Updates in Pathology for Retroperitoneal Soft Tissue Sarcoma

Round 1

Reviewer 1 Report

It was a pleasure to review this paper. It summarizes the knowledge on retroperitoneal tumors. The figures are clear and informative. References are appropriate.

I have only a few comments

Line 72: "Overall, LPS tends to respond better to chemotherapy than 72
other sarcoma subtypes [13]. " This statement would be considered controversial. Well-differentiated liposarcoma is considered a type of sarcoma which is quite resistant to chemotherapy. There are multiple references. I would recommend to remove this sentence

Line 73: "The role of neoadjuvant RT has recently been prospectively 73
evaluated in a randomized controlled trial (EORTC-62092: STRASS) which concluded that the routine use of neoadjuvant RT is not recommended in patients with high-grade retroperitoneal sarcomas, but may be considered in those with high risk of local (abdominal)
only recurrence [14]." This statement has some errors or misinterpretations of results. The study showed that neoadjuvant radiation is not recommended not only for high grade retroperitoneal sarcoma but actually for sarcomas of any grade. If any sarcomas benefit it would be liposarcomas (post hoc analysis). This should be clarified especially that it is a part of liposarcoma section of this paper

Line 112 "However, MDM2 overexpression may also be detected in other entities such as UPS, myxofibrosarcoma, and MPNST [27]." Maybe the statement should be slightly stronger "MDM2 expression alone is not a sufficient criterion for diagnosis of WDLP because..."

Line 117 "Tumours located in deep sites such as the retroperitoneum tend to recur repeatedly or dedifferentiate and metastasize" This sentence would need a reference, and it is not completely true. If the tumors dedifferentiate then they have metastatic potential, but actually WDLP is of a low metastatic potential and usually caused morbidity because of multiple local recurrences.

Line 150: " Interestingly, local recurrences of DDLPS may sometimes be entirely well-differentiated. " This sentence is not really precise. It describes not the recurrence of DDLPS, but recurrence of the WDLPS component of DDLPS. It should be rephrased.

Line 340: it may be worth mentioning little more about possible diagnostic challenges in differentiation between MPNST and melanoma, especially that both can be S100+ and SOX10+

Line 387: "Current treatment guidelines for Ewing sarcoma include neoadjuvant chemotherapy and radiation followed by complete surgical re
section". This statement is not precise. While we do usually start with neoadjuvant chemotherapy, these patients also receive extensive adjuvant chemotherapy.

Line 391: "Localized disease has a cure rate of 65-70%, however the 5-year survival rate for metastatic disease is less than 30%". It is true for all Ewing sarcomas, but I do not think it is correct for these rare retroperitoneal Ewing sarcomas. Please rephrase and update.

Section 8. I would recommend that you remove the section on GIST. It is almost never a retroperitoneal tumor.

Author Response

Thank you for you review and insightful feedback.  We are responding to your recommendations below each one individually, point by point.  

It was a pleasure to review this paper. It summarizes the knowledge on retroperitoneal tumors. The figures are clear and informative. References are appropriate.

I have only a few comments

Line 72: "Overall, LPS tends to respond better to chemotherapy than 72
other sarcoma subtypes [13]. " This statement would be considered controversial. Well-differentiated liposarcoma is considered a type of sarcoma which is quite resistant to chemotherapy. There are multiple references. I would recommend to remove this sentence

• Sentence removed

Line 73: "The role of neoadjuvant RT has recently been prospectively 73
evaluated in a randomized controlled trial (EORTC-62092: STRASS) which concluded that the routine use of neoadjuvant RT is not recommended in patients with high-grade retroperitoneal sarcomas, but may be considered in those with high risk of local (abdominal)
only recurrence [14]." This statement has some errors or misinterpretations of results. The study showed that neoadjuvant radiation is not recommended not only for high grade retroperitoneal sarcoma but actually for sarcomas of any grade. If any sarcomas benefit it would be liposarcomas (post hoc analysis). This should be clarified especially that it is a part of liposarcoma section of this paper

• Clarified previous clinical trial (EORTC-62092: STRASS) results, and current ongoing trial (EORTC-1809: STRASS II) research question.
• "Considering retroperitoneal sarcoma biology and the fact that our data do not support radiotherapy for leiomyosarcoma and high-grade retroperitoneal sarcoma, our next randomized study (STRASS 2; NCT04031677) will focus on these two groups"
• an exploratory analysis on patients with liposarcoma was recommended, because this was the largest subgroup (nearly 75% of the trial cohort) and had the highest risk of local recurrence. In the subgroup analyses exploring patients with liposarcoma only, there was a 10% absolute abdominal recurrence-free survival benefit in favour of the radiotherapy plus surgery group.
• Subgroup analyses of abdominal recurrence-free survival by sarcoma subtype and grade suggest that preoperative radiotherapy might improve the outcome in liposarcoma and in low-grade retroperitoneal sarcoma, whereas there did not appear to be a radiotherapy benefit for leiomyosarcoma and high-grade retroperitoneal sarcoma.22 However, these results should be regarded with caution because all subgroups were individually small, many patients were not evaluable for grade or differentiation

Line 112 "However, MDM2 overexpression may also be detected in other entities such as UPS, myxofibrosarcoma, and MPNST [27]." Maybe the statement should be slightly stronger "MDM2 expression alone is not a sufficient criterion for diagnosis of WDLP because..."

• Sentence deleted. Although IHC for MDM2 (and ?FISH) can be positive in other entities such as MFS, UPS, and MPNST, the subsequent sentence clarifies that these ancillary studies are adjuncts, and that the diagnosis can frequently be made on morphology alone.

Line 117 "Tumours located in deep sites such as the retroperitoneum tend to recur repeatedly or dedifferentiate and metastasize" This sentence would need a reference, and it is not completely true. If the tumors dedifferentiate then they have metastatic potential, but actually WDLP is of a low metastatic potential and usually caused morbidity because of multiple local recurrences.

• Sentence changed to: "Tumours located in deep sites such as the retroperitoneum tend to recur repeatedly [1]." (WHO reference)

Line 150: " Interestingly, local recurrences of DDLPS may sometimes be entirely well-differentiated. " This sentence is not really precise. It describes not the recurrence of DDLPS, but recurrence of the WDLPS component of DDLPS. It should be rephrased.

• Rephrased as: Interestingly, local recurrence from a previous DDLPS may consist entirely of the well-differentiated component.

Line 340: it may be worth mentioning little more about possible diagnostic challenges in differentiation between MPNST and melanoma, especially that both can be S100+ and SOX10+

• Added: This staining pattern is different from melanoma which is normally diffusely positive for SOX10 and S100 along with more specific melanoma markers including Melan-A and HMB45.

Line 387: "Current treatment guidelines for Ewing sarcoma include neoadjuvant chemotherapy and radiation followed by complete surgical resection". This statement is not precise. While we do usually start with neoadjuvant chemotherapy, these patients also receive extensive adjuvant chemotherapy.

• Expanded sentence: "Current treatment guidelines for Ewing sarcoma include neoadjuvant chemotherapy and radiation followed by complete surgical resection and additional adjuvant chemotherapy"

Line 391: "Localized disease has a cure rate of 65-70%, however the 5-year survival rate for metastatic disease is less than 30%". It is true for all Ewing sarcomas, but I do not think it is correct for these rare retroperitoneal Ewing sarcomas. Please rephrase and update.

• Sentence deleted: Localized disease has a cure rate of 65-70%, however the 5-year survival rate for metastatic disease is less than 30%
• New sentence: "Extraskelatal Ewing sarcoma occurs in about 12% of patients and has a wide anatomic distribution [1]. Few case reports have documented retroperitoneal Ewing's sarcoma, therefore survival statistics are lacking"

Section 8. I would recommend that you remove the section on GIST. It is almost never a retroperitoneal tumor.

• Suggested from editor comment "Moreover Angiosarcoma should be added" -
• Note: Retroperitoneal angiosarcoma is exceedingly rare and the literature is limited to few case reports (see below references), although GIST is also a rare entity to occur in the retroperitoneum in our experience it occurs more frequently than angiosarcoma. Therefore we would suggest keeping GIST within the review

• Yoo C, Kim JE, Yoon SK, Kim SC, Ahn JH, Kim TW, Suh C, Lee JL. Angiosarcoma of the retroperitoneum: report on a patient treated with sunitinib. Sarcoma. 2009;2009:360875. doi: 10.1155/2009/360875. Epub 2009 May 20. PMID: 19478954; PMCID: PMC2685913.
• Matsumura S, Yoshida T, Taniguchi A, Imanaka T, Yamanaka K, Kishikawa H. Primary perirenal angiosarcoma: A preoperative diagnostic challenge. Urol Case Rep. 2020 Apr 30;32:101228. doi: 10.1016/j.eucr.2020.101228. PMID: 32395430; PMCID: PMC7210400.

Reviewer 2 Report

The authors in the manuscript titled 'Updates in Pathology for Retroperitoneal Soft Tissue Sarcoma' described the pathological attributes of rare sarcomas. They concluded that a multidisciplinary approach is required for a thorough diagnosis. Overall the manuscript seems sound and can be published in the journal 'current oncology' pending minor revision. The critique is given as:

The introduction is short and should be expanded to include the basic knowledge about the sarcoma e.g. the cells of origin or molecular signature.

There are three figures and although placed respectively in their section, have not been described in the text. For example in figure 1 liposarcoma is shown, however, there is no information regarding where and how the images were taken and should be described in either figure legend or within the section describing the figure (or specific image). The scale bar is missing (it is not necessary but magnification can be mentioned). The staining features for most images are missing.

All figures have the aforementioned problem and should be rectified. 

Author Response

Thank you for taking the time to review our paper and providing helpful comments and feedback.  We have responded to each suggestion below, point by point. 

The authors in the manuscript titled 'Updates in Pathology for Retroperitoneal Soft Tissue Sarcoma' described the pathological attributes of rare sarcomas. They concluded that a multidisciplinary approach is required for a thorough diagnosis. Overall the manuscript seems sound and can be published in the journal 'current oncology' pending minor revision. The critique is given as:

The introduction is short and should be expanded to include the basic knowledge about the sarcoma e.g. the cells of origin or molecular signature.

We expanded the introduction as follows, to include general background to sarcoma.  For each entity, we also included relevant background (cell of origin, molecular, etc) as appropriate. The changes to the introduction are listed below:

Sarcomas are a rare type of malignancy derived from primitive multipotential mesenchymal precursors (line 1). Added: The etiology of most STT remains unknown. Less than 10% of cases can be attributed to genetic, environmental factors, irradiation, viral infections or immunodeficiency. The majority of cases seem to arise de novo without an apparent causative factor [1] (line 25). Added: Despite this morphologic classification, the cells of origin for most sarcomas are not well understood and are presumed to arise from mesenchymal-derived stem cell precursors. In recent years extensive molecular profiling of sarcomas has identified characteristic genetic alterations including unique translocations, oncogene activations, loss of tumour suppressors, and copy number variations [cite]

There are three figures and although placed respectively in their section, have not been described in the text. For example in figure 1 liposarcoma is shown, however, there is no information regarding where and how the images were taken and should be described in either figure legend or within the section describing the figure (or specific image). The scale bar is missing (it is not necessary but magnification can be mentioned). The staining features for most images are missing.

All figures have the aforementioned problem and should be rectified.