Gender-Based Differences in Pediatric Nuclear Medicine Adina L. Alazraki, MD, and Kiery A. Braithwaite, MD Gender-based differences commonly encountered in pediatric nuclear medicine reflect both basic embryologic differences of the sexes, which are evident from infancy, and evolving physiological changes due to gender, which occur as the pediatric patient grows, undergoes puberty, and matures to adulthood. It is important for a nuclear medicine physician or radiologist to know both the gender and the age of a patient when interpreting her or his studies. It is also important that the reading physician be familiar with the normally evolving physiological changes that are specific for that patient’s stage of development. It is particularly important that the reading physician consider such changes when comparing serial studies of the patient that are acquired during the patient’s transitions through her or his different significant stages of development. Many pediatric nuclear medicine imaging protocols are modifications or adaptations of the protocols for adult imaging. Physicians reading pediatric studies must routinely incorporate knowledge on age and gender that is relevant to the patient for any given study. The age-defined gender-based subtleties of potential findings in pediatric nuclear medicine studies are often underrecognized. However, they are often of interest and at times important in the workup of both benign entities and pathologic processes of the pediatric patient. Semin Nucl Med 44:451-460 C 2014 Elsevier Inc. All rights reserved.

Introduction

FDG-PET Imaging

G

Normal physiological patterns of FDG uptake have been extensively described in the medical literature.1 The patterns of normal FDG uptake in the male and female population are largely similar, with a few notable exceptions that are more obviously distinct in the adolescent population. Normal FDG uptake in the gonads is frequently seen, but it is more pronounced in the pediatric adolescent population than in the adult population. FDG uptake in the adult testis has been described as declining with age, even when corrected for testicular volumes.1,2 Conversely, moderately intense FDG uptake is frequently noted in the pediatric testes and increases with age during adolescence. A study by Goethals et al,3 although limited by a small sample size, found a statistically positive correlation between the mean bilateral testicular standardize uptake value (SUV) and patient age in young male individuals. In this study, which focused on male individuals aged 9-18 years, the mean SUV of the testes of its subjects steadily increased throughout late childhood and adolescence. The authors commented that the mean testicular volume also increased with age, and it was uncertain what percentage of change in SUV was secondary to increase in volume vs physiological uptake. It is important not to confuse this

ender-based differences specific to disease processes in the pediatric population are not uncommon. These differences are often inherent in the embryology of the fetus and in the sex-determination factors that influence development of male or female anatomy. Gender-based differences observed on nuclear medicine imaging of male and female individuals with disorders for which the management requires such imaging are few, but often critical. Sex plays a role in the evaluation of some abnormal structures and some normal structures. It is important to recognize when it does and why it does not play a role. The goal of this article is to highlight the more commonly encountered gender-specific physiological and pathologic differences one encounters when interpreting nuclear medicine studies in the pediatric population with hopes that this would provide the reader useful practical knowledge for application in the management of pediatric patients.

Department of Radiology and Imaging Sciences, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA. Address reprint requests to Adina L. Alazraki, MD, Department of Radiology and Imaging Sciences, Children’s Healthcare of Atlanta, Emory University, 1405 Clifton Rd, Atlanta, GA 30322. E-mail: [email protected]

http://dx.doi.org/10.1053/j.semnuclmed.2014.06.007 0001-2998/& 2014 Elsevier Inc. All rights reserved.

451

452 age-related increase in FDG uptake in the testes during late childhood and adolescence with testicular malignancies, both primary and secondary. This may be especially important in patients with hematologic malignancies, such as leukemia and lymphoma, as the testis is well known to be a site with a relatively increased risk of relapse, because of the blood-testis barrier. The endometrium and ovaries are the female analog to the testes. They also undergo, particularly during adolescence, both anatomical and physiological changes that can result in normal and abnormal FDG uptake. The endometrium and ovaries are dormant in the prepubescent child, but undergo significant change during puberty. The normal endometrium can have increased FDG uptake such that it tends to peak during menstruation.4 During ovulation, increased metabolic activity within the ovaries could be misinterpreted as pelvic disease if it is not recognized as a normal physiological phenomenon.4 Therefore, recording the last menstrual period of the female patient is pertinent to the interpretation of her FDG study. Normal physiological uptake of FDG in the breast tissue is frequently identified in postpubertal adolescent girls and premenopausal women, with uptake generally higher during menstruation.5,6 Dense breast tissues tend to have higher baseline FDG uptake and this is more common in the young, adolescent female population when compared with the adult population.5 However, it can be noted that the average SUV in dense breast tissue is still less than 2.5, which is the accepted SUV for background.7 All the aforementioned findings are considered normal patterns of uptake, but the variations in the patterns by gender are important to recognize and to use so as to correctly interpret a pediatric nuclear medicine study (Fig. 1). Brown fat is a type of adipose tissue that is involved physiologically in heat generation and the regulation of body temperature. It is present in humans from infancy through adulthood. Brown adipose tissue is frequently encountered as hypermetabolic on FDG-PET scans in both pediatric and adult patients. The literature suggests that these depots of active brown fat are more common in adult women than in adult men.8 However, this finding has not been substantiated in children. It has instead been shown that FDG uptake in brown fat in children is more dependent on age and adolescent development, that is, the Tanner stage. In a study by Drubach et al,9 involving 385 scans of 172 patients, no significant difference was found between the FDG uptakes in brown fat in boys and the uptakes in brown fat in girls (aged 5.3-20.8 years). In the same study, the frequency of identification of brown adipose tissue increased through childhood, reaching a maximum frequency near the age of 13 years in both male and female individuals. In the study, the uptake of FDG in brown fat was identified in nearly half of the adolescent patients, a frequency that is much higher than that reported for the adult population. Similar findings were reported in a smaller study (73 patients) by Gilsanz et al, which compared the volume of brown fat in pediatric patients that was detected using PET with the Tanner stage. Younger prepubescent children (Tanner stage 1) were shown to have less uptake in the brown fat than that in older children undergoing physiological changes of

A.L. Alazraki and K.A. Braithwaite

Figure 1 (A) CT and (B) PET axial images at the level of the breasts in a female adolescent patient. Dense breast tissue on the CT image and corresponding FDG uptake on the PET image can be noted.

puberty. The greatest volume of brown fat detected using PET/ CT by Gilsanz et al was that detected in the later stages of puberty (Tanner stages 4-5) for both adolescent girls and boys. Furthermore, a gender–based difference in the volume of brown fat was identified in the study by Gilsanz et al,10 but only in the aforementioned later stage of puberty. The volume was greater in male than in female individuals.10 Both studies demonstrate that brown adipose tissue is more reliably relatable to the inverse body mass index and that peak identification of metabolically active brown fat in adolescence correlates with the age of physiological development that is associated with less body fat and a marked increase in skeletal muscle mass.9,10 Brown fat is activated by exposure to cold. The result of such exposure can be a 5-fold increase in the uptake of FDG.11 Controlling the uptake of FDG within brown fat stores is important for accurate staging of disease. A number of pharmacologic and practical solutions have been suggested. Gelfand et al reported a significant decrease in the uptake of FDG within brown fat in children when fentanyl was administered before FDG. Gelfand et al12 reported no visible reduction following administration of low-dose diazepam. Similarly, other studies have shown a reportable decrease in brown adipose tissue activity when a beta-adrenergic antagonist, that is, propranolol, is administered before uptake.13,14 The most important factor in diminishing uptake in brown fat

Gender-based differences in pediatric nuclear medicine is warming of the patient and the room before the injection of FDG.15 It is important to be familiar with both gender- and age-related patterns of brown fat uptake, so as to not confuse normal variants of uptake with the progression of disease, particularly in a patient population that frequently requires follow-up imaging (Fig. 2).

Thyroid Disease Imaging Thyroid disease, both benign and malignant, is more common in the female pediatric population than in the male pediatric population. As there are no inherent differences in the use of radioactive iodide to treat thyroid disease in male and female children, most pediatric patients who undergo both imaging and treatment with iodine-123 (I-123) and I-131 are female individuals. Thyroid cancer rates are rising even in children. It is hypothesized that the rates are rising, in part, because there is now earlier diagnosis of asymptomatic disease.16 This being the case, the administration of radioactive iodine (RAI) to children and adolescents warrants a discussion regarding longterm counseling of the effects of such therapy. In pediatrics, 2 historic peaks in the incidence of thyroid cancer have been documented in the literature. The first is

Figure 2 An MIP image of a 16-year-old boy with acute lymphocytic leukemia who underwent whole-body FDG-PET/CT. The image shows intense uptake of tracer in the bilateral supraclavicular regions, corresponding to brown fat. This uptake is noted despite the administration of IV fentanyl for suppression before the uptake period in this adolescent patient. IV, intravenous; MIP, maximum-intensityprojection.

453 associated with the use of radiation therapy in the 1950s for the treatment of nonmalignant entities, such as enlarged thymus, tinea capitis, and chronic tonsillitis.17,18 Large, multicenter studies have shown an increased relative risk for subsequent development of hematologic and solid malignancies in pediatric patients treated with radiation for these nonmalignant conditions. Notably, being younger or female at the time of exposure results in higher relative risks than being older or male. The female thyroid gland is 3 times more sensitive to carcinogenesis from radiation than the male thyroid gland is.19,20 This gender difference is similar to quoted rates in the general population for thyroid cancer. As early as 5 years after the nuclear accident in Chernobyl, a second rise in the incidence of thyroid cancer was observed. This rise was noted in patients who varied in age from infancy to 17 years old. This age range and the study year indicate that the subjects were younger than 5 years at the time of the Chernobyl incident.21-23 Investigation of the effects of this devastating accident led to the indisputable observation that the pediatric thyroid gland is more sensitive to radiation exposure than the adult thyroid gland is. Many studies and meta-analyses have been published regarding the development of second primary malignancies following RAI therapy for thyroid cancer. Sawka et al,24 concluded that there is a 0.4% increased risk of leukemia in patients who have received RAI when compared with patients with thyroid cancer who have not received RAI. The small increased risk of a second primary malignancy from RAI is likely not outweighed by the benefit of RAI for the treatment of thyroid cancer. Another significant late effect of RAI therapy is development of pulmonary fibrosis. This risk is particularly high in patients with pulmonary metastases. The risk of this pulmonary complication is quite small if the recommended dosing guidelines are followed,25 with only 1% of adults being affected; however, in children, that risk rises to 10%.26 Published articles regarding the safety of I-131 therapy for thyroid cancer in women specifically, concerning fertility, claim no clinically significant decline in fertility following radioiodine therapy.27,28 Further, they report that the rates of secondary cancers in these patients have been very low and, as such, are quite rare.29 Vini et al reported that among 496 women of childbearing age treated with I-131, there were 4 premature births and 14 miscarriages, but no congenital anomalies among the 427 children born to 253 women. Only 1 woman who wanted to conceive was unable to do so.28 Congenital hypothyroidism is more common in female newborns by a factor of approximately 2:1.30 Congenital hypothyroidism is a relatively common condition, occurring in 1 of 3000-4000 live births. The thyroid hormone is critical to infantile neurodevelopment, and congenital hypothyroidism is so common that screening for it is mandatory in the current newborn state screen in all the 50 states in the United States. A recent study reported that the occurrence of congenital hypothyroidism in the United States is increasing by approximately 3% per year, and although ethnic predispositions are noted, the increase among boys and girls is equal at a national level.31 The most common cause of congenital hypothyroidism is thyroid dysgenesis; it accounts for nearly

A.L. Alazraki and K.A. Braithwaite

454 85% of cases.32 Thyroid dysgenesis includes athyreosis, thyroid hemiaplasia, and ectopic location of the gland. Ectopic thyroid tissue is typically lingual in location, reflecting the embryologic descent from the foramen cecum at the base of the tongue. Thyroid scintigraphy paired with ultrasound is the most common imaging approach used to screen for the presence of ectopic thyroid tissue. In young children and infants, this is typically accomplished with administration of technetium 99m (99mTc) pertechnetate, owing in large part to its lower radiation exposure to the patient when compared with using traditional thyroid imaging agents (I-123 and I-131).33 Planar imaging with pinhole and planar imaging with parallel collimator are most common. Imaging is generally of the neck and upper chest in frontal and lateral projections with the addition of SPECT, if additional precision in localization is needed or desired34,35 (Fig. 3).

Neuroblastoma, Pheochromocytoma, and Metaiodobenzylguanidine Imaging The primary indication for the use of I-123 and I-131 metaiodobenzylguanidine (MIBG) imaging in pediatrics is in the evaluation of adrenomedullary tumors, specifically neuroblastoma and pheochromocytoma or paraganglioma. MIBG is a derivative of guanidine that enters neuroendocrine cells by active uptake via the epinephrine transporter. MIBG is stored within the secretory granules of these cells and remains in both the cytoplasm and the storage granules of the

neuroblastoma cells.36 I-123 is typically used for imaging because of its lower energy and decreased radiation burden when compared with I-131. Following I-131 therapy, a posttherapy whole-body scan is highly recommended, as more metastatic lesions may be seen on a posttherapy scan than on the diagnostic I-123 MIBG pretherapy scan.37 The posttherapy scan shows the therapeutic distribution of I-131 MIBG. Neuroblastoma is the most common extracranial solid tumor of childhood. It typically affects young children, with presentations being more than 50% before the age of 2 years and more than 90% before the age of 5 years. The clinical course of neuroblastoma can be quite variable depending on age at presentation and specific cytogenetics.38 Tumors primarily arise from the adrenal gland or the sympathetic chain, and the pattern of distribution parallels the embryologic migration of precursor pluripotent neural crest cells. Pathologic disease classification is based primarily on age, grade of tumor, mitotic rate, and other genetic markers. There is a small gender-based bias with neuroblastoma, which presents slightly more often in boys than in girls.39 However, gender does not appear to influence disease progress or outcome. Childhood pheochromocytoma is rare and much less common than neuroblastoma. Pheochromocytoma is also typically MIBG avid with a specificity of 95%-100% and a sensitivity of up to 90%.36 In the pediatric population, it is more often encountered in older children and adolescents. There is a reported 2:1 prevalence of pheochromocytoma in male individuals; however, female individuals report a higher rate of symptomatology.40 Pheochromocytoma most typically presents with classic symptomatology, including hypertension. When evaluating a child for suspected pheochromocytoma, it is important to be aware that there is a higher incidence of

Figure 3 99mTc pertechnetate planar images of the head and neck of an infant with congenital hypothyroidism: (A) frontal projection shows a focus of uptake high in the neck, just below the chin and (B) lateral projection confirms sublingual location, in the expected position of the foramen cecum, consistent with the diagnosis of lingual thyroid.

Gender-based differences in pediatric nuclear medicine multiplicity of tumors, both adrenal and extra-adrenal, in the pediatric population as compared with that in adults.41 The normal physiological distribution of MIBG includes the nasopharynx, salivary glands, heart, and liver, with excretion seen in both the gastrointestinal and the genitourinary tracts. Generally, there is no significant difference in the uptake between genders. However, normal uptake has been described within brown fat, and more commonly in children.42 Brown adipose tissue has adrenergic receptors that take up MIBG when stimulated by cold or other sympathetic responses. Given the pathophysiology of brown fat and that its only purpose is to generate heat, the activation of this tissue by the sympathetic system is correctly inferable. Furthermore, the activation of glucose transporters contributes to the increased perfusion of brown fat. Both these mechanisms allow visualization of brown adipose tissue on I-123 and I-131 MIBG whole-body scintigraphy. The uptake of MIBG by brown fat in children is thus generally most prominent in adolescents and parallels the uptake of FDG that is previously discussed. Its potential presence on images dictates that it be considered as an explanation for certain uptakes visible on pediatric FDG and MIBG images (Fig. 4).

Gastrointestinal Imaging Gender-based differences in gastrointestinal nuclear imaging studies commonly encountered in the imaging of children are predominantly related to the occurrence of specific pathologies in girls vs boys. Briefly, we review 2 of the more common gastrointestinal conditions unique to children that often require scintigraphic imaging evaluation: first, the child with

455 gastrointestinal bleeding that is suspected to be secondary to Meckel diverticulum and second, the jaundiced infant. Meckel diverticulum is a congenital embryologic remnant of the omphalomesenteric duct. It is most commonly encountered at surgery approximately 60-100 cm (approximately 2 ft) proximal to the ileocecal valve and occurs in 1%-3% of the population. Its appearance is up to 3 times more common in male individuals.43 The typical presentation is painless gastrointestinal bleeding; however, it may less commonly be discovered as a lead point for intussusception or may mimic suspected appendicitis in the setting of Meckel diverticulitis. The Mayo clinic conducted a retrospective review of 1476 patients with Meckel diverticula and found that 84% of patients were asymptomatic.44 The study found a male-tofemale gender bias of 3:1 for both symptomatic and asymptomatic groups among children. More than half of symptomatic Meckel diverticula contain the gastric mucosa.43 The patients with these symptoms can present with painless bleeding because of acid secretion and resultant mucosal ulceration within the diverticulum. The Meckel scan uses 99mTc pertechnetate, which accumulates in the gastric mucosa and can therefore identify aberrant location of such tissue in nongastric structures45 (Fig. 5). Hepatocellular scintigraphy is often used to distinguish between the 2 most common causes of direct hyperbilirubinemia in the setting of neonatal jaundice: neonatal hepatitis and biliary atresia. The more common of the 2, neonatal hepatitis, has multiple etiologies, including but not limited to infectious, vascular, and metabolic causes. Neonatal hepatitis is 4 times more common in male infants than in female infants.46

Figure 4 Regional format whole-body images after injection of I-123 MIBG in a patient with neuroblastoma. The uptake of tracer in a linear distribution in the bilateral supraclavicular regions (arrows) corresponding to the distribution of brown fat in the neck can be noted.

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Renal Imaging

Figure 5 A single anteroposterior image of the abdomen and pelvis following injection of 99mTc pertechnetate in a young child presenting with painless gastrointestinal bleeding. Normal physiological intense uptake in the stomach as well as normal excretion in the bladder can be noted. An abnormal additional focus of uptake, equal in intensity to the stomach, in the right lower quadrant confirms suspicion for Meckel diverticulum.

Biliary atresia is a progressive, obliterative disease of the extrahepatic biliary tree that, although rare, is the most common indication for liver transplantation in children.47 Biliary atresia is twice as common in girls when compared with boys.46 The cause of biliary atresia is not known, and in most cases, this disease occurs in isolation. However, in most patients it occurs in association with other congenital malformations, including laterality malformations, such as asplenia and polysplenia. Time is critical in the diagnosis of biliary atresia. Liver transplant is the only option for patients who are not treated with surgical hepatoportoenterostomy before the age of 2-3 months. Without surgery, biliary atresia is uniformly fatal by 2 years of life.47 Distinguishing neonatal hepatitis from biliary atresia with dynamic hepatobiliary scintigraphy is based on the patency of the extrahepatic biliary tree. If tracer excretion from the liver to the small bowel is visualized, biliary atresia is excluded. However, failure to excrete tracer, while always seen in biliary atresia, can also occur in neonatal hepatitis, most commonly secondary to severe hepatic dysfunction.43,46 Choledochal cyst is caused by congenital dilatation of the biliary tree and can also present with jaundice. Approximately 15% of these patients have coexisting biliary atresia. Choledochal cysts are 2-3 times more common in female individuals than in male individuals.46 Ultrasonography with hepatic scintigraphy is traditionally used for the diagnosis of choledochal cysts. However, recent advances in MRI, specifically development of hepatobiliary contrast agents for MRI, may ultimately change the diagnostic approach.

Gender-based differences in pediatric renal imaging are largely based on anatomical differences owing to more frequent congenital urinary tract anomalies in male individuals. Notably, the most common indication for renal cortical imaging with dimercaptosuccinic acid (DMSA) labeled with 99mTc in children is to evaluate for renal cortical scar or pyelonephritis or both. Urinary tract infections occur more commonly in girls, with the notable exception of newborns, in which male infants are more affected.48 There is an ongoing debate as to the significance of vesicoureteral reflux (VUR) as a causative factor for pediatric urinary tract infection.49,50 The data suggest that overall 30% of children with urinary tract infections have VUR.51-53 However, it has further been reported that upper urinary tract infection, that is, pyelonephritis, occurs in more than half of patients without VUR, and in some studies, it is reported to occur in less than one-quarter of them.52-54 Etiology of renal scarring in children has gender-specific trends. VUR has been shown to be more common in girls. However, higher grades of reflux, which lead to more significant renal scarring, are more commonly encountered in male individuals because of congenital anatomical abnormalities, such as posterior urethral valves.55,56 Severe reflux nephropathy, encountered secondary to posterior urethral valves, is a problem unique to male individuals because of the longer urethra. The structure giving rise to the posterior urethral valve in male individuals, the verumontanum, becomes the female hymen.57 Prune-belly syndrome is a rare cause of renal dysplasia, which is seen almost exclusively in male individuals because of X-linked recessive transmission.58 In female individuals, renal scarring is more commonly an acquired result of recurrent urinary tract infections.59,60 These gender-related trends are echoed in recently revised recommendations in evaluating for VUR in pediatric patients presenting with first-time febrile urinary tract infection.61 The revised American Academy of Pediatrics guidelines recommend that children aged 2-24 months undergo sonography after first-time urinary tract infection, with a subsequent voiding cystourethrogram only if the ultrasound scan is unremarkable. However, this revision was met with concerns from urology colleagues who cautioned abandoning the voiding cystourethrogram. Although there are no gender-specific recommendations, in the first 2 months of life, urinary tract infection in the newborn is suspicious for an anatomical abnormality, especially in boys.61,62 DMSA is also useful in the evaluation of other congenital renal anomalies, when sonography is not conclusive. This includes renal dysplasia, renal agenesis, and renal ectopia, all of which are more common in male individuals than in female individuals.63,64 DMSA is frequently performed to distinguish a functioning but impaired kidney, secondary to hydronephrosis or renal cystic dysplasia or both, from a nonfunctioning, multicystic dysplastic kidney. A slight male predominance has been reported in the incidence of multicystic dysplastic kidney.65 Ureteropelvic junction (UPJ) obstruction has been cited as the leading cause of prenatal hydronephrosis.66 This too, is more common in boys. Diuretic renography is a technique

Gender-based differences in pediatric nuclear medicine used to distinguish an anatomically obstructed calyceal system, such as in UPJ obstruction, from a dilated but nonobstructed system related to stasis. Mercaptoacetyltriglycine labeled with 99m Tc is the current agent of choice for dynamic, functional renal scintigraphy. In children, common indications for serial renal scintigraphy include assessing recovery of renal function after treatment of obstructive uropathy, such as in UPJ obstruction and posterior urethral valves.67 In the setting of a duplicated collecting system, mercaptoacetyltriglycine serves 2 purposes: first, it serves to calculate the split function of upper and lower poles and second, it serves to evaluate for the presence of an obstructed moiety. It is noteworthy that the obstructed moiety can be associated with an ureterocele, which are 4-6 times more commonly encountered in female children than in male children.68 Finally, the prevalence of glomerular diseases is slightly higher in boys than in girls. There is an association between chronic kidney disease progression and male gender, which has been described more extensively in the adult literature but is mirrored in the pediatric nephrology data.69 The higher prevalence of more severe congenital, as opposed to acquired, urinary tract anomalies among male individuals is directly responsible for the higher use of renal nuclear imaging in male pediatric patients (Fig. 6).

Skeletal Imaging There are normal gender-based differences in the growing skeletons of children, which may affect the normal expected

Figure 6 Planar posterior projection centered over the kidneys of a female patient with bilateral duplex collecting systems and bilateral vesicoureteral reflux confirmed by prior VCUG. The image shows separation of upper and lower poles, allowing relative quantitative assessment of function in each segment. Decreased counts on the left are consistent with diffuse renal scarring. The upper pole on the right is obstructed. VCUG, voiding cystourethrogram.

457 physiological distribution of tracer uptake on skeletal scintigraphy. 99mTc methylene diphosphonate (MDP) is the most commonly used radiopharmaceutical for pediatric bone scintigraphy.70,71 Diphosphonates concentrate in amorphous calcium phosphate and crystalline hydroxyapatite. The distribution of 99mTc MDP reflects both blood flow and osteoblastic bone formation.70-72 The most striking difference in the scintigraphic appearance of the immature pediatric skeleton when compared with the adult is high uptake centered within the zone of provisional calcification adjacent to the physeal growth plate of long bones.73 Physiological high uptake within these growth centers is secondary to both the rich blood supply and active endochondral ossification.70-72 Uptake is also identified in apophyseal growth centers.72 A study by Yang et al evaluating the percentage uptake in the growth centers in children found that in children younger than 1 year, the total percentage whole-body and the regional percentage whole-body uptake for the distal femur, distal tibia, and fibula and the proportion of uptake in the lower limbs to the whole-body uptakes were significantly higher in male individuals than in female individuals. However, after the age of 1 year, no significant genderbased differences were identified for the total MDP epiphyseal plate uptake, which contributes to approximately 10% of the whole-body activity in children until 11-12 years for both genders; it then declines. This 10% of growth plate activity accounts for longitudinal growth.74 As a child approaches skeletal maturity, the distribution of tracer uptake gradually changes to the adult pattern.73,75 Girls reach skeletal maturity earlier than boys do.73 The physeal growth centers close earlier in girls than in boys.76 This may result in a later and longer period of physeal activity in male individuals when compared with female individuals.74 For example, closure of the tibial tubercle physis typically occurs between the ages of 13 and 15 years in female individuals and 15 and 19 years in male individuals.72 Symmetry of physiological physeal uptake is often helpful for the interpreting radiologist, although multiple pathologic conditions can affect activity, resulting in asymmetrical uptake, including but not limited to infection, trauma, and stress.73 Furthermore, some growth centers can demonstrate asymmetrical physiological uptake as a normal finding, such as the ischiopubic synchondrosis, which closes asymmetrically in approximately 20% of children,77 usually between the ages of 4 and 12 years.78 It is also important to recognize that diphosphonate uptake requires the skeletal structure to be either ossified or undergoing ossification.72 At birth, some of the pediatric skeleton is still cartilaginous, such as the proximal femoral epiphysis. Until these growth centers begin ossification, there is an absence of uptake, which should not be confused for avascular necrosis or osteomyelitis.70 For example, ossification of the proximal femoral epiphyses usually begins between the ages of 2 and 7 months. Ossification can also vary by sex. For example, the tarsal navicular bone typically ossifies between the ages of 1 and 3.5 years in girls but between the ages of 3 and 5.5 years in boys.72 Abnormal MDP uptake caused by pathology in the pediatric patient identified by skeletal scintigraphy is most commonly

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Figure 7 Whole-body planar bone scan images in anterior and posterior projections after the injection of 99mTc MDP. (A) A whole-body bone scan of a 16-year-old boy with a femoral Ewing sarcoma showing physeal uptake in the bilateral upper and lower extremities compatible with open physes. The uptake persisting in the wrists, knees, and ankles (arrows) can be specifically noted. (B) A whole-body bone scan of a 16-year-old girl showing a more typical adult pattern of distribution of tracer with minimal residual physeal uptake at the proximal humeri, the remaining physes are mature.

secondary to trauma, infection, or tumors, both benign and malignant. Differences in pathologic uptake based on gender in the pediatric skeleton mostly reflect the occurrence rate of the underlying disease. For example, chronic recurrent osteomyelitis has a slight female predominance whereas osteoid osteomas are more common in male individuals.72 Both Ewing sarcoma and osteosarcoma are more common in male individuals (Fig. 7).

Conclusion Gender-based differences in pediatric imaging begin during early embryology and continue through puberty into adulthood. Most of these differences that are evident on nuclear medicine imaging studies are related to the physiological differences in development that occur during normal childhood and adolescence, or simply secondary to the gender-related incidence of disease. Familiarity with these differences is important both in the interpretation of studies and for the counseling of patients and their families regarding radiation risk.

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