Planning of ¹³¹I Therapy for Graves Disease Based on the Radiation Dose to Thyroid Follicular Cells

MATERIALS AND METHODS

Systemically administered iodide is captured by the thyroid and organified and appears in the follicular colloid within minutes of administration, as demonstrated by autoradiographic studies in rats (3). In contrast, the biologic half-life of thyroidal iodine is quite long, varying from 15 to 60 d and yielding an effective half-life of 5–7 d for ¹³¹I. This means that most ¹³¹I decays occur within the colloid, that is, extracellularly.

In the current analysis, we considered only the β-radiation of ¹³¹I. The contribution of γ-radiation to total average gland absorbed dose (average thyroid absorbed dose from both γ-radiation and β-particles of ¹³¹I) increases with the gland size and depends on the gland shape; for a 20-g gland, it is 6% (Appendix). This component is not negligible and should be taken into account. However, because of the relatively long mean free path of γ-rays, compared with particle ranges, the absorbed energy distribution of γ-rays is expected to be uniform across the thyroid volume (i.e., insensitive to thyroid microarchitecture).

The β-radiation–absorbed dose to thyroid follicular cells, D_cell, is due to β-particles emanating from their own colloid (the self-dose [D_self]) and from β-particles coming from the colloid of neighboring follicles (the cross-dose [D_cross]):Eq. 1We assumed that a thyroid is composed of identical follicles. E₀ denotes the total energy of all β-particles emerging from the ¹³¹I distributed uniformly in the colloid of the thyroid follicles. Then D_self equals the energy absorbed in follicular cells originating from their own colloid E_self divided by the mass of follicular cells m_cells:Eq. 2Because of somewhat irregular arrangements of follicles, one cannot assume a regular geometric model of follicular packing. Such an irregular arrangement of follicles leads to the assumption that all radiation energy emanating from the follicles, E₀ − E_coll − E_self, is uniformly absorbed over the thyroid mass, m_thy, where E_coll is the radiation energy self-absorbed within the colloid. This yields the following equation for the nonself, or cross-, absorbed dose, D_cross:Eq. 3Combining Equations 1–3 yields the total follicular cell–absorbed dose:Eq. 4Assuming that all energy of β-particles and secondary radiation are totally absorbed in the thyroid (Appendix), E₀/m_thy is the average dose to thyroid tissue, assessed on the basis of the administered activity and measured thyroid uptake, mass, and effective half-life.

For clarity, we defined the dimensionless quantity, the relative absorbed dose to follicular cells, , as the ratio of D_cell to the average thyroid dose, E₀/m_thy:Eq. 5Multiplying the administered activity determined to deliver a prescribed mean absorbed dose to the thyroid by the quantity 1/ , termed the activity correction factor, yields the administered activity that would deliver the same prescribed dose specifically to follicular cells.

, the first term on the right side of Equation 5, is the relative self-absorbed dose to follicular cells:Eq. 6which equals the self-absorbed fraction of the follicular cells weighed by thyroid–to–follicular cell mass ratio. The relative cross-absorbed dose to follicular cells is simply the fraction of total energy of β-particles that leaves the original follicles:Eq. 7

Finally, the ratio of the relative self-absorbed and cross-absorbed doses to follicular cells equals the ratio of the respective absolute absorbed doses:Eq. 8To calculate the relative absorbed dose to follicular cells and its self- and cross-components, one should assess the fractions of total energy self-absorbed in the colloid and in the follicular cells and the thyroid-to-follicular cell mass ratio.

We used the Monte Carlo code EGS5 (4) to calculate the self-absorbed fractions E_coll/E₀ and E_self/E₀. The input model of the thyroid follicle was a unit-density water sphere, comprising a spheric shell of cells and a concentric inner sphere filled with uniform concentration of ¹³¹I. The initial electron energies were sampled from the ¹³¹I β-spectrum as calculated by Simpkin and Mackie (5). The emissions of discrete electrons were simulated as well. The numbers of simulated electron histories were always sufficiently large that the statistical uncertainties (errors) were less than 1%. Electrons and photons were followed until their energy reached the transport cutoff values, which were both set equal to 1 keV. Below this cutoff, the energy was deposited locally. Secondary particles were followed if their initial energy was greater than 1 keV. The calculations were performed for radii of colloid spheres ranging from 10 to 400 μm and follicular cell thicknesses of 5, 10, and 15 μm.

The thyroid–to–follicular cell mass ratio was calculated assuming that 90% of thyroid tissue is composed of follicles (6). Denoting by r the radius of colloid sphere and by h the thickness of epithelial cell layer, this ratio is:Eq. 9

RESULTS

The self-absorbed fraction in colloid spheres ranges from several percentage points for small radii (i.e., up to 50 μm) to 45% for large radii (i.e., 400 μm). The relative absorbed dose to follicular cells ranges from about 1, in the case of colloid radii below 50 μm, to about 0.77 for a 400-μm radius. The follicular cell thickness had minor effects (Table 1).

In terms of the practical useful activity correction factor, 1/, patients having colloid spheres with radii of 100, 200, 300, and 400 μm should be given 9%, 15%, 21%, and 30% more ¹³¹I activity than that administered to patients with colloidal spheres of radii of less than 50 μm.

DISCUSSION

The motivation for this work was our clinical results on the cohort of patients with Graves disease treated with radioiodine. The patients with a normoechogenic gland with a planned average thyroid dose of 200 Gy (ablative dose) had comparable outcomes to patients with a hypoechogenic gland with planned average thyroid doses of only 100–120 Gy (nonablative doses).

Within the thyroid, the majority of ultrasound reflections occur at interfaces between follicular cells and colloid. Thyroid glands, which are hypercellular (i.e., have relatively little colloid), have fewer reflective surfaces and thus are hypoechogenic, whereas normoechogenic (or hyperechogenic) patterns are seen in glands with normal (or high) colloidal content (i.e., with normal-size [or large] follicles and relatively small cellular volume) (7,8). Although at presentation the hyperactive glands are almost always hypoechogenic (7), antithyroid medication occasionally normalizes follicular structure. Consequently, patients who had prior antithyroid therapy present with a wide spectrum of echogenicities (9,10). In normal thyroids, follicular radii range from 100 to 500 μm, and untreated hyperactive glands are characterized by cell hypertrophy and hyperplasia and small, almost-emptied colloidal spaces due to accelerated hormone turnover (11). In practice, because of variable antithyroid drug–induced involution of thyroid tissue, a wide range of follicle sizes is expected. Thus, our clinical results (10) seem reasonable in terms of more radiation being “wasted” in the larger follicles of normoechogenic glands than in the smaller follicles of hypoechogenic glands.

However, the results of this simulation only partly explain our clinical results (10). Although the effect of the substantial fraction of radiation energy absorbed within large colloid spheres on diminishing the ¹³¹I radiation dose to thyroid follicular cells is significant, it is not as large as might be anticipated. To explain these results, one should consider the components of the relative absorbed dose to follicular cells. The colloid self-absorption diminishes the relative cross-absorbed dose to follicular cells, which depends solely on the fraction of radiation energy emerging from each follicle (Eq. 7). However, this effect is balanced to some extent by the opposing effect on the relative self-absorbed dose to follicular cells: the larger the colloid sphere, the lesser the fraction of follicular cells in thyroid mass and the greater the self-absorbed dose (Eq. 7). For small follicles, the cross-absorbed dose is several times larger than is the self-absorbed dose. However, as the follicle size and colloidal self-absorption increase, the relative contribution of cross-absorbed dose rapidly diminishes to about only 2 times the self-absorbed dose in the case of a 400-μm radius of follicular colloid.

The generalization of the current model, allowing for the distribution of follicle sizes in a thyroid, is also possible. The assumption of identical follicles was used only in Monte Carlo estimations of the self-absorbed fractions E_coll/E₀ and E_self/E₀; Equations 1–9, however, also hold in cases of nonuniform follicular sizes. Given the distribution of follicle sizes, the fractions of radiation energy self-absorbed in colloid and follicular cells can be estimated from the current results, assuming uniform concentration of radioiodine in all colloidal spheres.

The histologic data on the thyroid follicular sizes describe the distribution of the sizes of cross-sections of irregularly packed follicles in random cut planes. These data underestimate the actual follicular sizes, which can be assessed only in the follicular equatorial planes. In addition, the use of punch biopsies instead of surgical specimens (7,8) has never been evaluated, and one cannot exclude the possibility that pooling the punched tissue through a narrow metal cylinder selectively draws the subpopulation of smaller follicles. Data on the actual sizes of thyroid follicles are currently incomplete. In any case, the current study demonstrates that the thyroid microstructure may be at least partially responsible for more favorable clinical responses of hypoechogenic thyroids, with smaller colloidal spaces and therefore lower intracolloidal self-absorption of ¹³¹I β-radiation. However, the possible effects on follicular cell response of patient-to-patient differences in intrinsic radiosensitivity certainly cannot be ignored.

We used 2 assumptions in assessing the relative absorbed dose to follicular cells: the spatially uniform absorption of radiation emanating from the follicles (the fraction not self-absorbed in colloid and follicular cells) and close packing of the follicles, regardless of their size. The latter is suggested by micrographs of normal and hyperactive thyroid tissue showing that, although varying in size, follicles are always closely packed (11), with the assumption that follicles comprise 90% of the mass of the thyroid likewise based on animal data (6). The assumption of uniform distribution of cross-absorbed dose means that radiation emanating from a given follicle is not preferentially absorbed in any of the 3 thyroid compartments, colloid or follicular cells, or interfollicular spaces. Although the assumption may not be perfectly realistic in all patients, it agrees with partly irregular, close packing of follicles and avoids the need for a geometric model of follicular packing in assessing cross-dose.

Insight into follicular structure could also prove useful in ablative radioiodine therapies (toxic nodular goiter, metastases of differentiated thyroid carcinoma), at least as a prognostic factor. The predominance of the follicular cell cross-dose over the self-dose is specific for β-radiation of ¹³¹I. In the case of Auger emitters, such as ¹²⁵I, the opposite would be true, because the dose is largely confined to the follicle in which the electrons are emitted.

CONCLUSION

The characteristic histologic structure of thyroid tissue, organized in follicles, and the hormone kinetics, effectively segregating radioiodine in follicular lumen, affect the distribution of radiation-absorbed dose between the follicular cells and other gland structures, even in the case of the relatively long-range β-emitter ¹³¹I. This may require a patient-specific approach to radioimmunotherapy of Graves disease. Methods to assess the variable thyroid histology in clinical settings should be addressed.

APPENDIX