A Case of Placental Site Trophoblastic Tumour That Mimicked Missed Miscarriage

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This case report is clinically valuable and educational for its treatment of the clinical presentation of PSTT, a rare gestational trophoblastic neoplasm, that mimics missed abortion. A strong point is the detailed presentation of clinical, radiological, and histopathological correlations. However, in its current form, the study remains largely descriptive and contains some significant academic shortcomings. Strengthening integration with the literature and increasing the depth of discussion would significantly enhance the scientific contribution of the article.

Firstly, the main contribution of the article, the "mimicking missed miscarriage" aspect, should be presented more clearly and emphatically. While this condition is described in the current text, the reasons why it is clinically misleading and which findings can contribute to early differential diagnosis are not discussed in sufficient depth. In particular, the low but persistent β-hCG levels and the interpretation of ultrasonographic findings should be addressed more analytically. Secondly, the differential diagnosis discussion should be expanded. Differentiating PSTT from epithelioid trophoblastic tumors, choriocarcinomas, and other non-trophoblastic malignancies is a significant clinical issue; however, these differences have not been presented in a more systematic and comparative manner. The distinctive role of histopathological and immunohistochemical markers, in particular, could be made clearer with a table or structured summary. Thirdly, comparison with the literature is limited. In such rare case reports, comparison with similar cases is expected. It is recommended that the authors compare this case with other cases where PSTT was mistakenly assessed as missed abortion or early pregnancy loss, and more clearly define the case's place in the literature. In addition, the treatment approach and clinical management should be discussed in more detail. The patient's decision to receive chemotherapy with fertility preservation is a significant clinical decision; however, the rationale for this choice, alternative treatment options (e.g., hysterectomy), and its relationship to current guidelines should be addressed more clearly. While the text is generally understandable, fluency could be improved in some sections. There are repetitions in the discussion section, and the text could be made more focused. The use of terminology should be standardized (e.g., GTD/GTN usage could be more consistent).

While figure descriptions are adequate, they could be made more descriptive to better reflect the clinical significance of histopathological findings. Furthermore, the contribution of immunohistochemical findings to clinical diagnosis could be expressed more clearly. While references are generally sufficient, supplementing them with more recent and impactful publications could strengthen the discussion.

Author Response

Reviewer 1

This case report is clinically valuable and educational for its treatment of the clinical presentation of PSTT, a rare gestational trophoblastic neoplasm, that mimics missed abortion. A strong point is the detailed presentation of clinical, radiological, and histopathological correlations. However, in its current form, the study remains largely descriptive and contains some significant academic shortcomings. Strengthening integration with the literature and increasing the depth of discussion would significantly enhance the scientific contribution of the article.

• Firstly, the main contribution of the article, the "mimicking missed miscarriage" aspect, should be presented more clearly and emphatically. While this condition is described in the current text, the reasons why it is clinically misleading and which findings can contribute to early differential diagnosis are not discussed in sufficient depth. In particular, the low but persistent β-hCG levels and the interpretation of ultrasonographic findings should be addressed more analytically.

Reply: Thank you for the comments. We have improved it by adding a paragraph to describe how it actually could mimic missed miscarriage more clearly with an added reference. We have also added an ultrasound study comparing GTD and retained products of conception.

See page 5.

PSTT is rare, accounting for <1% of gestational trophoblastic disease (Hassadia 2005). Majority of cases of about 70% present as irregular bleeding, with or without preceding amenorrhoea. In addition, there is a mild degree of raised β-hCG that could easily mimicked missed miscarriage. This presentation was similarly observed in our case. 

A study by Betel et. al. using ultrasonography found that GTD cases were more likely associated with a larger mass, thin endometrium, myometrial-based mass, and vascular lakes, compared to retained products of conception. (Betel et al. 2006)

References:

Hassadia, A.; Gillespie, A.; Tidy, J.; Everard, R.G.N.J.; Wells, M.; Coleman, R.; Hancock, B. Placental site trophoblastic tumour: Clinical features and management. Gynecol. Oncol. 2005, 99, 603–607.

Betel C, Atri M, Arenson AM, Khalifa M, Osborne R, Tomlinson G. Sonographic diagnosis of gestational trophoblastic disease and comparison with retained products of conception. J Ultrasound Med. 2006 Aug;25(8):985-93. doi: 10.7863/jum.2006.25.8.985. PMID: 16870892.

• Secondly, the differential diagnosis discussion should be expanded. Differentiating PSTT from epithelioid trophoblastic tumors, choriocarcinomas, and other non-trophoblastic malignancies is a significant clinical issue; however, these differences have not been presented in a more systematic and comparative manner. The distinctive role of histopathological and immunohistochemical markers, in particular, could be made clearer with a table or structured summary.

Reply: We have created a table that summarises the clinicopathological features as well as the immunohistochemical profile of all GTD. See Table 1.

• Thirdly, comparison with the literature is limited. In such rare case reports, comparison with similar cases is expected. It is recommended that the authors compare this case with other cases where PSTT was mistakenly assessed as missed abortion or early pregnancy loss, and more clearly define the case's place in the literature. In addition, the treatment approach and clinical management should be discussed in more detail. The patient's decision to receive chemotherapy with fertility preservation is a significant clinical decision; however, the rationale for this choice, alternative treatment options (e.g., hysterectomy), and its relationship to current guidelines should be addressed more clearly. While the text is generally understandable, fluency could be improved in some sections. There are repetitions in the discussion section, and the text could be made more focused.

Reply: Thank you for the comments. We did some literature review on the published cases of PSTT in regards to its treatment modality and has added the following into the discussion. 2 new references are added.

See page 5.

PSTT is usually considered to be chemo-resistant. However, there were studied demonstrating complete remission after treated by combined curettage and chemotherapy. A study of 6 cases PSTT treated by chemotherapy without hysterectomy. After follow-up for 10 about 47 months, all achieved complete remission and had restored normal menstruation [17]. Numnum et al. (2006) reported a 29-year-old female with a strong desire for fertility and declined surgery. Similar to our case, she was initially thought to have a complete abortion. She declined surgery and was treated with chemotherapy alone who eventually responded well and her β-hCG returned to normal [18].

References:

Shen, X., Xiang, Y., Guo, L., Feng, F., Wan, X., Xiao, Y., & Ren, T. (2012). Fertility-preserving treatment in young patients with pla-cental site trophoblastic tumors. International Journal of Gynecological Cancer, 22(5), 869–874. https://doi.org/10.1097/IGC.0b013e31824a1bd6

Numnum, T. M., Kilgore, L. C., Conner, M. G., & Straughn, J. M. (2006). Fertility sparing therapy in a patient with placental site trophoblastic tumor: A case report. Gynecologic Oncology, 103(3), 1141–1143. https://doi.org/10.1016/j.ygyno.2006.07.039

• The use of terminology should be standardized (e.g., GTD/GTN usage could be more consistent).

Reply: We agree all terminology should be standardised and consistent. GTD and GTN are 2 separate entity where GTD encompass a wider spectrum of diseases related to gestation, while GTN, as the name implies neoplasm, is mainly confined to the neoplastic diseases in gestation trophoblasts. We have used the term specifically to highlight its different.

• While figure descriptions are adequate, they could be made more descriptive to better reflect the clinical significance of histopathological findings. Furthermore, the contribution of immunohistochemical findings to clinical diagnosis could be expressed more clearly. While references are generally sufficient, supplementing them with more recent and impactful publications could strengthen the discussion.

Reply: Thank you for the comments. Page 5 highlights to clinical importance of immunohistochemistry in the diagnosis of PSTT. In addition, key references describing P63 and GATA3 have been included in the case report (see reference 14 and 15).

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In their case study, the Authors reported a case of PSTT developed in a 32-year old woman presented with a symptoms characterized by an early pregnancy. A diagnostic criteria showed a PSTT that mimicked missed miscarriage. The Authors presented a case study with details and also they performed immunohistochemical assessment of GATA3, bHCG, PLAP, P63, and Ki67. Brief management and follow-up of the patient was also presented. Finally, they discussed the PSTT clinical symptoms and clinical management of the patient affected by this rare disease. Table 1, in my opinion, perfectly compared the clinicopathological and immunohistochemical features of different gestational trophoblastic diseases.

After reading, I truly recomment to accept this study for the publication in DIAGNOSTICS after minor revision.

1. I feel it will be of utmost important to present the follow-up of a patient who denied hysterectomy procedure. Please also present options for this woman after childbearing. What shoud be a safe period proposed for this woman between PSTT diagnosis and pregnancy planning?
2. What kind of target therapy or immunotherapy may be recommended for this patient?
3. Why hPL antibody was not immunohistochemically tested?
4. The „Conclusions” section should be reduced to 2-3 sentences only.
5. Please show the exact Ki67 proliferation index (…is about 20-30%... or …is about 25%....).
6. I recommend the final english language editing, otherwise I feel that the language is acceptable. However, some sentences sound strange, for example ….also seen are many multinucleated cells are identified…..

Comments on the Quality of English Language

I recommend the final english language editing, otherwise I feel that the language is acceptable. However, some sentences sound strange, for example ….also seen are many multinucleated cells are identified…..

Author Response

Reviewer 2

In their case study, the Authors reported a case of PSTT developed in a 32-year old woman presented with a symptoms characterized by an early pregnancy. A diagnostic criteria showed a PSTT that mimicked missed miscarriage. The Authors presented a case study with details and also they performed immunohistochemical assessment of GATA3, bHCG, PLAP, P63, and Ki67. Brief management and follow-up of the patient was also presented. Finally, they discussed the PSTT clinical symptoms and clinical management of the patient affected by this rare disease. Table 1, in my opinion, perfectly compared the clinicopathological and immunohistochemical features of different gestational trophoblastic diseases.

After reading, I truly recomment to accept this study for the publication in DIAGNOSTICS after minor revision.

Reply: Thank you for the positive comments.

• I feel it will be of utmost important to present the follow-up of a patient who denied hysterectomy procedure. Please also present options for this woman after childbearing. What should be a safe period proposed for this woman between PSTT diagnosis and pregnancy planning?

Reply: Thank you for the comment. We did some literature review and found a study that look at pregnancy outcome after chemotherapy for GTN. A sentence has been added to the discussion.

In a study of 51 cases diagnosed as GTN treated by chemotherapy, they found pregnancies conceived >12 months after treatment had a better outcome and less pregnancy terminations compared to those conceived earlier.

Reference: McCullough, L.; Niznanska, Z.; Danihel, L.; et al. Reproductive outcomes after treatment of gestational trophoblastic neoplasia in Slovakia. Bratisl. Med. J. 2026, 127, 1183–1189. https://doi.org/10.1007/s44411-025-00449-2

• What kind of target therapy or immunotherapy may be recommended for this patient?

Reply: Thank you for the comment. We did some literature review and added a sentence on the potential of using immunotherapy in PSTT.

PD-1/ PD-L1 checkpoint inhibitor, like Pembrolizumab, a humanized monoclonal antibody, has been regarded as a potential immunotherapy treatment option in cases of chemotherapy-resistant, metastatic, recurrent, or fertility-preserving situations.

Mangili, G.; Sabetta, G.; Cioffi, R.; Rabaiotti, E.; Candotti, G.; Pella, F.; Candiani, M.; Bergamini, A. Current Evidence on Immunotherapy for Gestational Trophoblastic Neoplasia (GTN). Cancers 2022, 14, 2782. https://doi.org/10.3390/cancers14112782

• Why hPL antibody was not immunohistochemically tested?

Reply: Thank you for the comment. hPL is a marker for PSTT. However, it is not essential for diagnosis. Unfortunately, our centre does not have hPL antibody. Hence it was not performed.

• The „Conclusions” section should be reduced to 2-3 sentences only.

Reply: The conclusion has been shortened as commented.

• Please show the exact Ki67 proliferation index (…is about 20-30%... or …is about 25%....).

Reply: Thank you for the comment. We have corrected it to 25%.

• I recommend the final english language editing, otherwise I feel that the language is acceptable. However, some sentences sound strange, for example ….also seen are many multinucleated cells are identified…..

Reply: Thank you for the comment. We have asked a graduate from UK university to check for grammar errors.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Congratulations to the authors for sharing a rare case of placental site trophoblastic tumour. I read the case with great interest. Although the case is well presented, I have some recommendations for improvement.

In the abstract, you should add a sentence such as, "This case highlights…". The microscopic findings are excessively detailed for the abstract format and may reduce readability. The conclusion of the abstract currently repeats known information rather than emphasising the significance of the case. You should state that, “Early recognition of PSTT is essential because its clinical presentation may mimic benign pregnancy-related conditions, and diagnosis relies heavily on histopathological and immunohistochemical evaluation.”

The introduction lacks brief discussion of the biological behavior of PSTT, its clinical importance and treatment implications compared with other GTNs.

At the end of the introduction, you should add a significant sentence such as, “This case highlights the importance of considering PSTT in patients with persistent low-level β-hCG elevation and atypical uterine lesions, particularly when clinical findings mimic retained products of conception or missed miscarriage.”

The manuscript alternates between “tumor” and “tumour”. Choose either British or American English and apply it consistently throughout.

In the case report, you should clarify disease staging, whether fertility preservation was intended, why surgery was not performed, why EMA-CO was selected and why it is referred to as “second-line” chemotherapy. This is a major issue because treatment decisions are clinically important in PSTT.

You should explain more clearly how PSTT was differentiated from ETT, exaggerated placental site, choriocarcinoma and retained products of conception.

The discussion should explicitly address what was diagnostically challenging in this case, why the diagnosis was difficult, how the diagnosis was ultimately established and what clinicians and pathologists can learn from this case.

The discussion repeatedly refers to hPL as an important marker; however, hPL staining was apparently not performed in this case. The authors should clarify whether hPL was unavailable, whether another marker was used instead and why diagnosis was still considered reliable without hPL.

The statement “the patient opted for chemotherapy without hysterectomy to preserve fertility” raises several important concerns. PSTT is relatively chemoresistant, hysterectomy is the standard treatment for localised disease, and EMA-CO is not universally effective in PSTT. The discussion should explain the rationale for conservative treatment, the disease stage, whether fertility-preserving therapy is evidence-based, why EMA-CO was selected, and the expected outcomes of non-surgical management. This is a major limitation of the manuscript.

The conclusion includes an extensive list of differential diagnoses, which may be more appropriate for the discussion section than the conclusion. A conclusion should highlight the key clinical lesson, the diagnostic significance, and the broader implications of the case. The lengthy list disrupts the flow and weakens the main take-home message.

Author Response

Reviewer 3

Congratulations to the authors for sharing a rare case of placental site trophoblastic tumour. I read the case with great interest. Although the case is well presented, I have some recommendations for improvement.

• In the abstract, you should add a sentence such as, "This case highlights…". The microscopic findings are excessively detailed for the abstract format and may reduce readability. The conclusion of the abstract currently repeats known information rather than emphasising the significance of the case. You should state that, “Early recognition of PSTT is essential because its clinical presentation may mimic benign pregnancy-related conditions, and diagnosis relies heavily on histopathological and immunohistochemical evaluation.”

Reply: Thank you for the constructive comments. We have corrected it according to your suggestion. See page 1.

• The introduction lacks brief discussion of the biological behavior of PSTT, its clinical importance and treatment implications compared with other GTNs. At the end of the introduction, you should add a significant sentence such as, “This case highlights the importance of considering PSTT in patients with persistent low-level β-hCG elevation and atypical uterine lesions, particularly when clinical findings mimic retained products of conception or missed miscarriage.”

Reply: Thank you for the constructive comments. We have corrected it according to your suggestion. See page 2.

• The manuscript alternates between “tumor” and “tumour”. Choose either British or American English and apply it consistently throughout.

Reply: Thank you for the comment. We have checked and corrected the spelling to British English.

• In the case report, you should clarify disease staging, whether fertility preservation was intended, why surgery was not performed, why EMA-CO was selected and why it is referred to as “second-line” chemotherapy. This is a major issue because treatment decisions are clinically important in PSTT.

Reply: Thank you for the comments. We have added a paragraph to describe the treatment modality, as well as added a few new references in regards to treatment.

See page 5.

In early-stage cases, like in our case (FIGO Stage I, confined to the uterus), a simple hysterectomy is usually curative for PSTT. However, our patient opted for chemotherapy without a hysterectomy to preserve fertility. PSTT is usually considered to be chemo-resistant. However, there were studied demonstrating complete remission after treated by combined curettage and chemotherapy. A study of 6 cases PSTT treated by chemotherapy without hysterectomy. After follow-up for 10 about 47 months, all achieved complete remission and had restored normal menstruation [17]. Numnum et al. (2006) reported a 29-year-old female with a strong desire for fertility and declined surgery. Similar to our case, she was initially thought to have a complete abortion. She declined surgery and was treated with chemotherapy alone who eventually responded well and her β-hCG returned to normal [18].

• You should explain more clearly how PSTT was differentiated from ETT, exaggerated placental site, choriocarcinoma and retained products of conception. The discussion should explicitly address what was diagnostically challenging in this case, why the diagnosis was difficult, how the diagnosis was ultimately established and what clinicians and pathologists can learn from this case.

Reply: Thank you for the comment. We have described in details using Table 1 to summarise the differences of each lesion in GTD. Please refer to Table 1.

• The discussion repeatedly refers to hPL as an important marker; however, hPL staining was apparently not performed in this case. The authors should clarify whether hPL was unavailable, whether another marker was used instead and why diagnosis was still considered reliable without hPL.

Reply: Thank you for the comment. hPL is a marker for PSTT. However, it is not essential for diagnosis. Unfortunately, our centre does not have hPL antibody. Hence it was not performed.

• The statement “the patient opted for chemotherapy without hysterectomy to preserve fertility” raises several important concerns. PSTT is relatively chemoresistant, hysterectomy is the standard treatment for localised disease, and EMA-CO is not universally effective in PSTT. The discussion should explain the rationale for conservative treatment, the disease stage, whether fertility-preserving therapy is evidence-based, why EMA-CO was selected, and the expected outcomes of non-surgical management. This is a major limitation of the manuscript.

Reply: Thank you for the comment. We have added a new paragraph on a literature review of treatment of PSTT using chemotherapy alone without hysterectomy. See above.

• The conclusion includes an extensive list of differential diagnoses, which may be more appropriate for the discussion section than the conclusion. A conclusion should highlight the key clinical lesson, the diagnostic significance, and the broader implications of the case. The lengthy list disrupts the flow and weakens the main take-home message.

Reply: Thank you for the comment. We agree the long differentials in conclusion is inappropriate and has deleted it, and has added a sentence to highlight the importance of awareness of this lesion.

See page 6.

Both obstetricians and pathologists should be aware of the possibility of PSTT in a case presented with missed miscarriage.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have adequately addressed and implemented suggestions.

Author Response

Reviewer #1

The authors have adequately addressed and implemented suggestions.

Reply: Thank you for the comments.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Please highlight all corrections. The abstract, introduction, and case report are not highlighted as stated in the response letter.

Author Response

Reviewer #3

Please highlight all corrections. The abstract, introduction, and case report are not highlighted as stated in the response letter.

Reply: We apologize for the oversight in the previous round. We have now implemented all the corrections and highlighted the changes accordingly.

Author Response File: Author Response.pdf

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

Congratulations to the authors. The case report was sufficiently improved.