Metabolic Subtyping of Pheochromocytoma and Paraganglioma by 18F-FDG Pharmacokinetics Using Dynamic PET/CT Scanning

Anouk van Berkel; Dennis Vriens; Eric P. Visser; Marcel J.R. Janssen; Martin Gotthardt; Ad R.M.M. Hermus; Lioe-Fee de Geus-Oei; Henri J.L.M. Timmers

doi:10.2967/jnumed.118.216796

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FIGURE 1.
Irreversible 2-tissue-compartment model for ¹⁸F-FDG metabolism. Measured PET signal is combination of intracellular activity concentration of free ¹⁸F-FDG (nonmetabolized ¹⁸F-FDG in tissue), intracellular activity concentration of ¹⁸F-FDG-6-phosphate (metabolized ¹⁸F-FDG-6-PO₄ in tissue), and fraction of activity concentration of ¹⁸F-FDG in blood plasma (V_b). By using dynamic PET/CT, pharmacokinetic rate-constants K₁ and k₂ (rate constants of transport of ¹⁸F-FDG into and out of tumor cell by glucose transporters, in mL/g/min), k₃ (rate constant of cytoplasmic phosphorylation of ¹⁸F-FDG by hexokinase, per minute), and V_b (in milliliters of blood per milliliter of tumor) can be determined using nonlinear least-squares regression of dynamic PET/CT data. Vertical dashed line represents cell membrane
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FIGURE 2.
Dynamic ¹⁸F-FDG PET/CT results in patient 24, with primary sporadic PPGL in left adrenal. (A) Parametric image of MR_glc from dynamic ¹⁸F-FDG PET scan. (B) Static ¹⁸F-FDG PET/CT scan. (C) CT scan. (D) Image-derived input function and tumor time–activity curve. (E) Patlak plot. Slope of Patlak plot equals influx constant K_i
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FIGURE 3.
Scatterplots showing MR_glc (A) and ¹⁸F-FDG SUV_max (B) in PPGLs across different genotypes. Horizontal bar represents median and interquartile range. Diamonds represent 3 different tumor locations in same patient (patient 7, Table 1). All SUVs are normalized for body weight and decay. P values are from Kruskal–Wallis with Dunn post hoc testing, and groups are compared as indicated. ns = not significant.
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FIGURE 4.
Pharmacokinetic rate-constants (K₁, k₂, and k₃) and blood volume fraction (V_b) in PPGLs across different genotypes. Horizontal bar represents median and interquartile range (IQR). Diamonds represent 3 different tumor locations in same patient (patient 7). P values are from Kruskal–Wallis with Dunn post hoc testing, and groups are compared as indicated. ns = not significant.
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FIGURE 5.
Receiver-operating-characteristic curve for pharmacokinetic rate-constant k₃ (A) and SUV_max (B). This curve was constructed from k₃ and SUV_max of cluster 1 tumors vs. other (cluster 2 and sporadic) tumors in patients with PPGL. Diagonal line represents line of no discrimination.

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TABLE 1

Patient Characteristics

Patient no.	Sex	Genotype	Age (y)	Tumor location	Status	Maximum tumor diameter (cm)	Biochemical phenotype
1	M	NF1	66	LA	Primary	1.2	E + NE
2	F	NF1	31	LA	Primary	4.0	E + NE
3	F	RET	62	LA	Primary	3.4	E + NE
4	F	RET	20	RA	Primary	3.5	E + NE
5	M	RET	35	RA	Primary	2.1	E + NE
6	M	RET	70	LA	Primary	3.0	E
7	F	SDHA	63	LA	Primary	NA	NE + DA
				EA (thoracic spine)	Metastatic	NA	NE + DA
				EA (paraaortic lymph node)	Metastatic	NA	NE + DA
8	M	SDHA	35	EA (retroaortic lymph node)	Metastatic	NA	DA
9	M	SDHB	46	EA (dorsolateral bladder)	Recurrent	NA	NE + DA
10	M	SDHD	64	RA	Primary	1.5	NE + DA
11	M	VHL	48	RA	Primary	2.2	NE
12	F	Sporadic	55	LA	Primary	11.0	E + NE
13	F	Sporadic	34	RA	Primary	5.0	E + NE
14	M	Sporadic	51	EA (retrocaval lymph node)	Metastatic	2.0	NE
15	F	Sporadic	33	LA	Primary	4.0	E + NE
16	F	Sporadic	56	EA (paraaortic lymph node)	Primary	1.4	NE
17	M	Sporadic	66	LA	Primary	1.8	E
18	M	Sporadic	85	RA	Primary	NA	NE
19	M	Sporadic	55	LA	Primary	3.5	E + NE
20	M	Sporadic	43	LA	Primary	10.0	E + NE
21	F	Sporadic	73	LA	Primary	12.5	NE + DA
22	F	Sporadic	55	RA	Primary	1.5	E
23	M	Sporadic	64	RA	Primary	5.0	E + NE
24	F	Sporadic	55	LA	Primary	6.0	E + NE

LA = left adrenal; RA = right adrenal; EA = extraadrenal; NA = not available; E = epinephrine; NE = norepinephrine; DA = dopamine.

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TABLE 2

¹⁸F-FDG PET/CT Parameters

Parameter	All tumor lesions (n = 26)	Primary tumors (n = 22)	Metastases (n = 4)
MR_glc (nmol⋅mL⁻¹⋅min⁻¹)	53.6 (13.2–412.4)	49.4 (13.2–412.4)	137.6 (14.6–219.8)
SUV_max (g⋅cm⁻³)	4.7 (1.3–21.1)	4.6 (1.3–19.6)	7.1 (2.0–21.1)
K₁ (mL⋅g⁻¹⋅min⁻¹)	0.42 (0.10–3.25)	0.41 (0.18–3.25)	0.46 (0.96–0.51)
k₂ (min⁻¹)	0.95 (0.13–2.82)	0.93 (0.13–2.83)	1.04 (0.24–1.15)
k₃ (min⁻¹)	0.032 (0.011–0.170)	0.032 (0.014–0.151)	0.049 (0.011–0.170)
V_b (mL⋅mL⁻¹)	0.148 (0.037–0.738)	0.144 (0.037–0.738)	0.182 (0.080–0.390)

Data are median followed by range in parentheses. No significant differences were observed between 2 groups (Mann–Whitney U test).

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TABLE 3

¹⁸F-FDG Pharmacokinetic Rate-Constants for Primary and Metastatic PPGLs

Rate constant	Hereditary cluster 1 tumors (SDHx, VHL) (n = 7)	Hereditary cluster 2 tumors (RET, NF1) (n = 6)	Sporadic tumors (n = 13)
K₁ (mL⋅g⁻¹⋅min⁻¹)	0.28 (0.10–3.25)	0.44 (0.23–0.65)	0.50 (0.18–1.01)
k₂ (min⁻¹)	0.79 (0.13–2.82)	1.08 (0.54–1.50)	0.99 (0.47–1.49)
k₃ (min⁻¹)	0.084 (0.015–0.170)^*	0.041 (0.015–0.062)	0.025 (0.011–0.059)
V_b (mL⋅mL⁻¹)	0.219 (0.080–0.738)^†	0.105 (0.037–0.128)	0.151 (0.072–0.300)

↵* Significantly higher than sporadic tumor values (P < 0.01, Kruskal–Wallis with post hoc Dunn test).
↵† Significantly higher than hereditary cluster 2 values (P < 0.01, Kruskal–Wallis with post hoc Dunn test).
Data are median followed by range in parentheses.

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TABLE 4

Determinants of MR_glc

	MR_glc (nmol⋅mL⁻¹⋅min⁻¹)
Parameter	R² (95% CI)	P
SUV_max	0.475 (0.291 to 0.882)	0.001^*
K₁ (mL⋅g⁻¹⋅min⁻¹)	0.066 (−0.629 to 0.156)	0.228
k₂ (min⁻¹)	0.145 (−0.732 to 0.073)	0.067
k₃ (min⁻¹)	0.358 (0.181 to 0.832)	0.002^*
V_b (mL⋅mL⁻¹)	0.107 (−0.103 to 0.677)	0.118