A Nondiagnostic 99mTc-PYP Scan with Absent Skeletal Uptake

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the opportunity to review this interesting image report describing a nondiagnostic 99mTc-PYP scan characterized by gastric and thyroid uptake with complete absence of skeletal uptake.

The case is educational and clinically relevant because 99mTc-PYP scintigraphy is increasingly used for the noninvasive diagnosis of transthyretin cardiac amyloidosis, and recognition of imaging pitfalls is essential for accurate interpretation. The manuscript conveys an important practical message: abnormal biodistribution should prompt consideration of a nondiagnostic examination rather than a negative study.

The report is concise, clearly written, and supported by illustrative imaging findings. Nevertheless, several aspects could be strengthened to enhance its educational value and scientific impact.

1. Expand the Differential Diagnosis of Abnormal Biodistribution

The manuscript appropriately attributes the imaging findings to free 99mTc-pertechnetate–like biodistribution. However, the discussion would benefit from a broader differential diagnosis of abnormal biodistribution patterns in 99mTc-PYP imaging.

Please discuss whether factors such as radiochemical purity failure, labeling inefficiency, injection errors, dose extravasation, or patient-related physiological factors could produce similar appearances and how they may be differentiated in clinical practice.

2. Provide Additional Technical Information

More information regarding radiopharmaceutical preparation and quality control procedures would be valuable.

Please clarify:

Whether routine radiochemical purity testing was performed before administration.
Whether any other patients scanned on the same day demonstrated abnormal biodistribution.
Whether any procedural irregularities were identified during subsequent investigation.

These details would improve the educational value of the report.

3. Emphasize the Role of SPECT/CT

The manuscript correctly demonstrates that planar imaging alone could potentially be misleading. However, the discussion should further emphasize how SPECT/CT contributed to avoiding misclassification and why tomographic evaluation should be considered essential in such cases.

4. Clinical Implications

The practical implications of misinterpreting such a study deserve additional discussion.

For example, what potential diagnostic or therapeutic consequences could occur if this scan were incorrectly interpreted as negative or equivocal rather than nondiagnostic?

5. Consider adding a brief schematic summary or teaching points box highlighting key imaging clues suggesting a nondiagnostic study.

6. The figure legends could be expanded slightly to improve educational clarity for readers less familiar with cardiac amyloidosis imaging.

7. The manuscript may benefit from citing additional literature describing abnormal biodistribution patterns or radiopharmaceutical preparation pitfalls in bone-avid tracer imaging.

8. Please clarify whether salivary gland uptake was present on the initial examination, as this may further support free pertechnetate biodistribution.

This is an educational and publishable image report that highlights an important diagnostic pitfall in 99mTc-PYP scintigraphy. With minor expansion of the technical discussion and practical teaching points, the manuscript would provide even greater value for clinicians and nuclear medicine physicians.

Author Response

1. Expand the Differential Diagnosis of Abnormal Biodistribution

The manuscript appropriately attributes the imaging findings to free 99mTc-pertechnetate–like biodistribution. However, the discussion would benefit from a broader differential diagnosis of abnormal biodistribution patterns in 99mTc-PYP imaging.

Please discuss whether factors such as radiochemical purity failure, labeling inefficiency, injection errors, dose extravasation, or patient-related physiological factors could produce similar appearances and how they may be differentiated in clinical practice.

 

Abnormal biodistribution in 99mTc-PYP imaging may result from several causes, including radiochemical purity failure, labeling inefficiency, inadvertent injection of an incorrect radiopharmaceutical, dose extravasation, and patient-related physiological factors. In clinical practice, these possibilities should be assessed by reviewing the distribution pattern, injection site, preparation and administration records, quality control procedures, and other examinations performed on the same day. In the present case, the combination of prominent gastric and thyroid uptake with complete absence of skeletal activity was most compatible with free 99mTc-pertechnetate–like biodistribution rather than dose extravasation or patient-specific physiology.

 

2. Provide Additional Technical Information

More information regarding radiopharmaceutical preparation and quality control procedures would be valuable.

Please clarify:

Whether routine radiochemical purity testing was performed before administration.
Whether any other patients scanned on the same day demonstrated abnormal biodistribution.
Whether any procedural irregularities were identified during subsequent investigation.

These details would improve the educational value of the report.

 

After the abnormal biodistribution was recognized, the radiopharmaceutical preparation and administration process was reviewed. Routine radiochemical purity testing had not been performed before administration in this case, and no clear procedural irregularity was identified. No other patient underwent 99mTc-PYP scintigraphy using the same preparation on that day. A qualitative post hoc test of the residual PYP kit preparation was performed by the supplier using a silver nitrate reagent under acidic conditions with acetic acid. This test did not suggest gross labeling failure of the residual preparation. However, it did not provide a quantitative radiochemical purity value at the time of administration and could not confirm the composition of the injected syringe. Therefore, the exact mechanism could not be definitively established. Possible explanations included incomplete radiolabeling with a high fraction of free 99mTc-pertechnetate or inadvertent administration of free 99mTc-pertechnetate instead of the prepared 99mTc-PYP.

 

3. Emphasize the Role of SPECT/CT

The manuscript correctly demonstrates that planar imaging alone could potentially be misleading. However, the discussion should further emphasize how SPECT/CT contributed to avoiding misclassification and why tomographic evaluation should be considered essential in such cases.

SPECT/CT was essential in this case because planar imaging alone showed mild apparent activity over the cardiac region and could have been misleading. Tomographic evaluation confirmed the absence of definite myocardial uptake and demonstrated abnormal systemic biodistribution, supporting classification of the initial examination as nondiagnostic.

 

4. Clinical Implications

The practical implications of misinterpreting such a study deserve additional discussion.

For example, what potential diagnostic or therapeutic consequences could occur if this scan were incorrectly interpreted as negative or equivocal rather than nondiagnostic?

 

Misinterpreting such a technically invalid study as negative or equivocal could delay repeat imaging and appropriate diagnostic evaluation for cardiac amyloidosis

 

5. Consider adding a brief schematic summary or teaching points box highlighting key imaging clues suggesting a nondiagnostic study.

 

Teaching points: Key imaging clues suggesting a nondiagnostic 99mTc-PYP study include prominent gastric or thyroid uptake, complete absence of skeletal activity, and discordance between apparent cardiac-region activity on planar imaging and absence of definite myocardial uptake on SPECT/CT.

 

6. The figure legends could be expanded slightly to improve educational clarity for readers less familiar with cardiac amyloidosis imaging.

 

In anterior planar imaging, slight uptake was observed in the cardiac region, and uptake was seen in the thyroid gland (arrowhead) and stomach (arrow) (Figure 1a). A fused SPECT/CT image at the upper abdominal level showed intense gastric uptake (arrow) and absence of uptake in the adjacent vertebral body (arrowhead), supporting abnormal systemic biodistribution (Figure 1b). A fused SPECT/CT image at the cardiac level showed no definite myocardial uptake (Figure 1c). Salivary gland uptake could not be assessed because the salivary glands were outside the imaging field of view. These findings suggested free 99mTc-pertechnetate–like biodistribution, and the examination was considered nondiagnostic.

 

7. The manuscript may benefit from citing additional literature describing abnormal biodistribution patterns or radiopharmaceutical preparation pitfalls in bone-avid tracer imaging.

Gastric uptake on 99mTc-PYP imaging may also suggest hypercalcemia, hyperparathyroidism, or free pertechnetate contamination, and should prompt review of clinical, laboratory, and radiopharmaceutical factors [6].

 

8. Please clarify whether salivary gland uptake was present on the initial examination, as this may further support free pertechnetate biodistribution.

 

In anterior planar imaging, slight uptake was observed in the cardiac region, and uptake was seen in the thyroid gland (arrowhead) and stomach (arrow) (Figure 1a). A fused SPECT/CT image at the upper abdominal level showed intense gastric uptake (arrow) and absence of uptake in the adjacent vertebral body (arrowhead), supporting abnormal systemic biodistribution (Figure 1b). A fused SPECT/CT image at the cardiac level showed no definite myocardial uptake (Figure 1c). Salivary gland uptake could not be assessed because the salivary glands were outside the imaging field of view. These findings suggested free 99mTc-pertechnetate–like biodistribution, and the examination was considered nondiagnostic.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The imaging case, “A Nondiagnostic 99mTc-PYP Scan with Absent Skeletal Uptake” by Hiroyuki Tokue, Azusa Tokue, and Yoshito Tsushima, presents a rare and clinically important finding. The case highlights a potential pitfall in the interpretation of 99mTc-PYP scintigraphy and will be of interest to readers. I recommend publication after the following minor revisions:

1. Please consider replacing the phrase “recorded as” in the title of Figure 1 with more appropriate terminology.
2. Please provide the normal reference range for the serum creatinine level.
3. Please add an arrow indicating the cardiac uptake in Figure 1.
4. Lines 66–67: Please verify the description of Figure 1b, as it may require correction or clarification.
5. Please consider including an example image of ATTR cardiac amyloidosis (Grade 2–3 uptake) demonstrating the expected distribution of 99mTc-PYP uptake in both the heart and skeletal structures for comparison.
6. Please add arrows to Figures 2a and 2c to facilitate identification of the relevant findings.
7. Lines 109–110: Based on the findings presented, I believe it would be appropriate to state more definitively that the patient did not have cardiac amyloidosis.
8. Please provide the serum creatinine level at the time of the repeat examination.

Overall, this is an interesting and educational case report that will benefit from these minor clarifications and additions.

Author Response

Please consider replacing the phrase “recorded as” in the title of Figure 1 with more appropriate terminology.

Figure 1. Initial examination presumed to be 99mTc-PYP scintigraphy.

 

Please provide the normal reference range for the serum creatinine level.

 

The patient had chronic kidney disease, with an estimated glomerular filtration rate of 29 mL/min/1.73 m² and serum creatinine of 1.78 mg/dL (reference range, 0.46–0.79 mg/dL). No serum monoclonal protein or urinary Bence Jones protein was detected.

 

Please add an arrow indicating the cardiac uptake in Figure 1.

 

In anterior planar imaging, slight uptake was observed in the cardiac region (yellow arrows), and uptake was seen in the thyroid gland (arrowhead) and stomach (arrow) (Figure 1a).

 

Lines 66–67: Please verify the description of Figure 1b, as it may require correction or clarification.

 

A fused SPECT/CT image at the upper abdominal level showed intense gastric uptake (arrow) and absence of uptake in the adjacent vertebral body (arrowhead), supporting abnormal systemic biodistribution (Figure 1b).

 

Please consider including an example image of ATTR cardiac amyloidosis (Grade 2–3 uptake) demonstrating the expected distribution of 99mTc-PYP uptake in both the heart and skeletal structures for comparison.

 

We thank the reviewer for this helpful suggestion. We agree that a typical ATTR cardiac amyloidosis case with Grade 2–3 uptake would provide useful comparison. However, we did not include an additional patient image because the focus of this report is the abnormal biodistribution pattern in the present case, and adding another case may broaden the scope of this image report. Instead, we have expanded the text and figure legends to clarify the expected finding of 99mTc-PYP scintigraphy, namely skeletal uptake with or without myocardial uptake depending on the presence of cardiac amyloidosis.

 

In a valid positive study, myocardial uptake is interpreted in relation to background skeletal, particularly rib, uptake.

 

Please add arrows to Figures 2a and 2c to facilitate identification of the relevant findings.

 

Figures 2a and 2c were changed.

 

Lines 109–110: Based on the findings presented, I believe it would be appropriate to state more definitively that the patient did not have cardiac amyloidosis.

 

Based on the repeat 99mTc-PYP findings, negative histopathological findings, and genetic analysis, cardiac amyloidosis was excluded.

 

Please provide the serum creatinine level at the time of the repeat examination.

 

The serum creatinine level at the time of the repeat examination was 1.75 mg/dL.

Author Response File: Author Response.pdf