because they can be locally aggressive, yet rarely metastatic. Using a combination of tumor histopathology from biopsy and imaging data is helpful in determining the tumor grade, which is the propensity of the tumor to behave aggressively.

Several retrospective studies and meta-analyses describe the utility of [18F]FDG PET in sarcoma clinical practice. It is recommended as a part of the clinical work-up for a patient undergoing diagnosis, disease staging, and treatment planning [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32]. Numerous studies describe [18F]FDG PET utility in both soft tissue and bone tumors as well as rhabdomyosarcomas and Ewing’s tumors in the pediatric population [33, 34, 35, 36, 37].

Tumor grade describes the probability of a tumor to exhibit malignant biological behavior. This implies patient outcome and survival. Following early studies in mixed sarcoma populations, additional studies have correlated patient prognosis with [18F]FDG PET tumor uptake measures prior to therapy. These have established [18F]FDG PET imaging in sarcomas as an independent biomarker for tumor risk stratification [30, 38, 39, 40, 41, 42, 43, 44]. Additional refinements in imaging techniques such as tumor uptake measures by dual-time point imaging, reporting tumor SUVmax versus total lesion glycolysis, necrosis volume, and combination with MR imaging characteristics may provide improvements in prognostic capabilities [45, 46, 47, 48, 49, 50, 51].

Several prospective and retrospective studies have described histologic type determined from the utility of [18F]FDG PET in sarcoma diagnosis. In soft tissue sarcoma, this imaging can reliably distinguish low-grade from high-grade tumors [52, 53, 54]. There is less ability to discriminate benign from low-grade tumors or intermediate-grade types from either high-grade or low-grade processes. Low-grade tumors are often difficult to distinguish through histologic criteria as well. Combinale et al. found that [18F]FDG PET could be used to identify malignant transformation in patients with neurofibromatosis type 1 (NF1) [55]. This finding implies that [18F]FDG PET could be used for other benign mesenchymal tumor conditions such as enchondromatoses and Paget’s disease where malignant transformation is a potential occurrence in existing masses. [18F]FDG PET has been used for effective tumor staging. It can be used to identify bone and soft tissue metastases and nodal metastases in those types where they occur (epithelioid and synovial sarcomas). While lung metastases are the most common site of metastases in patients with high-grade tumors, these are often small and are not visualized on [18F]FDG PET. For this reason, a complete staging examination for both soft tissue and bony sarcomas also consists of a high-resolution contrast chest CT scan.

Additionally, special features and [18F]FDG uptake are related to specific histologic types. For example, the atypical lipomas and the low-grade liposarcomas may have very similar tissue features and biological behavior. They often result in repeated local recurrence; nevertheless, in a large mass, the [18F]FDG appearance can be significant for identifying small areas of high-grade de-differentiation, which can lead to a much worse outcome than the low-grade majority of the tumor mass composition. Figure 4 shows several [18F]FDG PET examples of primary sarcoma tumors.
Fig. 4

Primary sarcoma presentations. (a and b) [F18]FDG PET and contrast CT of a patient with an unusual calcifying abdominal liposarcoma. (c) [F18]FDG PET right ankle Ewing’s sarcoma, [d] [F18]FDG PET left proximal humerus high grade undifferentiated soft tissue sarcoma with nodular extensions

The [18F]FDG image can also be helpful in identifying areas for diagnostic biopsy. Soft tissue sarcomas can be highly heterogeneous in their histologic characteristics, a feature which often confers heterogeneity in [18F]FDG spatial uptake distribution. These unique tumor features may account for high levels of treatment resistance and variable responses to multimodality therapy. Spatial heterogeneity in sarcoma uptake has been shown to be independently predictive of patient outcome. This finding reported by Eary et al. found that baseline [18F]FDG in diagnostic scans and tumor grade were somewhat weaker in outcome prediction, suggesting that new methods for incorporating [18F]FDG tumor uptake distribution and for incorporating SUV into diagnostic methods for sarcomas can provide significant tumor prognostic information [56]. Additional image analyses such as texture feature extraction may also provide important diagnostic and prognostic information [57]. Figure 5 shows several tumors with high levels of [18F]FDG uptake heterogeneity.
Fig. 5

(a-d) Primary sarcomas with high levels of spatial heterogeneity in [18F]FDG uptake

Sarcoma Treatment

Soft tissue sarcoma treatment plans are determined primarily by tumor grade. Large intermediate-grade and high-grade soft tissue sarcomas often receive neoadjuvant doxorubicin-based chemotherapy with or without preoperative radiation. After resection, if a response was obtained based on percent tumor necrosis in the resected tumor, adjuvant therapy is started. If an adequate response was not obtained, an alternative regimen usually replaces the ineffective treatment. Bone tumors are also treated through clinical protocols that have varying durations for neoadjuvant treatment, depending on patient age. Pediatric patients receive the most intense therapy, which yields good long-term outcome rates. Ewing’s sarcoma patients also participate in protocol studies, and therapy with bone marrow transplant is considered in some advanced cases.

[18F]FDG in Sarcoma Restaging and Treatment Response

A review of cancer treatment response for sarcoma as with other cancers begins with consideration of the pathological basis of the tumor process. Sarcomas are complex pathobiologic processes that may exhibit a wide range of blood flow, cell proliferation rate, cell viability, inflammation, pH, oxygenation, and numerous other processes. Because of these processes, treatment response can differ significantly from a standard treatment combination or from treatments with different mechanisms of action. The ability of [18F]FDG PET to identify treatment response is an important goal for the sarcoma patient population.

These tumors often do not change size in response to neoadjuvant chemotherapy because they can be composed of tissue elements that do not change in tumor response or undergo very slow changes in size reduction, such as in bone, cartilage, scar, and myxoid areas. Consequently, the RECIST criteria for treatment response do not apply well to this group, and [18F]FDG has an advantage, as described by Evelevitch [58]. In this work, a 60% decrease in tumor [18F]FDG uptake compared to baseline had a sensitivity of 100% and a specificity of 71% for histologic response, whereas RECIST criteria for response applied to the same group showed a sensitivity of 25% and a specificity of 100% [59, 60]. In sarcoma clinical practice, tumor treatment response assessments must provide information on the nature and timing of response.

Since clinical and histopathological response evaluations can be subjective, imaging tumor response quantitatively can provide clinically relevant objective information for treatment planning. For sarcoma patients where treatment choices are limited and often highly toxic, newer therapies that are directed at specific molecular targets may be cytostatic and result in tumor growth arrest, which can be observed effectively with [18F]FDG PET. These changes may indicate effective therapy for a patient, as opposed to direct cell killing mechanisms and tumor shrinkage, and they may indicate improved patient outcome [61].

Tumor cellular necrosis fraction is considered the hallmark of treatment response to chemotherapy in sarcomas; however, overinterpretation of tumor cellular necrosis in a tumor specimen may result in cases where necrosis was present as a distinguishing feature of the primary tumor. Figure 6 shows an example of a primary sarcoma where significant necrosis is present prior to therapy. Scarring is a common treatment response and is also common in radiation treatment. Compared to necrosis, scarring as a treatment response is metabolically active and can cause significant [18F]FDG uptake. In cases where granulation tissue formation precedes scarring, the inflammatory cells present may also elevate the apparent tumor bed tissue metabolism. Activated white cells can show as much as a tenfold difference in [18F]FDG uptake, complicating image interpretation. An important part of treatment response interpretation in sarcoma is identifying the treatment agent mechanism, tumor subtype, and timing of the scan observation in relation to the course and type of treatment. Early after therapy, observations may reveal very different findings from those obtained after the biological mechanisms involved in treatment response have reached a more static state. Radiation responses to tumor and surrounding tissues may have very different timescales in relation to the end of the final therapy response. Early detection of treatment response that indicates improved patient outcome with newer therapies is an area of active research.
Fig. 6

Primary pelvic sarcoma with a large central area of tumor necrosis at presentation

Many groups advocate the use of the [18F]FDG PET tumor SUV to measure sarcoma uptake and to monitor treatment response [58, 61]. If the [18F]FDG PET study is performed in a standard and consistent manner, the SUV is a robust value for comparison of one imaging study to another in the same patient at a later time and between patients in different groups. The optimum parameters for [18F]FDG imaging in cancer were described in a report of a National Cancer Institute consensus committee where standard techniques for the use of [18F]FDG as a biomarker for cancer treatment are presented [62]. The use of [18F]FDG PET as a biomarker or surrogate endpoint for patient outcome is the basis for clinical research studies that determine the sensitivity and specificity of the method for following response to treatment and for assessing normal tissue damage as a result of treatment. Few effective treatment strategies exist for sarcoma, yet there is a great potential for new therapy strategies. [18F]FDG PET can be a powerful tool for noninvasive treatment effectiveness evaluation [63, 64, 65, 66].

The most dramatic example of [18F]FDG PET as a biomarker for treatment response assessment is in gastrointestinal stromal tumors (GISTs) treated with Gleevec. GISTs are [18F]FDG avid and can yield impressive PET images. Goerres et al. found that median survival of patients who demonstrated an [18F]FDG PET response was 100% at 2 years compared to a group with residual tumor uptake after treatment. The study also demonstrated ability to separate patients by time to tumor progression based on [18F]FDG tumor uptake levels [67].

Early response to Gleevec in the GIST population detected by [18F]FDG PET has also been shown. As much as a 65% decrease in tumor [18F]FDG uptake was demonstrated at the end of 1 week of effective therapy, and as high as a 95% response detected by 1 month after treatment initiation has been found by other groups. Response detection using CT criteria was less accurate, including no significant CT responses noted in [18F]FDG-responsive patients [68, 69, 70, 71, 72, 73]. [18F]FDG PET imaging for GIST patients at baseline to observe for maximum tumor activity levels and for accurate staging is recommended. Repeat imaging is suggested in the first month after therapy initiation to observe response and to predict treatment effect. Another image may be helpful if treatment resistance is suspected and if a new baseline tumor uptake and location for treatment observation need to be established. [18F]FDG imaging for GIST treatment response evaluation has been incorporated into the guidelines for GIST management determined by an international consensus conference [74].

Treatment response in other sarcomas using [18F]FDG PET has been demonstrated in a number of studies. Soft tissue sarcomas represent the majority of sarcomas that occur in adults. Treatment response imaging for this group of patients is emerging [75, 76, 77, 78, 79]. In an extremity soft tissue sarcoma group treated with adriamycin-based neoadjuvant chemotherapy, Scheutze et al. showed that separating patients by their [18F]FDG response (>40%) showed a significant difference in survival for each of the groups [80]. Patients in the [18F]FDG PET nonresponse group had a 90% risk of disease recurrence at 4 years compared to [18F]FDG responders. These data, and that of others, may indicate the effectiveness and survival increase in soft tissue sarcoma patients treated with neoadjuvant chemotherapy prior to tumor resection. Figure 7 shows an example of a patient who had a treatment response documented by [18F]FDG PET for neurofibrosarcoma in the base of the neck. This imaging technique may be useful for patients who have tumor resistance during the course of therapy and, therefore, might benefit from treatment intensification or early resection.
Fig. 7

Two examples of sarcoma tumor treatment [18F]FDG PET responses. Shown in (a) is a patient with a right neck base malignant nerve sheath the tumor prior to neoadjuvant chemotherapy. (b) Response in base of neck tumor. (c) [18F]FDG PET image of a patient with a large high grade proximal thigh tumor. (d) Lack of response in large high grade proximal thigh tumor, with sacral metastasis development

A similar finding was shown in Ewing’s sarcoma population reported by Hawkins et al. [81]. Patients whose tumors increased SUV ratios between the baseline and pre-resection (after neoadjuvant chemotherapy) scans had significantly improved survival. In the future, good responders may be identified for less toxic treatment protocols. Studies in imaging osteosarcoma for treatment response have also been conducted. Early studies by Schulte et al. showed that changes in tumor [18F]FDG uptake correlated with tumor necrosis levels in patients treated with neoadjuvant chemotherapy. Implications for limb salvage surgery were described because such complex tumor resection procedures might not be considered in nonresponders [82]. Others have recently shown similar results for [18F]FDG imaging in osteosarcoma [83, 84].

Pediatric sarcomas are usually bony tumors, but they have been separated in studies because the treatment for pediatric patients differs compared to protocols for adults. Similar to their findings in Ewing’s sarcomas in this mixed group of osteosarcoma and Ewing’s sarcoma patients, Hawkins et al. found that the ratios in [18F]FDG uptakes correlated with histologic response [85]. Noting a need for prospective imaging studies to be conducted in the pediatric sarcoma populations, both Franzius et al. and McCarville et al. published data on small pediatric sarcoma subgroups to demonstrate the clinical utility of [18F]FDG imaging [86, 87]. The latter group included a rhabdomyosarcoma subgroup, a tumor subtype where most patients are treated under cooperative group therapy protocols. Correlation of longer survival with [18F]FDG changes in response to therapy in a large pooled patient group retrospective study in patients with rhabdomyosarcomas has been published showing similar results.

[18F]FDG imaging in treatment response can make a significant contribution to sarcoma patient care in identifying clinically relevant responses, or a lack thereof, and in providing predictive information for patient outcome. Although sarcomas are a less frequent form of malignancy in the population, they affect the entire human age span, and they constitute a large number of affected individuals in aggregate. Currently, treatment for the more aggressive high-grade tumors and for locally recurrent low-grade tumors often results in less than optimum treatment outcomes. Future clinical trials for newer treatment combinations for sarcoma patients will benefit from the incorporation of [18F]FDG PET imaging treatment response information as a part of their treatment strategies, as they have for patients with other cancer types. For the individual patient, [18F]FDG PET can provide critical information about treatment response and indicate further treatment planning. Increasingly for patients with standard therapy refractory disease, [18F]FDG PET has been effective in identifying response to newer combination treatments and experimental therapy clinical trials. Recent experience described by Andreou et al. demonstrated that [18F]FDG PET SUVmax in soft tissue sarcoma response to combination neoadjuvant isolated limb perfusion and TNF was correlated with response [88]. Similar imaging results have been reported in trials with sunitinib in extraskeletal myxoid chondrosarcoma [89], desmoid tumors with imatinib [90], insulin-like growth factor 1 in Ewing’s sarcoma [91], and regional hyperthermia for soft tissue sarcomas [92]. Often these imaging observed responses predicted overall survival [93, 94].

Although currently there are no specific recommendations for [18F]FDG PET in sarcoma patient care, the findings from the previously summarized reports indicate that baseline [18F]FDG PET is important for contributing information for disease grade and staging that complements other imaging and histologic diagnostic information. This information aids in treatment planning and sets the baseline quantitation for tumor metabolic activity for treatment response assessment. Treatment response assessment with [18F]FDG PET recommendations would be similar to those in other solid tumors. Approximately every 3 months on treatment, or when a change in treatment is envisioned, [18F]FDG PET imaging results can be especially helpful when complete response or treatment nonresponse is suspected, as it provides objective information on tumor viability. Table 6 describes suggestions for sarcoma evaluation and treatment response imaging.
Table 6

Suggested lines of imaging procedures for sarcomas in patient care

Staging

Soft tissue sarcomas

Bone sarcomas

 

MR of tumor region

MR and plain x-ray of tumor area

[18F]FDG PET

[18F]FDG PET and18F-fluoride PET

Whole body

Whole body

99mTc-MDP bone scan

99mTc-MDP bone scan

Whole body

Whole body

Lung CT with contrast

Lung CT with contrast

Treatment response

 

MR of tumor region

MR of tumor region

[18F]FDG PET

[18F]FDG PET and18F-fluoride PET

Whole body

Whole body

99mTc-MDP bone scan

99mTc-MDP bone scan

Whole body if positive at baseline

If lungs positive at baseline

Lung CT with contrast

Lung CT with contrast

PET/MR imaging experience in sarcomas is emerging. Current reports indicate that potential utility in sarcoma surgical resection planning may be improved with the better tumor edge detection provided by this imaging combination [95].

Other PET radiopharmaceuticals that are more specific than [18F]FDG for biologically relevant aspects of sarcomas are under investigation in the sarcoma population. Determination of levels of tumor hypoxia is a measurement with clinical significance for many tumors, including sarcoma [96, 97]. Hypoxia is known to confer resistance to both radiotherapy and chemotherapy in sarcomas. Most sarcomas have some level of hypoxia present that confers treatment resistance. Newer therapies that target hypoxic tumor tissues after identification of these regions may improve patient outcome. PET radiopharmaceuticals designed to quantify tumor proliferation will also play an important role in sarcoma patient diagnosis and treatment assessment [98, 99]. Since sarcomas are a highly variable group of tumors, with similarly variable clinical outcomes, their cellular proliferation levels likely indicate increased risk of metastasis and poor clinical outcome. Sarcoma patients are likely to benefit from these more biologically specific imaging techniques that may provide insight regarding treatment effectiveness. Molecular imaging research efforts in PET are directed toward identifying tumor characteristics that can be used to define patient risk for aggressive disease behavior and for noninvasive treatment monitoring.

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Suggested Reading

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Cancer Imaging ProgramNational Cancer Institute, National Institutes of HealthBethesdaUSA

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