Uterine sarcomas resembling dermatofibrosarcoma protuberans showing COL1A1-PDGFB fusion: a case report and review of the literature

doi:10.21203/rs.3.rs-1850991/v1

Download PDF

Case Report

Uterine sarcomas resembling dermatofibrosarcoma protuberans showing COL1A1-PDGFB fusion: a case report and review of the literature

https://doi.org/10.21203/rs.3.rs-1850991/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Collagen type 1α1–platelet-derived growth factor β-chain (COL1A1-PDGFB) fusion uterine fibrosarcoma is a rare, recently discovered uterine sarcoma characterised by unique gene rearrangements, of which only four cases have been reported. This subtype is found in the body of the uterus or cervix, with histological features resembling dermatofibrosarcoma protuberans (DFSP), diffuse CD34 expression in tumour cells and COL1A1-PDGFB fusion.

Case presentation: A 38-year-old female patient complaining of amenorrhea for 3 months presented with a cloudy hypoechoic fluid measuring 98 × 91 mm in the right adnexa on B-scan ultrasonography, for which laparoscopic lumpectomy was performed accordingly. Histological sections demonstrated high cellularity with mild to moderate atypia, morphological uniformity, a scant cytoplasm, oval to spindle-like nuclei, inconspicuous nucleoli and evident mitotic figures. Salient storiform and herringbone patterns of growth were observed. On immunohistochemical analysis, the tumour cells exhibited diffuse and strong positive expression of CD34; negativity for AE1/AE3, SMA, desmin, STAT6, S100 and SOX-10 and focal positivity for CD99, Bcl-2, CD10 and CylinD1. COL1A1-PDGFB fusion was identified by fluorescence in situ hybridisation. The patient remained disease-free within the 17-month follow-up with no additional treatment after the lumpectomy.

Conclusions: This is the fifth case of COL1A1-PDGFB fusion uterine fibrosarcoma reported in the literature. Previous studies have found that this subtype overlaps with DFSP in histopathological, immunohistochemical and molecular characteristics. Of these five cases, two resulted in mortality, implying a risk of poor prognosis.

COL1A1-PDGFB fusion

uterine fibrosarcoma

dermatofibrosarcoma protuberans

pathology

Uterine sarcomas are primary malignant tumours that arise from the mesenchymal tissue of the uterus, representing 1% of all female reproductive tract malignancies and 3–7% of all uterine malignancies [1]. Subtypes include leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma, adenosarcoma and the rare neoplasm known as perivascular epithelioid cell tumour [2]. Molecular testing has identified several inadequately understood uterine sarcomas with unique genetic alterations, including NTRK-rearranged uterine sarcoma [3], SMARCA4-deficient undifferentiated uterine sarcoma [4] and collagen type 1α1–platelet-derived growth factor β-chain (COL1A1-PDGFB) fusion uterine sarcoma [5].

COL1A1-PDGFB fusion uterine fibrosarcoma was first reported by Croce et al. [5] in a study of 13 uterine and vaginal sarcomas with morphological features resembling fibrosarcoma, during which COL1A1-PDGFB fusion was found in three neoplasms. The fourth case was reported by Grindstaff [6]. Only four cases have been described thus far in the literature. Here we describe the fifth case of uterine sarcoma with COL1A1-PDGFB infusion reported. A detailed analysis of the case and a literature review were performed to deepen the understanding and broaden the clinical experience in the pathological diagnosis of this subtype.

A 38-year-old female patient visited our hospital due to amenorrhea for 3 months after having had a normal menstrual cycle (30 days), with each period lasting 4 days. On B-scan ultrasonography, the uterus was anteverted, regularly shaped and measured 52 × 42 × 59 mm, with a distinct outline. Homogeneous echoes were reflected by the myometrium, and a 10-mm endometrium of heterogeneous echotexture, which was Y-shaped in the cross-section, was visualised. The right ovary measured 27 × 19 mm, and the right adnexa was filled with a cloudy hypoechoic fluid measuring 98 × 91 mm(Fig. 1), with dense punctate echoes and spare blood flow under colour Doppler flow imaging.

Clinical history

The patient had no significant medical history and showed no specific symptoms other than amenorrhea. The results of the physical examination and laboratory tests were unremarkable.

Operative details

A laparoscopic lumpectomy was performed accordingly. The laparoscopy revealed a pedunculate prominence on the right uterine wall measuring 10 cm in diameter. The peduncle was flimsy, resembled fish flesh, haemorrhage-prone and reached 2 cm in length. It had no membrane and was attached to other structures, including the peritoneum of the bladder, the right pelvic wall and the sigmoid mesocolon. The bilateral adnexa were normal in size and shape. A lumpectomy was performed under laparoscopy to separate the adhesions and remove the tumour along the uterine surface. Bleeding from the uterine incision was controlled by electrocoagulation. Tissues obtained from the patient were kept in specimen bags and processed with a pulveriser before use.

Pathology

As observed with the naked eye, the tumour tissue fragments excised under laparoscopy were greyish-white, delicate and resembled fish flesh on the surface. The tumour displayed a similar histological pattern to dermatofibrosarcoma protuberans (DFSP), which is a proliferation of tumour cells with morphological uniformity, mild to moderate atypia, scant cytoplasm, oval to spindle-like nuclei, inconspicuous nucleoli and a mitotic index of 5/10 high-power fields (HPF). Salient storiform and herringbone patterns of growth were observed(Fig. 2). A scattered proportion of the tumour cells had a star-like appearance, accompanied by mucoid degeneration of the mesenchymal tissue(Fig. 3). Multifocal foam cell aggregation was observed(Fig. 4). In addition to adhesion to the peritoneum of the bladder, the right pelvic wall and the sigmoid mesocolon, adipose tissue involvement in the tumour tissue was also found(Fig. 5), which indicates border infiltration.

The immunohistochemistry (IHC) analysis was diffusely positive for CD34(Fig. 6); negative for AE1/AE3, SMA, desmin, STAT6, S100 and SOX-10 and focally positive for CD99, Bcl-2, CD10 and CylinD1. Ki67 concentrations ranged from 5–10%.FISH analysis using dual fusion probes suggested COL1A1-PDGFB fusion in 50% of the tumour cells(Fig. 7).

On follow-up, the attending gynaecologist spoke to the patient after the lumpectomy and decided not to provide any additional treatment after conducting doctor–patient consultation. The patient was recurrence- and metastasis-free of recurrence during the 17-month follow-up period.

In the past, the pathological diagnosis of uterine sarcoma depended heavily on histological patterns and IHC analysis. This has changed with recent research developments and the extensive use of molecular pathology testing, which has contributed to the identification of novel subtypes and previously unknown classes of uterine sarcomas. Molecular pathology testing has transformed the means of gaining knowledge of diseases and establishing pathological diagnoses. Genetic alterations often reveal the nature of newly discovered diseases and have become a common consideration in naming them.

COL1A1-PDGFB infusion uterine sarcoma was first described by Croce et al. [5] in 2019 as having similar morphological features to DFSP. The present case report describes the fifth case of COL1A1-PDGFB infusion uterine sarcoma since cases were reported in 2019 and 2020. A summary of these five cases is given in Table 1. Usually affecting patients aged 38–82 years, COL1A1-PDGFB infusion uterine sarcoma could affect the cervix (n = 2), the body of the uterus (n = 2), or the entire uterus from the cervix to the fundus (n = 1). The tumours measured 5.8–21.5 cm and were composed of strongly diffuse, uniform and short spindle cells arranged in storiform and herringbone forms, with scant cytoplasm and poorly defined borders, mild to moderate nuclear atypia and oval to spindle-like nuclei. Mitotic activity varied from 5/10 HPF to 45/10 HPF. Necrosis was observed in two cases. Lymphovascular invasion was not observed. Infiltrating borders were seen in four of the five cases. A typical leiomyoma was detected in one case, whereas areas of scattered, star-like tumour cells were seen in another case. The patients in the four previous cases were compliant with follow-up, of whom two were clinically classified as stage IB and achieved disease-free survival after surgery. The other two patients who were diagnosed with stage IIIB and IVA cancer died. This suggests that the prognosis is worse at a later stage.

The second patient listed in Table 1 was diagnosed with a DFSP on her back about a year prior to the identification of the cervical lesion. The DFSP was removed and considered as an independent lesion instead of a metastasis. Based on this case, the lesions in the skin and cervix may be ascribed to the same disease with COL1A1-PDGFB infusion, which has varied manifestations in different parts of the body. Sarcomas with similar genetic alterations may be found in other body parts and organs as more case reports become available.

As to the IHC markers, CD34 was diffusively expressed, whereas desmin, ER, PR, BCOR and S-100 were absent, and cyclinD1 was expressed at varying degrees (10–90%) in tumour cells. A summary of these five cases is given in Table 2.

Studies have demonstrated that the formation of the COL1A1-PDGFB fusion gene is a molecular event specific to DFSP. The molecular mechanism involves reciprocal translocations of chromosome 17 and supernumerary ring chromosomes that stimulate rearrangements of molecular structures and generate a DFSP-specific combined gene called COL1A1/PDGFB fusion gene with COL1A1 on chromosome 17 and the PDGFB on chromosome 22 [7、8、9]. Molecular changes in COL1A1-PDGFB fusion uterine fibrosarcoma are identical to those in DFSP.

For the three cases reported by Croce et al. [5], intrachromosomal breaks involving COL1A1 on chromosome 17q21.33 and PDGFB on chromosome 22q13.1 were found in the array-CGH genomic profiles of two cases. Dual-fusion fluorescence in situ hybridisation (FISH) demonstrated COL1A1-PDGFB fusion in 56%, 86% and 74% of the tumour cells with an unbalanced 17–22 rearrangement in all three cases. COL1A1-PDGFB fusion was also present in the case reported by Grindstaff et al. [6]. In this case report, FISH analysis using break-apart probes suggested PDGFB gene-associated breaks in 50% of the tumour cells. COL1A1-PDGFB fusion is an essential diagnostic criterion for COL1A1-PDGFB fusion uterine fibrosarcoma and can be identified by FISH, the most useful and accurate diagnostic tool for such cases.

DFSP is a low-grade, slow-growing malignancy, which entails a low risk of distant metastases but has a striking local recurrence rate and potential fibrosarcomatous transformation [10]. Excision is the mainstay of treatment. However, imatinib has been approved by the U.S. Food and Drug Administration as molecular targeted therapy for DFSP when surgical treatment is not optional for those with locally advanced, metastatic or recurrent DFSP[11]. Since very limited information is available from the few reported cases regarding the treatment of COL1A1-PDGFB fusion uterine fibrosarcoma, surgical excision is currently presumed to be the first-line treatment. In the case reported by Grindstaff et al., the tumour was excised with no gross residual disease on inspection with the naked eye. However, the patient responded poorly to the postoperative chemotherapy and showed significant disease progression on imaging. Imatinib treatment was initiated after COL1A1-PDGFB fusion was discovered by molecular testing, and the tumour decreased from 22.4 cm to 6.5 cm. However, further progression was noted following 6 months of treatment. This case report has broadened our experience and indicates the potential of targeted therapy for treating COL1A1-PDGFB fusion uterine sarcoma. Molecular testing (if available), as well as conducting clinical trials and individualised targeted therapy based on corresponding test results, is advised to help guide the treatment and predict the outcomes of uterine sarcomas.

Table 1

Clinical and Pathological Features of Cases
Case	Age(years)	Size(cm)	Tumor location	Nuclear atypia	Mitoses /10HPFs	Necrosis	Lymphovascular invasion	Tumor border	Tumor stage	Follow-up(months)
1	82	8.2	Cervix	Mild	8	Yes	No	Infiltrating	ⅠB	NED10
2	60	5.8	Cervix	Mild	20	No	No	Infiltrating	ⅢB	DOD60
3	48	12	Corpus	Moderate	20	No	No	NE	ⅠB	NA
4	43	21.5	Cervix and Corpus	Mild	45	Yes	NA	Infiltrating	IVA	DOD34
5	38	9.8	Corpus	Mild	5	No	No	Infiltrating	ⅠB	NED 17

NA not available, NE not evaluable;NED no evidence of disease, DOD dead of disease;

Table 2

Immunohistochemical data
Case	CD34	SMA	Desmin	ER	PR	BCOR	CyclinD1	S-100
1	D	ND	N	N	N	N	15%	N
2	D	ND	ND	N	N	N	10%	N
3	D	ND	N	N	N	N	90%	N
4	D	F	N	ND	ND	ND	ND	ND
5	D	N	N	N	N	N	10%	N
F focal < 50% of tumor cells, D diffuse, > 50% of tumor cells, N negative, ND not done.

Ethics approval and consent to participate

All methods were carried out in accordance with the relevant guidelines and regulations, and all the experimental protocols of this study were approved for clinical use at Affiliated Hospital of Yangzhou University. The use of human samples was approved by the Institutional Review Board of the Affiliated Hospital of Yangzhou University, Yangzhou, China.

Consent for publication

Consent for publication of the clinical details and pathological images was obtained and copies of the consent form are available.

Competing interests

The authors declare that they have no competing interest.

Authors' contributions

Wang Zheng wrote the main manuscript text, Zhou Jie prepared figures 1-7, Liu Shuang prepared Table 1-2, Ding Yongling reviewed the manuscript. All authors read and approved the final manuscript.

Funding

This study was conducted without any financial support.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Mbatani N, Olawaiye AB, Prat J. Uterine sarcomas [J]. Int J Gynecol Obstet, 2018,143: 51–58.
WHO Classification of Tumours Edorial Board. WHO classification of tumours. Female genital tumours [M]. 5th ed. Lyon: IARC Press, 2020:283–306.
Chiang S, Cotzia P, Hyman DM, et al. NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma [J]. Am J Surg Pathol, 2018,42(6):791–798.
Kolin DL, Dong F, Baltay M, et al. SMARCA4-deficient undifferentiated uterine sarcoma
(malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma [J]. Mod Pathol, 2018,31(9):1442–1456.
Croce S, Hostein I, Longacre TA, et al. Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms [J]. Mod Pathol, 2019,32(7):1008–1022.
Grindstaff SL, DiSilvestro J, Hansen K, et al. COL1A1-PDGFB fusion uterine fibrosarcoma: A case report with treatment implication [J]. Gynecol Oncol Rep, 2020,31:100523.
Kiuru-Kuhlefelt S, El-Rifai W, Fanburg-Smith J, et al. Concomitant DNA copy number amplification at 17q and 22q in dermatofibrosarcoma protuberans[J]. Cytogenet Cell Genet, 2001, 92(3–4):192–195.
Zheng Z, Piao J, Lee JH, et al. Dermatofibrosarcoma protuberans: a study of clinical, pathologic, genetic, and therapeutic features in Korean patients[J]. Yonsei Med J, 2015, 56(2):440–446.
COL1A1-PDGFB gene fusion in dermatofibrosarcoma protuberans: a useful diagnostic tool and clinicopathological analysis. Li N, Zhou T, Chen S, Yang R, Zhu Q, Feng Z.Int J Clin Exp Pathol. 2018 Aug 1;11(8):4052–4059. eCollection 2018
Thway K, Noujaim J, Jones RL, Fisher C. Dermatofibrosarcoma protuberans: pathology, genetics, and potential therapeutic strategies. Ann Diagn Pathol. 2016;25:64–71.
UgurelL S, Mentzel T, Utikal J, et al. Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase II DeCOG trial with long-term follow-up[J]. Clin Cancer Res, 2014, 20(2):499–510.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Uterine sarcomas resembling dermatofibrosarcoma protuberans showing COL1A1-PDGFB fusion: a case report and review of the literature

Status:

Version 1

Abstract

Figures

Introduction

Case Report

Clinical history

Operative details

Pathology

Discussion

Declarations

References

Additional Declarations

Status:

Version 1