Neuroendocrine Tumor Arising within Mature Cystic Teratoma of the Pancreas: Literature Review and Case Report

Round 1

Reviewer 1 Report

This manuscript is a case report of a patient with neuroendocrine tumor arising within mature cystic teratoma of the pancreas which was surgically resected. This case will likely be of interest to clinicians in the field as it is a rare condition.

However, I have major and minor issues with this manuscript as described below.

 

Major

1.     There are two previous reports which described a case with neuroendocrine tumor arising within mature cystic teratoma of the pancreas. The author should discuss pancreatic teratoma concomitant with neuroendocrine tumor referring to these cases, including the present case. I recommend that the authors summarized characteristics of each case using a table, which can help readers’ understanding.

2.     Did you find any cases of neoplasms arising within mature cystic teratoma? This information can provide readers informative knowledge in the clinical setting.

 

Minor

1. Please provide an EUS image.

2. Cytopathological analysis of the FNA sample revealed mucinous cystic neoplasm. The authors should comment the dissociation between the FNA diagnosis and the final diagnosis of cystic teratoma.

3. Please provide a mapping of the resected specimen where each different structure existed.

4. (figure 4) The magnification is too low to judge it as neuroendocrine tumor.

 

5. Did the tumor markers in this patient decrease after operation?

 

Author Response

Reviewer 1

 

Comments and Suggestions for Authors

This manuscript is a case report of a patient with neuroendocrine tumor arising within mature cystic teratoma of the pancreas which was surgically resected. This case will likely be of interest to clinicians in the field as it is a rare condition. 

However, I have major and minor issues with this manuscript as described below.

We thank you for your review of our manuscript and for your valuable comments. We have carefully addressed the points raised and submitted a revised manuscript in which all changes are marked with red. We have also added a few more references and numbered the remaining references accordingly.

Major

1. There are two previous reports which described a case with neuroendocrine tumor arising within mature cystic teratoma of the pancreas. The author should discuss pancreatic teratoma concomitant with neuroendocrine tumor referring to these cases, including the present case. I recommend that the authors summarized characteristics of each case using a table, which can help readers’ understanding.

Thank you for your comment. We have discussed our case with former two cases separately and added a whole new paragraph in the discussion section (lines 163 to 169). We also added a table to summarize characteristics of our case and the former two cases (lines 171 to 175).

2. Did you find any cases of neoplasms arising within mature cystic teratoma? This information can provide readers informative knowledge in the clinical setting.

Thank you for your remark. We have not found any other case of a neoplasm arising within a mature cystic teratoma of the pancreas. However, mature cystic teratomas are a common ovarian pathology, and in two large case series, the incidence of malignant transformation of mature cystic teratomas was reported to be from 2.4% to 3.5%. The most common neoplasm was squamous cell carcinoma, whereas adenocarcinoma or malignant melanoma were extremely rare. We have added these information in the discussion (lines 155 to 161).

Minor

1. Please provide an EUS image.

Thank you for your suggestion. We added an EUS image (Figure 3) in the case presentation section (lines 88 to 91). Consequently, the remaining figures were numbered accordingly.

2. Cytopathological analysis of the FNA sample revealed mucinous cystic neoplasm. The authors should comment the dissociation between the FNA diagnosis and the final diagnosis of cystic teratoma.

Thank you for your comment. We have discussed the dissociation between FNA and final diagnosis in the discussion (lines 225 to 233).

3. Please provide a mapping of the resected specimen where each different structure existed.

We understand the importance of the mapping of the resected specimen, but unfortunately, we were unable to provide an image of the mapping of the resected specimen. Although mapping is always performed prior to pathological sectioning and is noted in the pathologic description, we do not routinely take images of the resected specimens. However, the specimen included the duodenum, 10 cm of the jejunum, the head of the pancreas, the choledochal duct, the cystic duct, and the gallbladder. The cystic tumor was located in the head of the pancreas.

4. (figure 4) The magnification is too low to judge it as neuroendocrine tumor.

Thank you for noticing that the magnification was too low. We have added a new figure with higher magnification of the neuroendocrine tumor (lines 123 to 127). The figure has been numbered accordingly (No 5) due to the new figure of the EUS.

5. Did the tumor markers in this patient decrease after operation?

Yes, the tumor marker decreased to normal values. We have added the info in case presentation section (line 130).

 

 

Author Response File: Author Response.docx

Reviewer 2 Report

There is confusion as to whether this teratoma arose from pancreatic cells or from extragonadal cells that arrested during their migration.  Throughout both the abstract and the body of the report, it is stated that this tumor is a primary pancreatic tumor, but the description and presented images suggest that it sits posterior to the pancreases on the anterior IVC wall (the later can be readily explained as arrested migration, the former would be novel and require an explanation to the embryology of a teratoma from pancreatic cells).

The authors distinction between mature and immature teratomatous elements and whether they are benign or malignant is not accurate or clear.  For the sake of this presentation, I do not think it necessary.

Author Response

Reviewer 2

We thank you for your review of our manuscript and for your valuable comments. We have carefully addressed the points raised and submitted a revised manuscript in which all changes are marked with red. We have also added a few more references and numbered the remaining references accordingly.

Comments and Suggestions for Authors

There is confusion as to whether this teratoma arose from pancreatic cells or from extragonadal cells that arrested during their migration.  Throughout both the abstract and the body of the report, it is stated that this tumor is a primary pancreatic tumor, but the description and presented images suggest that it sits posterior to the pancreases on the anterior IVC wall (the later can be readily explained as arrested migration, the former would be novel and require an explanation to the embryology of a teratoma from pancreatic cells).

Thank you for your remark. In the manuscript, we wanted to emphasize that the diagnostic workup in our patient was unclear until the final diagnosis. Indeed, US (both transabdominal and endoscopic) as well as abdominal CT could not clarify whether the tumor was in the pancreas or behind it. However, MRI showed that the tumor was confined to the pancreas. In addition, both abdominal exploration and histologic examination also showed that the tumor was located in the head of the pancreas. To avoid this confusion, we added a few sentences about the surgical procedure in the case presentation (lines 94 to 97).

The most established hypothesis is that extragonadal germ cell tumors originate from primordial cells that have arrested in their migration along the midline of the body. Another, less established hypothesis states that extragonadal tumors represent metastases of the undetected germ cell tumors of the gonads. We were able to partially reject the latter hypothesis, however, we were unable to elucidate the precise etiology of the cystic teratoma in our case. We have added a whole new paragraph on the etiopathogenesis of extragonadal germ cell tumors to improve the background of our manuscript (lines 145 to 155). Again, to avoid any potential confusion, we have rephrased the sentences in the abstract and introduction that stated that the pancreas is “very rare as a primary site” to “very rare as a site of occurrence” (line 14 and line 33).

The authors distinction between mature and immature teratomatous elements and whether they are benign or malignant is not accurate or clear.  For the sake of this presentation, I do not think it necessary.

Thank you for your remark. In order to exclude a possible immature component, the whole tumor was sampled. Histologic analysis revealed a mixture of benign tissues (respiratory epithelium, squamous epithelium, salivary glands, fibroadipose tisssue). However, throughout the tumor, we have not observed any solid areas, areas with primitive neuroectodermal components – spindle cells, rosettes, pseudorosettes or primitive tubules that are consistent with immature teratomas. In addition, we have not observed any areas with hemorrhages or necrosis which are commonly related to malignancy. Therefore, the findings were consistent with mature cystic teratoma. We have updated histologic section in case presentation section (lines 103 to 104 and lines 107 to 110).

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I appreciate that the authors revised the manuscript according to my suggestion. The revised manuscript is much improved.

However, the following minor issues require clarification:

 

Minor

1. The construction in the Discussion section should be reconsidered. I recommend that the authors firstly discuss the characteristics of cystic teratoma of the pancreas, followed by ones of concomitant mature cystic teratoma of the pancreas and neuroendocrine tumor using Table 1.

2. The authors pointed out the presence of the macroscopic fat, a characteristic finding consistent with teratoma in Figure 1. Please describe it in the main text.

3. (Figure 5) Please add a histopathological image with higher magnification.

3. (Conclusion) I think a tip learned from this case report is as follows: Neuroendocrine tumor arising within mature cystic teratoma of the pancreas should be taken into consideration in case of symptomatic large cystic lesion in young patients accompanied by tumor marker elevation.

I recommend the authors add that kind of sentence in Conclusion.

Author Response

Reviewer 1 – round 2

I appreciate that the authors revised the manuscript according to my suggestion. The revised manuscript is much improved.

We thank you again for you constructive review and for noticing that our revised manuscript has improved. We have carefully addressed the points raised and submitted a new revised manuscript in which all changes are marked with red. In addition, we unmarked the previous changes for better review.

However, the following minor issues require clarification:

Minor

1. The construction in the Discussion section should be reconsidered. I recommend that the authors firstly discuss the characteristics of cystic teratoma of the pancreas, followed by ones of concomitant mature cystic teratoma of the pancreas and neuroendocrine tumor using Table 1.

Thank you for your suggestion. We have changed the structure of the Discussion according to your recommendation and have therefore moved Table 1 and the paragraph about concomitant mature cystic teratoma of the pancreas and neuroendocrine tumor to lines 237 to 249. We have also rephrased the first sentence of the last paragraph to better emphasize that the last paragraph and Table 1 are a brief review of cases of concurrent mature cystic teratoma of the pancreas and neuroendocrine tumor (lines 237 to 239).

2. The authors pointed out the presence of the macroscopic fat, a characteristic finding consistent with teratoma in Figure 1. Please describe it in the main text.

Thank you for noticing that we forgot to include this characteristic, but not so common, finding in the main text. We have therefore added it in the Discussion (lines 201 to 203).

3. (Figure 5) Please add a histopathological image with higher magnification.

Thank you for your remark. We have added a new Figure 5 with an even higher magnification.

3. (Conclusion) I think a tip learned from this case report is as follows: Neuroendocrine tumor arising within mature cystic teratoma of the pancreas should be taken into consideration in case of symptomatic large cystic lesion in young patients accompanied by tumor marker elevation. I recommend the authors add that kind of sentence in Conclusion.

Thank you very much for this great suggestion. We have added a similar kind of sentence in the Conclusion of our manuscript (lines 254 to 256).

Author Response File: Author Response.docx