Review Reports - Thyrotroph Pituitary Neuroendocrine Tumors: Molecular Pathology, Diagnostic Challenges, and Receptor-Targeted Therapeutic Strategies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors provide a comprehensive and logically structured review of the latest insights into thyrotroph PitNETs. The manuscript is clear and informative. I have several minor comments that may further improve clarity and precision:

1. Regarding TRH stimulation test, it may be helpful to specify the administered dose of TRH, as this would enhance reproducibility and clinical clarity (lines 275–282).
2. A brief mention of the potential utility of short-acting SSAs in the diagnostic setting may provide additional perspective, although their role in differential diagnosis is not as well established as that of GHRP-2 (lines 254–313).
3. The notation “p27^Kip1” appears in several places. Although this may be due to journal formatting conventions, the authors may wish to consider either formatting “Kip1” as superscript consistently or using “p27Kip1,” in accordance with the journal’s preferred style (Line 90 and elsewhere).

Author Response

We sincerely thank the reviewers for their constructive and insightful comments. We have carefully revised the manuscript and believe it has been substantially strengthened. All modifications are detailed below.

1. Regarding TRH stimulation test, it may be helpful to specify the administered dose of TRH, as this would enhance reproducibility and clinical clarity (lines 275–282).

Response: The TRH dose (5oo μg) has been specified to improve reproducibility (line 382).

A brief mention of the potential utility of short-acting SSAs in the diagnostic setting may provide additional perspective, although their role in differential diagnosis is not as well established as that of GHRP-2 (lines 254–319).

Response: A brief comment on short-acting somatostatin receptor ligands in diagnostic settings has been added (lines 493–509).

The notation “p27^Kip1” appears in several places. Although this may be due to journal formatting conventions, the authors may wish to consider either formatting “Kip1” as superscript consistently or using “p27Kip1,” in accordance with the journal’s preferred style (Line 90 and elsewhere).

Response: The notation of p27Kip1 has been standardized throughout.

Reviewer 2 Report

Comments and Suggestions for Authors

Attached is my report for the author

Comments for author File: Comments.pdf

Author Response

Responses to Reviewer 2:

1. Response: (line 98) A literature identification paragraph has been added, and recent publications from the past five years were incorporated.

Response: (line 273) We have expanded Section 5 to include a structured, stepwise diagnostic pathway that explicitly addresses assay interference, binding abnormalities, macro-TSH, peripheral markers, dynamic testing, imaging, SRL response, and TRβ genetic evaluation. The diagnostic sequence is summarized in the revised Table 1 and new Figure 1.
Response: (line 364) The dynamic testing section has been revised to clarify limitations and safety considerations. GHRP-2 testing is now framed as preliminary and hypothesis-generating.
Response: (line 205) The pathology section now includes Ki-67, mitotic count, p53, and discussion of tumor behavior frameworks.
Response: (line 493) The SRL section now includes quantitative ranges for biochemical control (70–90%) and tumor shrinkage (40–60%), predictors of response, and a brief comment on pasireotide.
Response: (line 595) The future perspectives section now includes receptor-targeted imaging and PRRT.
Response: (line 113) Epidemiology has been expanded with specific prevalence data and discussion of diagnostic delay.

Minor comments

1-Terminology consistency: Use “thyrotroph PitNETs” consistently; introduce “TSHoma” once as legacy terminology and avoid switching terms repeatedly.

Response: Thyrotroph PitNETs, historically referred to as TSH-secreting adenomas; TSHomas.

2-WHO classification clarity: Ensure the “2022 WHO classification” citation is

accurate and described consistently throughout.

Response: We thank the reviewer for this important comment. We have revised the manuscript to ensure consistent and accurate reference to the 2022 WHO Classification of Endocrine and Neuroendocrine Tumours (5th edition).

3-Tables: Table 1 and Table 2 are referenced; please ensure they are optimised for

practical bedside use. For Table 1, consider adding assay interference checks,

alpha-subunit (if discussed), peripheral markers (e.g., SHBG), MRI findings, TRH

response patterns, SSA response, and TRβ genetic testing.

Response: Table 1 summarizes a practical, stepwise approach to inappropriate TSH secretion, incorporating assay interference, peripheral markers, dynamic testing, imaging findings, and genetic evaluation.

Table 2 has been revised to provide a practical, scenario-based treatment framework, incorporating quantitative biochemical control rates, tumor shrinkage expectations, predictors of response, and clinical considerations relevant to bedside decision-making.

We believe these modifications substantially enhance the clinical usability of the tables.

4-Bone health paragraph: This is valuable; consider clarifying whether vertebral

fracture risk is primarily driven by thyroid hormone excess versus other pituitary or

treatment-related contributors.

Response: (line 547) Skeletal fragility appears primarily driven by chronic thyroid hormone excess rather than intrinsic pituitary tumor effects, although cumulative endocrine disturbances may contribute in selected cases.

5-Figure 1 legend: Consider adding a brief note that receptor expression can be

heterogeneous and that SSTR2 scoring methods vary, to avoid overgeneralization

of predictive claims.

Response: (new Figure 2) Receptor expression may be heterogeneous, and SSTR2 scoring methods vary among studies, which may influence predictive interpretation.

Minor comments have been addressed throughout.

We appreciate the reviewers’ suggestions, which have significantly improved the clarity and clinical applicability of the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This review provides a thorough overview of the molecular pathology, diagnosis, and therapeutic strategies for thyrotroph PitNETs (TSHomas) with logical structure and robust evidence. It is acceptable for publication after addressing the following minor revisions: Add common clinical manifestations of TSHomas (e.g., thyrotoxicosis-related symptoms, mass effect manifestations) and characteristics predisposing to misdiagnosis (atypical clinical presentations, rarity, overlapping biochemical profiles with other thyroid conditions). Integrate the fragmented discussions on TSHoma differential diagnosis (present in Sections 1.1 and 5) into one unified section to enhance readability.

Author Response

Review 3

We thank the reviewer for the positive evaluation and constructive suggestions.

We have added a new subsection 2.3. (“Clinical Presentation and Diagnostic Challenges”) summarizing common thyrotoxicosis-related symptoms, mass effect manifestations, and factors predisposing to misdiagnosis, including atypical clinical presentations, disease rarity, biochemical overlap with RTHβ, and inappropriate initial treatment with antithyroid drugs.
To improve readability and structural coherence, we have consolidated the differential diagnosis discussion into Section 5 and removed fragmented references to differential diagnosis in earlier sections. This restructuring provides a unified and sequential diagnostic narrative.

We believe these modifications enhance clarity and clinical relevance.