Patient preparation

All patients must fast for at least 4 h before an ¹⁸ F-FDG PET/MRI scan. Directly before the ¹⁸ F-FDG radiotracer injection, we confirm that the blood glucose concentration is below 175 mg/dL.

Radiotracer

We typically inject 3 MBq/kg of ¹⁸ F-FDG; followed by a radiotracer uptake time of 45 min. Considering the time to place the patient in the PET/MRI scanner and apply the surface coils, the PET scan starts 60 min after injection. The effective dose from the ¹⁸ F-FDG injection can be calculated using the age-specific conversion factors published by the International Commission on radiological protection ( ). While the main radiotracer for pediatric PET/MRI is ¹⁸ F-FDG, a few alternate radiotracers can be advantageous for specific clinical questions and will be discussed ahead.

PET/MRI protocol

To set up a time-efficient protocol, whole body axial PET acquisition slabs (25 cm axial field-of-view; 3–4 min per slab) are our time-limiting step. Each bed position is subsequently “filled” with suitable MRI sequences. Different investigators suggested a wide variety of T1-and T2-weighted sequences for anatomical coregistration of ¹⁸ F-FDG PET data in children ( ; ; ; ; ). Pediatric tumors can be equally well delineated on Gd-enhanced (CE) T1-weighted scans and unenhanced T2-weighted scans ( ). However, intravenous contrast improved vessel and tumor delineation compared to unenhanced T1-weighted scans, especially when faster T1-weighted sequences were applied. We found CE T1-weighted gradient-echo scans particularly useful for accurate tumor measurements and surgical planning. Therefore, our WB staging protocol always includes CE breath-hold Liver Acquisition with Volume Acquisition (LAVA; 3D Fast Spoiled Gradient Echo) sequences for anatomical coregistration of PET data. These CE scans are acquired sequentially or simultaneously, depending on the contrast agent used (see below). In addition, we acquire axial in and out-of-phase T1-weighted LAVA sequences for attenuation correction and diffusion-weighted imaging (DWI) sequences simultaneously with PET. After completing the WB scan, we add an axial periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) sequence through the lungs to screen for lung nodules. Note that both MRI and PET have limited sensitivity for the detection of subcentimeter pulmonary nodules ( ). Finally, we apply a surface coil and add T1-and T2-weighted Fast Spin Echo (FSE) sequences in appropriate orientations for local staging of the primary tumor. PET data are reconstructed using a 3D time of flight iterative ordered subsets expectation-maximization algorithm (24 subsets, three iterations, temporal resolution =400 px, matrix 256 × 256: voxel size 2.8 × 2.8 × 2.8 mm), accounting for attenuation from coils and patient cradle.

MRI contrast agent

The MRI component of a PET/MRI is often enhanced with gadolinium (Gd)-chelates. When using gadolinium chelates, we perform (1) head-to-toe axial PET and DWI images, followed by Gd-injection, and (2) a second series of head-to-toe LAVA sequences. Considering the growing concern about Gd deposition in the brain, we have introduced the iron oxide nanoparticle compound ferumoxytol (Feraheme) as a contrast agent. Ferumoxytol is FDA-approved as an iron supplement for treating anemia in adult patients and can be used “off-label” as a contrast agent for MRI and PET/MRI. Ferumoxytol provides a long-lasting vascular enhancement for the entire duration of a WB scan and, therefore, can be integrated into the protocol (1) above, eliminating the need for Gd (2). Ferumoxytol enhanced MRI added value to ¹⁸ F-FDG PET scans by providing anatomical detail and facilitating the differentiation between reconverted hematopoietic marrow and bone marrow metastases ( ). Nanoparticle-enhanced ¹⁸ F-FDG PET/MRI might also improve tumor response assessments to immunotherapies ( ; ).

Clinical background

Lymphomas comprise up to 10% of newly diagnosed cancers in children (0–14 years) and up to 23% of newly diagnosed cancers in adolescents (15–19 years). Lymphomas are classified as Hodgkin (HL) or non-Hodgkin lymphoma (NHL) ( ). HL has an overall incidence of 1.3 per 100,000 cases ( ), is the most commonly diagnosed cancer in adolescents ( ), and is twice as common in boys as in girls aged 0–14 years, (0.8 vs. 0.4 per 100,000 cases, respectively) ( ). Histological classification of HL includes nodular lymphocyte-predominant (5% of HL cases) and classic HL (95% of HL cases). Classic HL is subcategorized as nodular sclerosis, mixed cellularity, lymphocyte depleted, and lymphocyte-rich ( ). In contrast to HL, while the overall incidence rate of NHL is 1.3 per 100,000 cases, NHL has a higher incidence in male children and adolescents (1.8 M vs. 0.8 F per 100,000 cases, respectively) ( ). According to the World Health Organization (WHO) classification, NHL is phenotypically classified as B cell, including Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL), T cell, and natural killer (NK) cell NHL ( ). The overall survival rate of HL is significantly higher than NHL ( ).

Diagnosis

Early diagnosis and correct staging of lymphoma can improve optimized therapies and thereby maximize survival. HL staging is performed using the modified Ann Arbor staging system ( ), while the staging of NHL is based on the St. Jude classification ( ). The Lugano classification is simplified and applies to both initial staging and subsequent follow-up ( ). Imaging plays a critical role as the disease stage will determine the treatment ( ). ¹⁸ F-FDG PET/CT has been established as the standard technique for WB staging of lymphoma ( ). MRI, compared to CT, can potentially detect additional lesions in the case of involvement of bones, bone marrow, and soft tissues. ¹⁸ F-FDG-PET helps to identify tumors based on their high ¹⁸ F-FDG avidity. This feature resulted in the incorporation of ¹⁸ F-FDG-PET/MRI in the staging of lymphoma and can replace bone marrow biopsies in evaluating bone marrow metastases ( ; ).

18F-FDG-PET/MRI

While ¹⁸ F-FDG-PET could be combined with both CT and MRI for attenuation correction and anatomical coregistration of radiotracer data, utilizing MRI as an ionizing radiation-free modality can reduce the radiation exposure ( ). In both HL and NHL ¹⁸ F-FDG-PET/MRI ( Fig. 6.1 ) has proven to be a reliable and lower radiation dose alternative to ¹⁸ F-FDG-PET/CT ( ).

Fifteen-year-old patient with Burkitt Lymphoma.

(A) Whole-Body PET MIP; abnormal metabolic activity in the right cervical soft tissues and at multiple osseous sites in bilateral upper and lower extremities. (B–D) Axial PET/CE T1-weighted MRI fusion images demonstrate FDG-avid lymphomatous involvements of the left frontal bone (B), right parapharyngeal and carotid spaces (C), spongiosa of right femur and cortex of the left femur (D).

Diffusion-weighted imaging (DWI) has been utilized for the WB staging of lymphoma in adults and children ( ; ). WB DWI could be easily integrated into tumor staging protocols for pediatric lymphoma patients ( ). The addition of DWI improved staging agreement with FDG-PET/CT ( ). Furthermore, in staging pediatric patients with lymphoma, Littooji et al. introduced WB DWI as a radiation-free alternative to FDG-PET/CT ( ). DWI results in higher sensitivity and accuracy in diagnosing specific subtypes of lymphomas, for example, MALT lymphomas, which have variable or no FDG uptake ( ).

DWI could also be utilized to predict clinical response at the end of treatment. Concordant changes of DWI and ¹⁸ F-FDG uptake tend to correlate with the response at the end of treatment in pediatric lymphoma patients. Moreover, several patients may demonstrate partial or complete responses also on interim scans ( ). Interim-apparent diffusion coefficient (ADC) can also help recognize nonresponder lesions in HL patients ( ).

Clinical background

Ewing sarcoma, the second most common bone malignancy in the pediatric population ( ), has an incidence of 1–3 cases per 10 ⁶ children and accounts for approximately 3% of pediatric malignancies. Ewing sarcoma family of tumors comprises classic osseous Ewing sarcoma of the bone, primitive neuroectodermal tumor, and Askin tumor. They all share a common translocation between chromosomes 11 and 22 and contain similar small round blue cells ( ). At diagnosis, 15%–46% of patients present with distant metastases ( ). Despite recent advancements in treatment, the overall prognosis remains poor (5-year survival rate of approximately 25%–30% in metastatic patients).

Diagnosis

Classic osseous Ewing sarcoma can affect any bone but predilects the femur, ilium, tibia, humerus, fibula, ribs, and sacrum. Ewing sarcomas of the long bones are often diaphyseal and demonstrate aggressive permeative destruction with associated soft tissue components. Before cross-sectional imaging, a radiograph of the primary tumor should be obtained. On radiographs, the typical pattern would be that of a nongeographic, permeative, and moth-eaten appearance with a wide zone of transition, usually accompanied by cortical destruction, soft tissue components, and characteristic onion skin or hair on end periosteal reaction ( ). The absence of tumor osteoid helps to differentiate it from osteosarcoma.

18F-FDG-PET/MRI

MRI imaging features closely mirror the radiographic findings: a large permeative soft tissue component extending from the bone marrow through the cortex. The soft tissue component usually demonstrates homogeneous and intermediate T1w signal and homogeneous low to intermediate T2w signal, secondary to the high cellularity of this tumor ( ). Larger lesions can be heterogeneous with central hemorrhage and necrosis. Enhancement may be homogeneous or peripheral and nodular. Spiculated subperiosteal low signal corresponds to the radiographic hair on end periosteal reaction.

On ¹⁸ F-FDG-PET, the tumor may show areas of up-regulated glucose metabolism which correlate with its biological aggressiveness. ¹⁸ F-FDG-PET can help to decide the areas to biopsy.

Areas of metabolic activity may or may not overlap with areas of diffusion restriction. However, a high degree of overlap is indicative of highly aggressive sarcomas. Besides local staging, ¹⁸ F-FDG-PET/MRI also provides excellent WB staging ( Fig. 6.2 ). Metastases are hematogenous and predominantly hit the lungs and bone marrow ( ). FDG-PET combined with MRI is sensitive even for subtle bone marrow metastases. Since osseous metastases in Ewing sarcoma are lytic, PET has better sensitivity in detecting such hypermetabolic lesions than bone scans ( ). One of the limitations of the PET/MRI is identifying subcentimeter pulmonary metastases which are not metabolically active ( ). Mean SUV values of the primary tumor range from 5.3 for patients with no metastases at presentation to 11.3 for patients with metastases at presentation ( ).

Eight year-old patient with left scapular Ewing sarcoma.

(A) WB PET MIP; (B) WB T2w fat saturated (FS); (C) Fused PET/WB T2w MRI demonstrating a large, infiltrative, heterogeneously T2w hyperintense and FDG avid mass ( arrow ) arising from left scapula.

Assessment of treatment response using MRI alone is less accurate since only minimal morphological changes may be evident despite significant tumor viability reduction ( ). FDG-PET allows better detection of progression or response since the biochemical changes in the tumor occur before morphological changes ( ; ).

Clinical background

Osteosarcomas, the most common primary malignant bone tumors in the pediatric population, arise from mesenchymal stem cells or from committed osteoblast precursors ( ). They are characterized by the production of osteoid tumor matrix. According to WHO, they are classified into eight different subtypes: conventional, parosteal, periosteal, telangiectatic, small cell, low-grade central, secondary, and high-grade surface ( ). Other uncommon subtypes include gnathic osteosarcoma and osteosarcomatosis, not included in the WHO classification. This discussion is focused predominantly on conventional osteosarcoma, the most common subtype.

Diagnosis

Common sites of involvement include the metaphysis of the long bones, predominantly of the distal femur, proximal tibia, proximal humerus, and proximal femur. Other bones, such as the pelvis and mandible, can also be involved. Primary osteosarcoma of the wrist and ankle are extremely rare. On the radiographs, it usually presents as a sclerotic, nongeographic aggressive and permeative mass with a sunburnst periosteal reaction ( ).

18F-FDG-PET MRI

Initial staging

Evaluation for potential involvement of adjacent joints, muscles, and neurovascular structures plays a major role for planning local tumor resection. These features are depicted with exquisite details by MRI. It is important to evaluate the adjacent vasculature for tumor thrombosis by assessing flow voids and enhancement patterns. Occasionally, linear FDG uptake along the vessels, corresponding to the tumor thrombus, can be visualized ( Fig. 6.3 ).

Sixteen-year-old patient with right distal femoral osteosarcoma.

(A) WB-PET MIP; (B) WB fused coronal PET/T2w MRI; (C) fused axial PET/CE T1w MRI. A right distal femoral OS ( arrow ) demonstrated increased FDG uptake. Linear activity along the medial aspect reflects popliteal artery vascular invasion (A). In (C), synovial enhancement and FDG uptake ( arrow ) represent involvement of the knee joint.

On MRI, skip lesions can be diagnosed as areas of abnormal marrow signal, marrow replacement, or enhancement. Diagnosing skip lesions on MRI becomes challenging in patients with physiologic red marrow changes which show high T2w, low T1w signal, and contrast enhancement. In such instances, FDG-PET can diagnose metabolically avid skip lesions.

Osteosarcomas metastasize early and hematogenously, particularly to bones and lungs. Since PET/MRI is limited in assessing lung metastases, chest CT is included for staging ( ).

Treatment monitoring

Since sarcomas do not demonstrate significant reduction in size posttreatment, PET can provide important prognostic information. Percentage necrosis on histology may used for quantifying treatment response ( ).

Clinical background

Soft tissue sarcomas constitute about 7% of all solid pediatric tumors ( ). Rhabdomyosarcoma is the most common subtype. They arise from the mesenchymal cells and can differentiate and dedifferentiate into multiple cell lineages. A single soft tissue mass can contain more than one histotype; therefore, these lesions are classified according to the predominant component. Moreover, long-standing indolent benign-appearing lesions can differentiate and dedifferentiate into malignant ones; one such example is the low-grade liposarcoma-atypical lipoma spectrum.

Diagnosis

MRI allows the assessment of various morphologic features including size, shape, margins, and internal characteristics, such as necrosis, fibrous tissue, calcium, blood degradation products. Furthermore, DWI can highlight the areas of hypercellularity, and contrast enhanced sequences can highlight the areas of neovascularity and active cellular proliferation. The excellent soft-tissue contrast of MRI is also advantageous to evaluate the local extent of disease, for example, involvement of neurovascular bundles, which could alter the surgical management.

Size, shape, and margins have limited utility in differentiating benign from malignant soft tissue tumors. However some imaging features can help narrow the differential. While some benign entities such as hemangiomas, vascular malformations, lipomas, ganglions, schwannomas, and elastofibromas can be usually diagnosed with confidence based on imaging, in other instances, biopsy is needed.

Although MRI is excellent for the initial diagnosis and staging of soft tissue sarcomas, evaluating previously treated areas becomes challenging. PET is particularly useful in such cases. The combination of the morphological MR details with the metabolic PET data is advantageous ( ). PET/MRI results in higher detection of soft tissue sarcomas compared to MRI or PET alone and is the ideal hybrid imaging tool to assess for recurrence after treatment.

Rhabdomyosarcoma (RMS)

Rhabdomyosarcoma is an aggressive tumor that may arise from almost any part of the body except from bones ( ). It is the most common pediatric soft tissue sarcoma accounting for 4% of the cases. Three major histological subtypes are embryonal, alveolar, and pleomorphic types ( Fig. 6.4 ).

Four-year-old female with intra-abdominal rhabdomyosarcoma.

(A) WB PET MIP; (B) T2-weighted FS, and (C) fused PET/T2-weighted MRI. A large intraperitoneal complex cystic lesion ( arrow ) demonstrates abnormal FDG uptake and corresponds to pathology proven sarcoma.

Synovial sarcoma

Synovial sarcomas don’t originate from the joints but adjacent to the joints, most commonly around the knee. On MRI, the triple signal (high, intermediate, and low or “bowl of grapes” appearance on T2-weighted sequences) occurs in 35%–57% of synovial sarcomas; it is suggestive but nonspecific of SS since it might also be seen in other neoplasms, such as malignant fibrous histiocytoma. The intermediate signal is due to solid elements, the high signal to hemorrhage or necrosis, and the low signal to calcified or fibrotic components. On T1-weighted sequences, the lesion appears as a heterogeneous soft tissue mass, slightly hyperintense than muscles. Blood-fluid levels can also be visualized. Concurrent evaluation of the radiographs is essential since 30% of them may have eccentric calcifications. Involvement of the adjacent bone is rare ( ).

Desmoplastic small round blue cell tumor (DSRCT)

DSRCT most often occurs in young male patients. The predominant pattern is multifocal bulky nodular omental or peritoneal masses without a definitive organ of origin and occasional calcifications ( ). The primary site is usually in the retro-vesical or retro-uterine region. The tumor tends to mildly enhance and contains areas of necrosis and calcification. It spreads by intraperitoneal seeding. Metastases to lymph nodes, liver, lung, and pleura are also common. The diagnosis is particularly challenging because of imaging overlap with other mesenteric masses such as rhabdomyosarcoma, mesothelioma, intraabdominal desmoid, peritoneal carcinomatosis, and infections, like tuberculosis ( ). Although primarily intraperitoneal, rare cases of widespread disease involving intracranial compartments, salivary glands, breast, ovary, bones, etc., have also been reported ( ).

Fibrosarcoma

Congenital or infantile fibrosarcoma, although histologically identical to the adult form, has different biological behavior and better prognosis. Patients are usually younger than 5 years; this tumor can be discovered even at birth. The most common sites of origin are the proximal extremities, trunk, head, and neck region, and rarely the retroperitoneum. On clinical exam and ultrasound, it usually mimics hemangioma. Internal hemorrhage, central necrosis, and heterogeneous enhancement are present. Although few lesions can show T2w hypointensity due to fibrous components, they are usually T1w isointense, heterogeneously hyperintense on T2w, and enhance heterogeneously ( ). The T2w hyperintensity is due to actively proliferating fibroblasts. This tumor has high local recurrence rates and rare metastatic potential.

Epithelioid sarcoma

Epithelioid sarcomas usually present as a subcutaneous or deep dermal multinodular aggressive masses in the distal extremities, particularly the forearms and hands ( ), extending along the fascial planes with intense perilesional edema. Local recurrence and metastases are common. On MRI, hemorrhage or necrosis may be detected ( ). The factors which predict adverse outcomes are proximal location, large size, depth of infiltration, and presence of hemorrhage, necrosis, vascular invasion, and metastases ( ). There are two types: proximal and conventional, with different histological and clinical features. The proximal type has a predilection for the genitalia.

Alveolar soft part sarcoma

These are rare tumors that comprise less than 1% of all soft tissue sarcomas ( ) and are more common in adolescent girls or young women. They usually present as slowly enlarging or less likely as painful masses in the extremities, mostly in the thigh or buttock. They can also involve the orbit or tongue. Although these lesions are usually small and slow-growing, they have very high metastatic potential given the extreme vascularity and early microinvasion. Approximately 30% of the children present with metastases at the diagnosis, especially in the lungs, brain, and liver ( ; ). Since distant metastases dictate the prognosis, WB PET/MRI can play a crucial role.

Large feeding arteries and draining veins, with early hyperenhancement and delayed washout, are often visualized in ASPS. The delayed washout is likely due to venous thrombi. On the other hand, arteriovenous malformations, given the high flow, account for hyperenhancement, and washout. ASPSs usually have intermediate to high T1w signal, high T2w signal, and vascular flow voids. A peripheral fibrous capsule can also be responsible for low peripheral signal. The most common feature of this tumor is represented by the intratumoral and peritumoral flow voids. Unbalanced p11; q25 translocation resulting in the formation of the ASPL-TFE3 fusion protein is seen exclusively in ASPS and in a few pediatric RCC and peri endothelial epithelioid cell carcinomas.

Liposarcoma

Although traditionally the vast majority of lipomatous neoplasms were thought to be lipomas or liposarcomas, a whole new entity named atypical lipomatous tumors (ALT) or undifferentiated liposarcoma has emerged to clinical attention; ALT are locally aggressive and often do not metastasize ( ). Imaging features that favor ALT over benign lipoma include size greater than 10 cm, septa thicker than 2 mm, nodules, and <75% fat content. On MRI, liposarcomas exhibit increased complexity with enhancing nonlipomatous components. The degree of complexity correlates with higher grades. The enhancing nonlipomatous components are usually metabolically avid on FDG-PET. Liposarcomas can dedifferentiate and contain other sarcomatous elements such as osteosarcoma, chondrosarcoma, etc. Although benign lipomas do not exhibit abnormal metabolic activity, hibernomas, which are benign brown fat tumors, are metabolically active on FDG-PET, causing diagnostic challenges. They exhibit homogenous fatty signal without any complex features on MRI, thus proving the advantages of hybrid imaging.

Soft tissue Ewing sarcoma

Soft tissue Ewing sarcoma is rare and includes extraskeletal Ewing sarcoma/soft tissue primitive neuroectodermal tumor. They fall under the same spectrum of osseous Ewing sarcoma and most commonly present as a large soft tissue mass in the paraspinal region or lower extremity. Askin tumor is a type of extraskeletal Ewing sarcoma of the chest wall, often presenting as a pleural based mass with associated pleural effusion ( ). Local and WB imaging features are similar to classic osseous Ewing sarcoma.

Clinical background

Malignant peripheral nerve sheath tumors (MPNST) are soft tissue sarcomas that arise from perineural cells outside of the central nervous systems. Approximately 50% of MPNST are sporadic, and 50% occur in neurofibromatosis 1 (NF1) patients. MPNST is often associated with chromosomal rearrangements (17q11.2, loss or rearrangement of 10p, 11q, 17q, 22q). In patients with NF1 (mutations of chromosome 17, which encodes the tumor suppressor protein neurofibromin), MPNST often arises from a precursor plexiform neurofibroma. The molecular pathway from neurofibroma to MPNST in patients with NF1 is multifactorial and not fully characterized. Only about 10% of all NF1 patients eventually develop MPNST ( ). Therefore, screening patients with NF1 is typically done with WB MRI, which allows for yearly (or more frequent) scans without radiation exposure. Once an MPNST is suspected, a PET scan is often requested.

Diagnosis

The most common anatomic sites where MPNST can be found include proximal upper extremities, lower extremities, and trunk. MPNST are known to have high metastatic potential and a poor prognosis, with a 50% survival rate in the case of curative surgical resection. In patients with metastasized MPNST, the prognosis is very poor. Therefore, it is of utmost importance to diagnose MPNST at an early stage, before occurrence of metastases. At the same time, surgical excision of benign neurofibromas would cause unnecessary pain and potential iatrogenic morbidities. Therefore, an imaging test with high sensitivity for detecting early MPNST and high specificity for differentiation of benign and malignant tumors is urgently needed for these patients.

Local staging

In patients with localized disease, complete surgical resection with clear margins is critical to achieving survival. Therefore, it is important for the radiologist to tridimensionally evaluate the relationships to adjacent vascular structures, muscles, fasciae, bones, and/or visceral organs. Tumors deep to muscular fasciae tend to have a worse prognosis, similarly to tumors with large size and inability to resect them with clear margins. Metastasized tumors may be addressed by chemotherapy or radiation, although the efficacy of these therapies is limited. While tumor responses are often based on RECIST criteria, it is advised to always provide three-dimensional tumor measurements to ensure that the longest diameter is being recorded. Even in the case of curative resection MPNST, there is a high risk (13%–86%) of local recurrence. Therefore, postsurgical follow-up imaging is necessary.

Whole-body staging

MPNST most commonly metastasizes to the lungs, followed by the bones and pleura. Since the primary tumor is usually evaluated with MRI, WB ¹⁸ F-FDG PET/MRI provides a time-efficient and highly accurate approach to also assess for metastases in that same session ( ) ( Fig. 6.5 ). Given the limitation of MRI in detecting small pulmonary nodules, a staging chest CT is needed.

Eighteen-year-old male with NF-1.

(A) Coronal WB-PET MIP from 18F-FDG-PET/MRI PET and (B) Coronal Whole-Body PET/T2w MRI fused images demonstrate innumerable and markedly FDG avid peripheral nerve sheath tumors ( arrows ), particularly involving the thoracic neural foramina.

Future developments

Future studies might introduce more specific biomarkers to improve the differentiation between benign and MPNSTs. For example, topoisomerase II α is overexpressed in MPNSTs but not in benign neurofibromas ( ). While imaging topoisomerase II is challenging, recent investigations reported the successful development of fluorescent biomarkers ( ). In addition, the development of both biomarkers and therapeutics that target the mTOR and hsp90 pathways might have significant potentials ( ).

Clinical background

Neuroblastoma is a malignancy originating from aberrant differentiation of the primordial neural crest cells that form the sympathetic nervous system ( ). It is the most common extracranial solid tumor in children worldwide, accounting for about 8%–10% of all childhood cancers ( ; ). Nearly 70% of neuroblastomas occur in the retroperitoneum, especially in the adrenal glands, while the remaining 30% develop in the mediastinum (15%–20%) and other regions (7%–10%) ( ). Prognosis varies from an overall long-term survival rate >90% for low and intermediate-risk patients, to <40% for high-risk patients ( ). Imaging plays a crucial role in risk assessment by defining the extent of the disease, vital organ involvement, and the presence of viable tumor at surgical resection. Complete surgical resection is the cornerstone for localized disease, while combined therapies are necessary for metastatic diseases.

Diagnosis and staging

The diagnosis of neuroblastoma is based on the International Neuroblastoma Staging System (INSS) criteria ( ): positive conventional histology (with or without immunohistology and increased urine or serum catecholamine or metabolites) or, presence of unequivocal tumor cells in the bone marrow and increased urine or serum catecholamines or metabolies ( ). Cross-sectional imaging is used to assess the extent of the disease, especially hepatic, bone marrow, and spinal canal involvement. Iodine 123 ( ¹²³ I) metaiodobenzylguanidine (MIBG) is the first-line functional imaging agent for identifying both the primary tumor and the metastases ( ). One unequivocal MIBG-positive lesion at a distant site is sufficient to define the disease as metastatic. A single equivocal lesion on MIBG requires confirmation by another imaging modality (plain radiographs, and if negative, MRI) and/or biopsy ( ). Bone marrow involvement should be assessed by two aspirates and two biopsies from bilateral sites ( ). A biopsy is not required for infants <6 months ( ; ; ).

Future directions

Various PET tracers have been studied over the years. ¹⁸ F Fluorodeoxyphenylalanine ( ¹⁸ F DOPA) PET/CT has higher accuracy than ¹²³ I-MIBG scan, and holds prognostic value in the evaluation of patients with neuroblastoma ( ; ; ; ; ). ¹⁸ F-DOPA-PET outperforms ¹⁸ F-FDG-PET for the assessment of possible intracranial lesions given the lack of uptake in normal brain tissue ( ). ¹⁸ F-labeled meta-fluorobenzylguanidine ( ¹⁸ F-MFBG) has a biodistribution similar to ¹²³ I-MIBG but much faster blood clearance ( ; ; ). ¹⁸ F-MFBG PET/CT has higher sensitivity than ¹²³ I-MIBG ⁹³ (122 lesions detected by ¹⁸ F-MFBG PET/CT vs. 68 lesions detected by ¹²³ I-MIBG) ( ). ¹⁸ F-MFBG-PET/CT also detected all lesions shown by ¹²³ I-MIBG.

Clinical background

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies that arise from neuroendocrine cells. They account for about 0.5% of all newly diagnosed malignancies, with a female predominance of around 2.5:1 Presentation can vary from slow-growing and indolent tumors, incidentally found on imaging, to highly aggressive malignancies with poor prognosis. Twelve percent to 22% of patients are metastatic at presentation ( ; ). The most frequent primary sites are the gastrointestinal tract/pancreas (62%–67%) and the lung (22%–27%). Most NETs are sporadic, but they can also be associated with hereditary syndromes, like multiple endocrine neoplasia type 1 (MEN-1), MEN-2, von Hippel-Lindau (VHL) syndrome, neurofibromatosis, and tuberous sclerosis ( ; ). They can develop in the context of a carcinoid syndrome induced by serotonin hypersecretion from enterochromaffin cells ( ). Tumor markers include urinary 5-hydroxyindole acetic acid (5-HIAA), a serotonin metabolite, and plasma chromogranin A (CgA), a glycoprotein secreted with serotonin ( ; ). CgA levels correlate with tumor bulk, differentiation, and secretory activity, which may predict treatment response and overall survival (fast-rising levels portrend a poor prognosis) ( ; ). Staging is essential since surgery remains the optimal treatment in nonmetastatic disease ( ; ).

Diagnosis and staging

The 2017 WHO NETs classification subdivides NET tumors into three pathologic grades (G1–G3) based on the number of mitoses on high-powered microscopy, the Ki-67 index, and the presence or absence of tumor necrosis and apoptosis ( ). Histopathology characterization is fundamental for diagnosis confirmation and staging. A combination of clinical features and biochemical tests (gastrin, insulin, glucagon, serotonin catabolites) is essential to determine tumor activity. Cross-sectional imaging is based on CT and MRI. Metabolic imaging is based on the somatostatin analogs described in Chapter 2 ( ; ). ⁶⁸ Ga-DOTATATE imaging is also essential for eligibility assessment of patients who will benefit from radionuclide therapy with ¹⁷⁷ Lu-DOTATATE.

¹⁸ F-FDG PET/MRI has limited value in well differentiated tumors, but it is useful for assessing tumor aggressiveness and metastases in high grade NETs ( ). A characteristic “flip-flop” phenomenon can be visualized in NETs, that is, low-grade highly differentiated hormone-secreting tumors are usually positive on SSTR-PET and negative on ¹⁸ F-FDG PET, and vice versa ( Fig. 6.6 ); this is explained by decreased expression of SSTRs in aggressive and poorly differentiated tumors ( ).

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