Clinicopathological characteristics and outcomes in men with mesothelioma of the tunica vaginalis testis: analysis of published case-series data

Purpose Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumor, and currently, there are no published treatment recommendations. Methods We performed a systematic literature review and synthesized clinical presentation, clinicopathological factors associated with metastatic disease, treatment options, and outcomes in men with MTVT. Results We included 170 publications providing data on 275 patients. Metastatic disease occurred in 84/275 (31%) men with malignant MTVT: Most common sites included retroperitoneal lymph nodes (LNs) (40/84, 48%), lungs (30/84, 36%), and inguinal LNs (23/84, 27%). Invasion of the spermatic cord or scrotum was the only risk factor for local recurrence [odds ratio (OR) 3.21, 95% confidence interval (CI) 1.36–7.57]. Metastatic disease was associated with age ≥ 42 years (OR 3.02, 95% CI 1.33–6.86), tumor size ≥ 49 mm (OR 6.17, 95% CI 1.84–20.74), presence of necrosis (OR 8.31, 95% CI 1.58–43.62), high mitotic index (OR 13.36, 95% CI 1.53–116.51) or angiolymphatic invasion (OR 3.75, 95% CI 1.02–13.80), and local recurrence (OR 4.35, 95% CI 2.00–9.44). Complete remission in the metastatic setting was observed in five patients, most of whom were treated with multimodal therapy. Median survival in patients with metastatic disease was 18 months (IQR 7–43). Conclusion Malignant MTVT is a rare but aggressive disease. Since local recurrence is a risk factor for metastatic progression, we recommend aggressive local treatment. Survival and response to any treatment in the metastatic setting are limited. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-021-03533-6.


Introduction
Mesothelioma typically involves the pleura or peritoneum and only rarely the tunica vaginalis testis (Gurdal and Erol 2001;Plas et al. 1998a). Due to the low prevalence of mesothelioma of the tunica vaginalis testis (MTVT), treatment recommendations have not been developed. We collated published case reports of men with MTVT to describe clinicopathological factors associated with local recurrence or metastatic disease as well as outcome from treatments used.

Data acquisition and search strategy
A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement (Moher et al. 2009(Moher et al. , 2015. Prior to data acquisition, the study protocol/search strategy was published on the PROSPERO registry (http:// www.crd.york.ac.uk/PROSP ERO; Registration Number CRD42019129595). Our search identified articles published up to 14th January 2019 and utilised the following electronic databases: MEDLINE ® , Embase ® , Scopus ® , the Cochrane Database of Systematic Reviews, and Web of Science. To identify all relevant articles, a clinical medical librarian applied a broad approach using several combinations, synonyms and related search terms to "para-/intra-/testicular mesothelioma", "epididymal mesothelioma", or "para-/intra-/ testicular mesenchymal tumor/neoplasm". Non-English literature was excluded unless the abstract was available in English or the full text in French, Spanish, Italian, Portuguese, or German. Moreover, the reference lists of the identified publications were screened manually to identify additional studies. For the search strategy, see Supplementary File 1. After deduplication, two authors (JBG, JNF) screened the titles and abstracts independently and data from the same study that appeared in multiple publications were included only once. Finally, disagreements were discussed and resolved by consensus or by third-party arbitration (CDF).

Types of outcome measures included and data extraction
Studies containing data on patient characteristics, clinicopathological features, treatment of local or metastatic disease, site of metastases, and follow-up information were eligible for this review. The data extraction sheet was developed according to the Cochrane Consumers and Communication Review Group's data extraction template. Whenever possible, data were gathered at the single-patient-level.

Statistical analysis
Categorical variables are presented as percentages and were compared using the Chi-square test of independence. The assessment of normality for continuous variables was performed visually and using the Shapiro-Wilk test. The results for normally distributed variables are expressed as mean ± standard deviation (SD), while non-normally distributed variables are presented as median and interquartile ranges (IQRs). The independent samples t test was used for normally distributed data and the Mann-Whitney U test for variables with non-normally distributed data. Weighted medians were used to estimate previously processed statistical data from cohort studies as well as individual patient data from single-case reports. The optimal cut-off value for continuous variables was determined using receiveroperating curve (ROC) analyses and the maximal Youden's index (= Sensitivity + Specificity-1) (Youden 1950). All p values < 0.05 were considered statistically significant; all statistical tests were two-sided.

Included studies
After deduplication and title as well as abstract screening, 194 of the originally identified 8,188 publications were eligible for full-text review (Fig. 1). We finally included 170 studies, resulting in a dataset of 275 patients, consisting of 140 single-case reports and 30 case series.

Adjuvant therapy
Lymph-node dissection (LND) was performed in 21 men of whom 12 had inguinal LND, 8 retroperitoneal LND, 7 pelvic LND, and 6 LND in multiple locations. In 5 of the 21 patients (24%), histological analysis showed lymph-node metastases (LNs), one without recurrence during followup. Two patients were alive with disease (one with ongoing chemotherapy and one with no further therapeutic interventions). Two patients died from metastatic spread after palliative radiotherapy and radiochemotherapy, respectively. An additional three patients without positive lymphadenectomy results displayed evidence of distant recurrence during follow-up. Thus, 6 of the 21 patients (29%) developed systemic disease despite adjuvant LND. Local and/or metastatic relapse after adjuvant chemotherapy or chemoradiotherapy was observed in 5/9 (56%) patients. Used chemotherapy agents included Doxorubicin, Carboplatin, or combination therapy with Adriamycin plus Cyclophosphamide or Paclitaxel, and the radiation field included the retroperitoneal and pelvic lymph nodes and pelvic region. 6/11 (55%) men relapsed after several radiotherapy protocols including radiation of the scrotum as well as the retroperitoneal and inguinal LNs with maximum doses between 55 and 60.5 Gy.

Treatment and outcome in men with metastatic disease
During a median follow-up of 18 months (IQR 7-43), 55/84 metastatic MTVT patients (65%) died, and 13/84 (15%) were alive with disease, while 11 patients were either lost to follow-up or without information on survival. Complete remission in the metastatic setting was reported in five men (Supplementary Table 2): the first patient (#7) with an epithelial MTVT was treated with an orchiectomy and RPLND showing involvement of one retroperitoneal lymph node. Data about staging CT at diagnosis as well as information about further treatment during follow-up were not available. This patient remained free of disease for at least 66 months (Bertolotto et al. 2016). The second patient (#12) with an epithelioid MTVT developed mediastinal LN metastases 36 months after primary radical orchidectomy. After six cycles of Cisplatin and Pemetrexed and maintenance with Pemetrexed, there was no evidence of disease after 42 months of follow-up (Doris et al. 2015). The third patient (#35), with a malignant MTVT of unknown histological subtype and peritoneal metastases at initial staging, was treated with testis-sparing surgery, peritonectomy, and intraperitoneal hyperthermic perfusion chemotherapy. He remained free of disease after a follow-up of 18 months (Schure et al. 2006). The fourth patient (#42), who had epithelioid MTVT with extension to the spermatic cord in the inguinal canal and metastatic spread within the pelvis and the abdomen, was initially treated with hemiscrotectomy with resection of the inguinal mass and abdominal cytoreductive surgery with extensive stripping all peritoneal surfaces followed by intra-operative, intra-peritoneal chemotherapy using Cisplatin and Doxorubicin. This patient was recurrence-free survival at 5 years (Sebbag et al. 2001).
The fifth patient (#60), with epithelioid MTVT invading the tunica albuginea, the spermatic cord and external scrotal layers, was treated with a primary hemiscrotectomy. After resection of visible metastases in the retroperitoneum, six cycles of chemotherapy with Adriamycin and Cyclophosphamide and radiation therapy of 25 Gy over 3 weeks, the patient was disease-free at 36 months (Lopez et al. 1995).
Of metastatic cases with available follow-up, 20 out of 21 (95%) patients treated with surgery only and 64 out of 68 (94%) patients treated with multimodal therapies progressed.

Discussion
Our analysis of published case series is the largest and most comprehensive summary of the available literature regarding MTVT. It also extends the previous reviews (Bisceglia et al. 2010;Plas et al. 1998b;Vimercati et al. 2019;Zhang and Goldsztajn 2019), and therefore, several important insights can be discussed. The highest incidence was found in men in their sixties; however, there is a wide age range, even patients under 20 years can be affected. MTVT usually presents as a testicular mass or is incidentally discovered during or after inguino-scrotal surgery. Therefore, the primary local treatment depends on the clinical scenario, but treatment should also be planned in the knowledge that MTVT can show multifocal growth and that local recurrence might be associated with metastatic disease.
In men with first presentation, several recommendations might help to guide clinicians in decision-making, but those are based on very limited evidence or expert opinion only. Men in whom MTVT is suspected at initial presentation, primary hemiscrotectomy, and en-bloc orchidectomy should be performed. In men with suspicious findings discovered during surgery, we recommend completing the hydrocelectomy as planned and only proceeding thereafter to a hemiscrotectomy if the final histopathology confirms the diagnosis of MTVT. This is mainly since most men scheduled for routine scrotal surgery such as hydrocelectomy are not consented for a hemiscrotectomy and the diagnostic accuracy of intraoperative frozen section remains ill-defined. For men with an incidental diagnosis of MTVT in the hydrocelectomy specimen, we recommend timely completion of a hemiscrotectomy because of potential tumor seeding.
Well-differentiated papillary mesothelioma and benign multicystic mesothelioma are clearly benign entities that require complete resection as definitive therapy; thereafter, only follow-up for local relapse is advisable. By contrast, malignant MTVT exhibited metastatic spread in one-third of cases, suggesting repeated cross-sectional imaging of the chest and abdomen is required for staging and follow-up. The available data do not support the regular use of adjuvant treatment. Half of all cases had involved retroperitoneal LNDs, and only in a proportion, other organs were also affected. Despite the use of RPLND, all patients treated with lymphadenectomy, who did not receive additional chemoor radiotherapy, progressed. Thus, RPLND as monotherapy does not have the potential to cure patients. Only a few men received adjuvant chemo-or radiotherapy which does not allow any conclusions.
Patients with metastatic disease have a poor prognosis, and standard treatment recommendations are not available. Given the experience in pleural mesothelioma and the scarce data on MTVT, surgical resection within a multimodal treatment approach can be offered; however, the choice of chemotherapy and the role of radiotherapy remain unclear. Pleural mesothelioma guidelines recommend Platinum, Pemetrexed plus minus Bevacizumab (Opitz et al. 2020) and in one case Pemetrexed led to complete response. Additionally, Cisplatin and Doxorubicin or Adriamycin and Cyclophosphamide could be suggested as a few responses have been observed.

Limitations
The published literature only consists of retrospective case reports and small case series with a low number of outcome events and missing single-patient data, and multivariable analysis was therefore not possible. Our search strategy was designed and reviewed by both clinicians and librarians, and was predefined in a peer-reviewed protocol. However, the possibility remains that not all potentially relevant studies were identified; this is an additional source of potential bias. Larger and more consistent datasets are needed to develop prediction models involving several risk factors. Nevertheless, the current analysis provides a unique overview of the published experience with MTVTs. Due to the absence of prospective trials, we recently opened the OrphAn Testis Histologies (OATH) to provide more conclusive recommendations regarding clinical course, management, and follow-up of these rare entities. We encourage collaborators to contribute data regarding patients with rare testis cancer histologies (http://bit.ly/OATH-regis try).

Conflicts of interests
The authors have no relevant financial or nonfinancial interests to disclose. The results presented in this paper have not been published previously.
Ethics approval According to the Swiss Ethics Committee and the Ethics Committee of Zurich (KEK), this study does not require a formal ethics approval. The study was performed in accordance with the Declaration of Helsinki.
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