Round 1

Reviewer 1 Report

 

Dear authors,

I have read with interest your manuscript entitled “Fast track management of primary thyroid lymphoma in the very elderly patient”. The manuscript is interesting as dealing with a rare entity that needs not be missed. The discussion section is very detailed but too long and should be shortened. Further comments are provided below.


Abstract

Line 39 : DLBCL : abbreviation not defined in the abstract

 

Introduction section

The authors miss two main points :

1.     it is now of utmost importance to differentiate primary thyroid lymphoma from anaplastic carcinoma as we now have at our disposal targeted therapies which are greatly improving disease specific survival in the latter

2.     The diagnosis of anaplastic carcinoma thus has now become an emergency and CNB and quick NGS (droplet test) play a pivotal role here.

Those two points should be stressed both in the introduction and discussion sections.

 

 

Line 46 : “Primary thyroid lymphoma (PTL) is an uncommon disease, representing less than 5% of thyroid malignancies” : add a reference please.
Suggested reference : Fagin JA, Wells SA Jr. Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med. 2016 Sep 15;375(11):1054-67. doi: 10.1056/NEJMra1501993. PMID: 27626519; PMCID: PMC5512163.

 

Line 48 : “especially in women with Hashimoto's thyroiditis (HT)”. It has been shown that 89% of thyroid lymphomas arise in a context of previous auto-immune disease. Please quote this reference and discuss it in the discussion section :

Suzuki N, Watanabe N, Noh JY, Yoshimura R, Mikura K, Kinoshita A, Suzuki A, Mitsumatsu T, Fukushita M, Matsumoto M, Yoshihara A, Katoh R, Sugino K, Ito K. The Relationship Between Primary Thyroid Lymphoma and Various Types of Thyroid Autoimmunity: A Retrospective Cohort Study of 498 Cases, Including 9 Cases with Graves' Disease. Thyroid. 2022 May;32(5):552-559. doi: 10.1089/thy.2021.0613. Epub 2022 Apr 12. PMID: 35229626.

 

Line 57 : add a comma after “surgery”.

 

Case presentation section

 

Line 82 : “EuTIRADS 5” : please correct to EU-TIRADS 5 and also for all other recurrences.
Line 83 : “neovasculature”. Description could be a little more detailed to explain this expression more precisely and also adding a word on the high resistive index.

Line 107 : “Levothyrox” : please change to International Nonproprietary Name

 

Discussion section

 

In general : too long and a little confuse. Should be a little shortened and presented in a more clear way.

Line 160 : “painless mass” : the case presented here is described in the case presentation section with an “intense painful dysphagia” (line 68). Primary thyroid lymphoma and anaplastic carcinoma are consistently painful. Please correct.

Lines 185-187 : “The relative risk of a HT patient to develop PTL has been estimated 185 to be 40 to 80 times greater than in the general population and to take on average 20 to 30 186 years to develop after the onset of lymphocytic thyroiditis [1].” Please add reference quoted above from Suzuki et al.

Lines 187-189 : “HT usually features EuTI-RADS2 score as diffuse hypoechogenicity [8] of the thyroid gland without a nodule or a 188 mass.” EU-TIRADS scoring is only for nodules. HT can never be classified as EU-TIRADS 2. Please delete.

Lines 198-201 : “When 198 an elderly patient has a rapidly enlarging firm thyroid nodule, very careful assessment of its characteristics on morphological US, Doppler, elastography as well as the contralateral thyroid lobe should be helpful.” I believe that most of the time, it is very difficult to differentiate primary thyroid lymphoma from anaplastic carcinoma with ultrasound alone. This should be a key point of the discussion.
Lines 239-240 : “pushing manually the needle into the lesion while avoiding any arterial tumoral vessel, then firing the biopsy gun”. Please use correct wording : “pushing manually the stylet into the lesion while avoiding any arterial tumoral vessel, then firing the cutting canula”.

Lines 242-244 : “CNB to FNA has shown that thyroid CNB has a superior diagnostic value, with a sensitivity and positive predictive value PPV of 94.3% and 100% for PTL versus 80.1% and 100% for ATC respectively”. The authors are comparing CNB and FNA. The diagnostic value is unclear or not mentioned by the figures. Please correct.

 

 

Table 1

 

“Hashimoto Thyroiditis” : please correct : Hashimoto’s thyroiditis.

 

Author Response

Dear Sir,

We do agree with the suggestions and thank the reviewer . The modifications have been made accordingly  as follows in red in the manuscript. We hope  modifications will meet Reviewer 's expectations.

Yours Sincerely

I have read with interest your manuscript entitled “Fast track management of primary thyroid lymphoma in the very elderly patient”. The manuscript is interesting as dealing with a rare entity that needs not be missed.

The discussion section has been shortened, and modifications regarding anaplastic thyroid carcinomas (ATC) have been made in the introduction and discussion chapters, in red. 
we have deleted the following sentences to shorten the discussion line 173-175: 

"This can be carried out by using multiparametric US assessment (elastography, color Doppler, power Doppler, microvascular imaging, multiple US probes of various frequency) and mass depiction of convex contours."

and:

The following has also been deleted: "HT usually features EuTIRADS2 score as diffuse  hypoechogenicity [8] of the thyroid gland without a nodule or a mass".

Abstract

Line 39 : DLBCL : abbreviation not defined in the abstract

DLBC has been explained and clarified in the text as  diffuse large B cell lymphoma .

Introduction section

Line 46 : “Primary thyroid lymphoma (PTL) is an uncommon disease, representing less than 5% of thyroid malignancies” : add a reference please.
The suggested reference  has been added as reference 1:

Fagin JA, Wells SA Jr. Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med. 2016 Sep 15;375(11):1054-67. doi: 10.1056/NEJMra1501993. PMID: 27626519; PMCID: PMC5512163.

The authors miss two main points :

1. it is now of utmost importance to differentiate primary thyroid lymphoma from anaplastic carcinoma as we now have at our disposal targeted therapies which are greatly improving disease specific survival in the latter
2. The diagnosis of anaplastic carcinoma thus has now become an emergency and CNB and quick NGS (droplet test) play a pivotal role here.

Those two points have been stressed both in the introduction and discussion sections in red as follows:

Introduction:

A rapid growing painful mass in the neck in the elderly with clinical compression raises three main diagnoses of thyroid malignancy: primary thyroid lymphoma (PTL), anaplastic thyroid carcinoma (ATC) and less frequently metastasis to thyroid gland (MTT). PTL is an uncommon disease, representing less than 5% of thyroid malignancies [1]. It has been shown that 89% of thyroid lymphomas arise in a context of previous auto-immune disease [2].  PTL   includes two main types that have different prognosis and treatment; the aggressive life- threatening diffuse large B cell type (DLBC) particularly in the   elderly patient and the indolent mucosa-associated lymphoid tissue (MALT) lymphoma; mixed subtypes are also reported [3].   Thyroid high frequency ultrasound (US) and fine needle aspiration cytology (FNAC) using immunohistochemistry remain the main modalities used to suggest malignant lymphoma. Percutaneous ultrasound-guided core needle biopsy (CNB) may achieve full accurate diagnosis thus further limiting the role of invasive thyroid surgery [4]. DLBCL is aggressive, and survival outcome increases with multimodality therapy incorporating monoclonal antibodies, chemotherapy, and radiation therapy. Prognosis may vary owing to the heterogeneous nature of thyroid malignant lymphomas [1,3,5-7].   Regarding ATC, prognosis is even poorer, differential diagnosis from PTL is urgent and now can be performed by using CNB droplet digital polymerase chain reaction; thus targeted therapies may greatly improve disease specific survival of ATC patients [8].  

Buffet et al's paper has been added as reference !: Buffet C, Allard L, Guillerm E, Ghander C, Mathy E, Lussey-Lepoutre C, Julien N, Touma E, Quilhot P, Godiris-Petit G, Lacorte JM, Leenhardt L, Denis JA. Detection of BRAFV600E by digital PCR on fine-needle aspirate enables rapid initiation of dabrafenib and trametinib in unresectable anaplastic thyroid carcinoma. Eur J Endocrinol. 2022 Aug 2;187(3):K33-K38. doi: 10.1530/EJE-22-0366. PMID: 35900324.

Discussion: line 182-187:

As disease specific survival may be significantly improved by using targeted therapies, differentiating ATC from PTL is of utmost importance and becomes an emergency. Given the aggressive course and resistance to chemotherapy, radiotherapy and radioactive iodine, and the potential to identify a targetable mutation, all patients must undergo expeditious staging, histological confirmation and broad-spectrum next-generation sequencing testing on CNB specimens [20].  

we also added the following to put the stress on the difficulty of differentiating PTL from ATC on US imaging features alone, line 212-215: 

"Identifying echogenic fibrous strands (Fig 1B) that are typical features in favor of PTL could be the key- point  for differentiating PTL from ATC. However, it is very difficult to differentiate PTL from ATC by using ultrasound alone in most of the cases";

-LINE 48: The following reference has been added as requested:

Suzuki N, Watanabe N, Noh JY, Yoshimura R, Mikura K, Kinoshita A, Suzuki A, Mitsumatsu T, Fukushita M, Matsumoto M, Yoshihara A, Katoh R, Sugino K, Ito K. The Relationship Between Primary Thyroid Lymphoma and Various Types of Thyroid Autoimmunity: A Retrospective Cohort Study of 498 Cases, Including 9 Cases with Graves' Disease. Thyroid. 2022 May;32(5):552-559. doi: 10.1089/thy.2021.0613. Epub 2022 Apr 12. PMID: 35229626.

-LINE 57 :  comma after “surgery” has been added as requested.

-LINE 82 : “EuTIRADS 5” :  "EU-TIRADS 5"  has been also modified here and  for all other recurrences.
-LINE 83 : “neovasculature”. Description could be a little more detailed to explain this expression more precisely and also adding a word on the high resistive index. The following modifications have been made :

“Sword like” vessel is abnormal aberrant tumor artery merely noticed in dedifferentiated thyroid cancers ATC and PTL (arrow A, C, D) and high resistive index (RI=1) on spectral analysis (D) are shown [10]. High RI >0.75 is typical of malignant neoangiogenesis.

-LINE 107 : “Levothyrox” : has been changed to International Nonproprietary Name: Levothyroxine.

Discussion:

-LINE 160:  "painless" mass has been modified:  "A painful  mass of the neck with presence of clinical compressive symptoms in an elderly patient > 60- 70 years old are..." 

Lines 185-187 : "Suzuki" reference has been added.  “The relative risk of a HT patient to develop PTL has been estimated to be 40 to 80 times greater than in the general population and to take on average 20 to 30years to develop after the onset of lymphocytic thyroiditis [2].” 

-Lines 187-189 : “HT usually features EuTI-RADS2 score as diffuse hypoechogenicity [8] of the thyroid gland without a nodule or a  mass.” EU-TIRADS scoring is only for nodules. HT can never be classified as EU-TIRADS 2. Please delete.  The following has been deleted: "HT usually features EuTIRADS2 score as diffuse  hypoechogenicity [8] of the thyroid gland without a nodule or a mass".

-Lines 198-201 : “When  an elderly patient has a rapidly enlarging firm thyroid nodule, very careful assessment of its characteristics on morphological US, Doppler, elastography as well as the contralateral thyroid lobe should be helpful.” I believe that most of the time, it is very difficult to differentiate primary thyroid lymphoma from anaplastic carcinoma with ultrasound alone. This should be a key point of the discussion. Modifications have been made accordingly as follows:

"Identifying echogenic fibrous strands that are typical of PTL could be the key point of differential diagnosis from ATC. However, it is very difficult to differentiate PTL from ATC by using ultrasound alone in most of the cases."

-Lines 239-240 : “pushing manually the needle into the lesion while avoiding any arterial tumoral vessel, then firing the biopsy gun”. 

Correct wording as requested has been performed as  : “pushing manually the stylet into the lesion while avoiding any arterial tumoral vessel, then firing the cutting canula”. Correction has also been made in Fig 2 caption, and video S1 file caption.

 

-Lines 242-244 : “CNB to FNA has shown that thyroid CNB has a superior diagnostic value, with a sensitivity and positive predictive value PPV of 94.3% and 100% for PTL versus 80.1% and 100% for ATC respectively”. The authors are comparing CNB and FNA. The diagnostic value is unclear or not mentioned by the figures. Please correct. Correction has been made in Table 1 in red.

Table 1 “Hashimoto Thyroiditis” : please correct : Hashimoto’s thyroiditis.

Corrections has been made accordingly.

Reviewer 2 Report

The text is interesting, it raises some important questions on the importance of diagnosis and treatment of thyroid lymphomas.

I have some suggestions for improving the manuscript

There are punctuation marks missing through the text.

The use of English language is adequate, but I would suggest for the spelling to be checked, there are some misspellings, I have noted some below, but there are others.

Line 64 PET CT to PET/CT or PET-CT that was used later

Line 70 pleas explain what ECOG-PS scoring is

Line 79 I would suggest using generic names of the medications used, and also later in the text

Line 96 “anteriorly and laterally the oesophagus” to “anteriorly and laterally, and the esophagus”

Line 102 please explain what ADC is

Line 142 Fig. 3 is not mentioned in the text, nor is PET/CT mentioned in section 2. Case presentation, I would suggest expanding the section with that subject.

Line 161 “very suggestive of three a gressive thyroid malignancies” please rephrase, this is confusing

Line 249 you are using both MTT and MTC, pleas choose one and stick with it

The use of English language is adequate, but I would suggest for the spelling to be checked, there are some misspellings in the text

Author Response

Sir,

We do agree with the suggestions and thank the reviewer . The modifications have been made accordingly  as follows in blue in the manuscript. We hope  modifications will meet Reviewer's expectations.

Yours Sincerely

 

I have some suggestions for improving the manuscript

-There are punctuation marks missing through the text. Missed punctuation marks have been added in the manuscript body. 

The use of English language is adequate, but I would suggest for the spelling to be checked, there are some misspellings, I have noted some below, but there are others.

-Line 64 PET CT to PET/CT or PET-CT that was used later. Corrections have been made.

-Line 70 pleas explain what ECOG-PS scoring is: Eastern Cooperative Oncology Group performance status. This has been added in the text. 

-Line 79 I would suggest using generic names of the medications used, and also later in the text: Modifications have been made as follows: levothyroxine, prednisolone, Rituximab, Leurocristine and Prednisolone, Methyl Prednisolone, Doxorubicin.

-Line 96 “anteriorly and laterally the oesophagus” to “anteriorly and laterally, and the esophagus”. This has been modified accordingly line 105.

-Line 102 please explain what ADC is apparent diffusion coefficient. This has been added. 

-Line 142 Fig. 3 is not mentioned in the text, nor is PET/CT mentioned in section 2. Case presentation, I would suggest expanding the section with that subject.

We thank the Reviewer, we have added  line 157- 158 the following : "FDG PET- CT disclosed high uptake foci into both left thyroid mass and gastric remnant, and no medullary bone involvement [Fig 3]. "

-Line 161 “very suggestive of three a gressive thyroid malignancies” please rephrase, this is confusing.

We have modified as follows: "A painful mass of the neck associated with compressive symptoms in the elderly is very suggestive of aggressive thyroid malignancy." 

-Line 249 you are using both MTT and MTC, pleas choose one and stick with it; we thank the Reviewer, we have stuck with MTT spelling, namely in Table 1 caption, and manuscript body.

 

Reviewer 3 Report

Thanks the Editor to give me the opportunity to revise this article. The manuscript is of great interest in the field of current research. 
The work is well written and adequately structured. The literature review was carried out correctly and examined an adequate number of articles. The conclusions are well written and represent a clear and appropriate conclusion to the review. The table and figures,  are well constructed, clear and provides a relevant contribution to the whole article.

In particular, the clinical case was well developed in a complete and extensive way, prompting the authors for an in-depth literature review on the management of rapidly growing neck masses in elderly patients.

Underlining the need to obtain a rapid diagnosis in these cases which allows as soon as possible to undertake the right treatment which could be life-saving is very appreciable: and in this sense, the execution of the CNB of the thyroid is fundamental, which allows to have a clear histological diagnosis in a shorter time and with lower risks than a surgical biopsy.

Having said this, I suggest to the authors only to add, to lines 177-178, also "breast cancer "as a possible source of secondary tumor lesions of the thyroid, referring to the recent work by Patrizio et al (Thyroid Metastasis from Primary Breast Cancer, J Clin Med 2023).

 

Author Response

Sir,

We do agree with the suggestions and thank the reviewer .

The modifications have been made accordingly  as follows in green in the manuscript. We hope  modifications will meet Reviewer's expectations.

Yours Sincerely

 

 I suggest to the authors only to add, to lines 177-178, also "breast cancer "as a possible source of secondary tumor lesions of the thyroid, referring to the recent work by Patrizio et al (Thyroid Metastasis from Primary Breast Cancer, J Clin Med 2023). We thank  the Reviewer for his comments and have made modifications in green color.

We have added this reference as follows as reference 37: 

Patrizio A, Ferrari SM, Stoppini G, Palmisano E, Elia G, Ragusa F, Paparo SR, Balestri E, Mazzi V, Botrini C, Proietti A, Famà F, Benvenga S, Antonelli A, Fallahi P. Thyroid Metastasis from Primary Breast Cancer. J Clin Med. 2023 Apr 4;12(7):2709. doi: 10.3390/jcm12072709. PMID: 37048792; PMCID: PMC10095414.

As the authors Patrizio et al  report a very rare and interesting case of hypoparathyroidism due to secondary tumor infiltration of both thyroid and parathyroid glands, we added the following in the Table 1 caption:

"*Hypoparathyroidism has been recently reported as due to concomitant thyroid and parathyroid gland metastasis [37]. "