Abstract
Background/Aim: Rhabdomyosarcoma (RMS) is a rare tumor with distinct morphological types and challenging diagnosis. This study aimed to investigate clinicopathological characteristics, survival outcomes, and factors influencing prognosis in adult patients with sinonasal RMS, addressing a critical gap in knowledge. Patients and Methods: This retrospective cohort study employed various statistical analyses to investigate patients with RMS. Descriptive statistics summarized demographic and clinical characteristics, while survival analysis using the Kaplan-Meier method and Cox proportional hazards model explored the relationship between covariates and survival outcomes. Results: We analyzed 13 cases (7 males, 6 females) of sinonasal RMS. The average age at onset was 42.5 years (standard deviation 18.9). Tumors were observed in multiple locations, predominantly in the maxillary sinus (n=7), followed by the ethmoid sinus (n=5), and the sphenoid sinus (n=1). The study revealed a low survival rate, with 12 patients succumbing to the disease and only one patient surviving. Over time, survival probabilities declined from 92.31% (at 0.5 months) to 7.69% (at 45 months). The analysis indicated a borderline statistically significant positive association between age at diagnosis below 40 years and survival (p=0.05). Sex was found to be significantly associated with survival (p=0.03), with male patients exhibiting a higher survival rate (hazard ratio=0.08, 95%CI=0.01-0.81). Conclusion: This study highlights the complex nature of sinonasal RMS in adults. The low survival rate and distinct tumor locations emphasize the need for further research to improve diagnosis and treatment outcomes.
Rhabdomyosarcoma (RMS) is a malignant tumor that belongs to the group of sarcomas and demonstrates differentiation towards skeletal muscles. Within RMS, several morphological types are distinguished, including embryonal RMS (ERMS), alveolar RMS (ARMS), pleomorphic RMS, and spindle cell/sclerosing RMS (Sp/ScRMS) (1).
RMS accounts for approximately 5% of malignant tumors in children and is the most common sarcoma in this age group. It occurs in the head and neck region in approximately 30% of cases, with ERMS being the most frequent morphological type (2). Among adults, RMS is a rare tumor, representing less than 1% of all malignant tumors. It typically develops in the extremities but rarely affects the head and neck region (3). However, when found in the head and neck, it can be located in the parameningeal region, including the nasopharynx, ear and temporal bone, sinonasal tract, orbital area, and nonorbital nonparameningeal sites. Tumors in the parameningeal region, especially the sinonasal sinuses, have a worse prognosis due to the potential involvement of the skull base and central nervous system (CNS) (4).
Symptoms of sinonasal RMS are not disease-specific and usually manifest when the disease is already advanced. Common presenting symptoms include nasal obstruction, painless neck mass, epistaxis, and rhinorrhea (5). Pathomorphological diagnosis is crucial for initiating appropriate therapy. Typically, specimens for examination consist of biopsies from the primary lesion or lymph nodes. The most common morphological types that develop in the sinonasal tract are ERMS and ARMS (5). Microscopic appearance, especially in cases with limited sample volume, may not fully exhibit characteristic features of specific RMS morphological types and often requires differentiation from tumors with distinct prognosis and treatment approaches (6). In the context of the nasal cavity and paranasal sinuses, the differential diagnosis includes Ewing sarcoma, melanoma, hematolymphoid tumors, carcinoma, neuroendocrine tumors, and olfactory neuroblastoma (1).
To establish a proper pathomorphological diagnosis, an extensive differential diagnostic workup is necessary, which involves a wide panel of immunohistochemical (IHC) examinations. The diagnosis of RMS is supported by the detection of skeletal muscle-specific protein expression, such as myogenin, myoblast determination protein 1 (MyoD1), and desmin (7). In some cases, molecular testing may be required. Rearrangements of genes occur in approximately 85% of ARMS cases. The most common fusion genes include PAX3-FOXO1 and PAX7-FOXO1, present in 70-90% and 10-30% of ARMS cases, respectively (8). In ERMS, point mutations in RAS, TP53, and PIK3CA genes, loss of heterozygosity at chromosome 11p15.5, and amplification of 12q15 (MDM2) are observed (9).
The treatment of patients with RMS, including sinonasal RMS, is multimodal and based on chemotherapy, radiotherapy, and surgery (4). Despite advanced treatment approaches, the prognosis for patients with sinonasal tract RMS remains poor, with a 5-year survival rate of 30-35% for patients with RMS of the head and neck (10, 11).
The aims of the study were to assess the clinicopathological characteristics and outcomes of adult patients with sinonasal RMS, evaluate the survival probability, and investigate the relationship between various factors, including age, sex, tumor stage, and site, and survival outcomes.
Patients and Methods
Data source. This study utilized a retrospective cohort design and relied on data sourced from patients who received a diagnosis of malignant tumor in Maria Sklodowska-Curie National Research Institute of Oncology, Poland between January 1, 2012, and December 31, 2022. Inclusion criteria encompassed patients diagnosed with RMS, including all subtypes (International Classification of Diseases for Oncology 3.2 morphological code range 8900/3-8921/3), and with tumor localization in the accessory sinuses, including maxillary, ethmoid, frontal, sphenoid, and overlapping lesions (ICD-O topographical code C31.0-C31.9). Furthermore, cases were identified based on the ICD-10 codes C30-31, which denote malignant neoplasms of the nasal cavity and accessory sinuses.
Data extraction. A comprehensive set of variables was extracted for the cases meeting the aforementioned inclusion criteria. The extracted data encompassed essential demographic information, including sex (male, female) and date of birth. Clinical information comprised the date of diagnosis, age at diagnosis (in years), primary cancer site (determined based on medical imaging - ethmoid, maxillary, sphenoid), involvement of other sites (orbit, skull base, and CNS, including meninges), tumor size (≤5 cm, >5 cm), regional lymph node involvement (yes, no), metastasis (yes, no), Intergroup Rhabdomyosarcoma Study Group (IRSG) staging system (12) (1, 2, 3, 4), treatment received (surgery with/without neoadjuvant therapy, neoadjuvant/adjuvant radiotherapy, neoadjuvant/adjuvant chemotherapy) and results of fluorescence in situ hybridization (FISH) analysis for FOXO1 translocation.
Histological type and immunohistochemistry confirmation. The histological type of RMS and the architectural pattern of ARMS, including the alveolar and solid patterns, were verified by reviewing hematoxylin and eosin (HE) stained slides. IHC plays a crucial role in confirming the diagnosis, and therefore, slides containing markers such as desmin, myogenin, MyoD1, S100, cytokeratin AE1/AE3 (CKAE1/3), synaptophysin, and CD56 were reassessed to validate the results obtained from IHC testing.
Vital status check. For all patients included in the study, we checked the vital status as of May 31, 2023.
Statistical analyses. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study population. Categorical variables, including sex, histological type, site, orbit invasion, skull base involvement, CNS involvement, surgery, neoadjuvant treatment, post-surgery radiation therapy, post-surgery chemotherapy, and tumor stage, were analyzed by calculating the frequencies and proportions.
For the age at diagnosis variable, histogram, Q-Q plot, and density plot were created to assess the distribution. The mean and standard deviation (SD) were calculated to summarize the central tendency and dispersion of the age at diagnosis.
Survival analysis was conducted using the Kaplan-Meier method to estimate the survival probability over time. The resulting Kaplan-Meier survival curve was plotted to visualize the survival outcomes. Furthermore, the Cox proportional hazards model was used to explore the relationship between various covariates and survival outcome. The covariates considered in the model included age group at diagnosis (<40, ≥40 years), sex, tumor stage, site, and histological type. All statistical analyses were performed with a significance level set at p<0.05. Statistical analysis was performed using the R studio (version 1.3.959 Middlemist Red; Posit; Boston, MA, USA).
Ethical compliance and adherence to reporting guidelines. This retrospective study, which involved no patient exposures, did not require approval from a bioethical committee. We conducted the study in compliance with international guidelines, including the Helsinki Declaration, ensuring patient privacy and data confidentiality.
We adhered to the SAMPL (Statistical Analyses and Methods in the Published Literature) and STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines in reporting and analyzing our study findings.
Results
Clinical findings. The study cohort comprised 13 patients diagnosed with sinonasal RMS, including 7 males and 6 females (Table I). The average age of the patients was 42.5 years (SD 18.9), ranging from 18 to 76 years. Tumor involvement was observed in multiple locations in all cases, with the predominant tumor mass primarily located in the maxillary sinus (n=7), followed by the ethmoid sinus (n=5), and the sphenoid sinus (n=1). Radiological examinations demonstrated orbital invasion in nine cases, skull base invasion in 10 cases, and CNS involvement in five cases.
Characteristics of the study population.
Among the cases, four exhibited a maximum tumor dimension of 5 cm or less, while nine cases presented with a dimension exceeding 5 cm. Lymph node metastases were detected in eight cases, and distant metastases were identified in three cases. The distribution of patients across different IRSG stages was as follows: stage 1 (n=0), stage 2 (n=3), stage 3 (n=7), and stage 4 (n=3).
Pathologic features. The majority of patients in this study were diagnosed with ARMS (n=11, 85%), while the remaining cases presented with ERMS (n=2, 15%). Microscopic examination of ARMS cases revealed the presence of nests and sheets composed of small to medium-sized round cells characterized by limited cytoplasm, hyperchromatic nuclei, and prominent mitotic activity. Within four ARMS cases, a variable number of rhabdomyoblasts was identified. Notably, seven ARMS cases exhibited fibrous septa of varying thickness, which served to separate the cellular nests. Moreover, the sheets and nests of cells displayed a loss of cellular cohesion in the central regions, resulting in the formation of alveolar-like spaces or exhibiting areas of necrosis. A distinct layer of clinging cells to the fibrous septa was observed. Conversely, four cases of solid-type ARMS lacked fibrous septa, presenting a different histological pattern (Figure 1). Furthermore, one ARMS case displayed clear cell change, denoting a unique pathological feature. The two cases of ERMS were characterized by the presence of primitive round to spindle-shaped cells with limited cytoplasm, hyperchromatic nuclei, and a variable number of rhabdomyoblasts.
Alveolar rhabdomyosarcoma (ARMS). A) Pseudoalveolar pattern, showing nests separated by fibrous septa composed of round cells and rhabdomyoblasts. There is visible loss of cellular cohesion; however, the peripheral cells are attached to the fibrous septa (HE 200×); B) ARMS with thick fibrous septa (HE 100×); C) ARMS composed of medium-size cells with monomorphic nuclei, nucleoli, and mitotic activity (HE 400×); D) Solid variant of ARMS (HE 100×); E) ARMS infiltrating sinus mucosa, with the crash artifact visible in the right upper corner (HE 100×); F) ARMS with clear cell change (HE 200×); G) Diffuse cytoplasmic expression of desmin (100×); H) Diffuse nuclear expression of myogenin (100×).
Immunohistochemical and molecular findings. In all cases of both ARMS and ERMS, positive expression of desmin was observed in all specimens (13/13; Table II). Among the performed immunohistochemical tests, myogenin showed positive results in 11 out of 11 cases, while MyoD1 exhibited positive staining in nine out of nine cases. Co-expression of desmin with MyoD1 and/or myogenin was detected in all examined cases. Additionally, S100 staining was performed in nine cases, revealing two cases with positive expression, while CKAE1/3 staining was conducted in seven cases, with two cases showing positive staining in both immunohistochemical analyses (2/9 and 2/7, respectively). Notably, none of the patients exhibited synaptophysin expression. However, CD56 expression was detected in 33% of the cases (four out of 12 examined).
Patient characteristics: rhabdomyosarcoma (RMS) type, immunohistochemical findings, and molecular Results.
FISH analysis was performed in eight patients to evaluate the rearrangement of the FOXO1 gene. Positive results were obtained in six cases diagnosed with ARMS, while two cases were excluded from analysis due to inadequate sample quality.
Survival and prognosis analysis. Kaplan-Meier analysis. The survival analysis using the Kaplan-Meier method demonstrated a decline in the survival probability of patients with RMS over time (Figure 2). The outcome of the study showed that 12 patients succumbed to the disease, while only one patient survived. Subsequent time points showed a gradual decrease in survival, with probabilities ranging from 92.31% (at 0.5 months) to 7.69% (at 45 months).
Kaplan-Meier survival curve for sinonasal rhabdomyosarcoma patients. The continuous line represents the observed survival probability, while the dotted lines represent the 95% confidence interval around the survival estimate.
Cox proportional hazards regression analysis. The Cox proportional hazards regression model was used to assess the relationship between various factors and survival outcomes. The model included 13 patients, with 12 observed events (deaths) during the follow-up period (Table III).
Results of Cox proportional hazards regression analysis.
The hazard ratio for age at diagnosis above 40 years was 22.53 (95%CI=0.95-537.20), indicating a trend towards increased survival in patients aged less than 40 years compared to those aged 40 years or older. However, this association did not reach statistical significance (p=0.05).
The variable sex was found to be significantly associated with survival (p=0.03). Male patients had a hazard ratio of 0.08 (95%CI=0.01-0.81), suggesting an increased survival compared to female patients.
Regarding tumor stage, the hazard ratios for stage 3 and stage 4 were 5.09 (95%CI=0.26-99.74) and 0.07 (95%CI=0.00-2.09), respectively, when compared to stage 2, the reference level. However, neither of these associations reached statistical significance (p=0.28 and p=0.13, respectively).
Site of tumor involvement was found to be significantly associated with survival. Patients with tumors located in the maxillary sinus had a hazard ratio of 102.06 (95%CI=2.82-3,690.00), indicating a substantially increased risk of mortality compared to ethmoid sinus. Similarly, patients with tumors in the sphenoid sinus had a hazard ratio of 432.56 (95%CI=1.72-109,100.00) compared to ethmoid sinus, indicating a significantly higher risk of death.
The morphology of the tumor (embryonal vs. alveolar) did not show a significant association with survival (p=0.93). The concordance index, a measure of predictive accuracy, was calculated to be 0.88, indicating a reasonably good fit of the model. The likelihood ratio test (p=0.02) and score (log-rank) test (p=0.05) suggested overall significant associations between the predictors and survival, while the Wald test did not reach statistical significance (p=0.30).
Discussion
Added value of this study. Adult RMS is a rare sarcoma, with around 9% of cases occurring in the head and neck region, including the sinonasal tract (3, 10). Limited literature exists on the clinicopathological characteristics, diagnosis, and treatment of RMS specifically in the sinonasal tract in adults, mostly based on small patient groups (6, 13). Previous studies either focus on RMS in the head and neck region in general or include both adults and children in their analysis (2-5, 11, 14, 15), making result comparisons challenging.
This study offers valuable insights into the characteristics and outcomes of patients with sinonasal RMS, contributing to our understanding of this rare malignancy. The analysis provides detailed information on tumor location, histological patterns, and immunohistochemical markers, enhancing our knowledge of this uncommon tumor. Furthermore, the survival analysis using the Kaplan-Meier method demonstrates a decrease in survival probability over time, underscoring the need for improved treatment approaches. The Cox proportional hazards regression model highlights the impact of age, sex, and tumor site on survival outcomes. These findings expand upon existing knowledge and serve as a foundation for further research in this complex disease.
Findings of the study in the context of the literature. Our study aimed to provide a comprehensive analysis of clinical-pathomorphological features and survival outcomes in 13 adult patients with sinonasal tract RMS diagnosed at a single center over a ten-year period. The number of patients included in our study was similar to that in a multicenter study by Thompson et al., where a total of 52 patients were evaluated, including 12 from a single institution (6). We observed similar ratios of female to male patients and mean age compared to the aforementioned study.
Regarding the morphological characteristics, the majority of cases were diagnosed as ARMS, with two patients having ERMS. These morphological types belong to the group of small round blue cell tumors. However, diagnosing RMS often requires an extensive panel of immunohistochemical tests that consider markers associated with various differentiations, such as epithelial, mesenchymal, melanocytic, lymphoid, and neuroendocrine (16). This comprehensive approach is particularly important in the diagnosis of sinonasal tract tumors and lymph node metastases, which can be the first diagnostic material obtained from an unknown origin metastasis. Co-expression of desmin, MyoD1, and myogenin markers is characteristic of both ARMS and ERMS (17). Our study demonstrated the expression of desmin and co-expression of MyoD1 and/or myogenin in all patients. However, it should be noted that some cases of RMS may also show expression of epithelial markers (CKAE1/3, CAM5.2), neuroendocrine markers (synaptophysin, CD56), and S100. We also observed the expression of CD56, CKAE1/3, and S100 in some patients within our study group.
Furthermore, it is important to consider that tumors within the head and neck region may contain rhabdomyoblasts and exhibit focal expression of skeletal muscle-specific markers. These include malignant peripheral nerve sheath tumors (malignant Triton tumors), sarcomatoid carcinoma, olfactory neuroblastoma, teratocarcinosarcoma, and melanoma (18). Therefore, alongside immunohistochemical examinations, molecular studies play a crucial role in the differential diagnosis of RMS. Specific molecular alterations have been identified in different morphological subtypes of RMS (19). In ARMS, rearrangements of the FOXO1 gene (chromosome 13q14) occur in association with fusion genes involving PAX3 (chromosome 2q35) or PAX7 (chromosome 1p36) in 59% of cases (20). The specific fusion gene formed has been described as a prognostic factor, with patients harboring FOXO1-PAX3 fusions exhibiting worse prognosis compared to those with FOXO1-PAX7 fusions (9). Our study detected rearrangement of the FOXO1 gene in ARMS patients through FISH analysis. However, specific fusion gene characterization was not performed, limiting further analysis of differences in disease progression based on the specific fusion gene involved.
The outcomes of our study revealed a significant burden of morbidity and mortality in adult patients with sinonasal tract RMS. Among the 13 patients included, a distressing majority of 12 patients experienced fatal outcomes, with only one patient surviving. Thus, the 5-year survival rate was 8%. This result is substantially lower than the 5-year overall survival rates reported in the literature for both adults with head and neck RMS (36%) and adults with sinonasal RMS alone (32%) (6, 21). Potential reasons for treatment failure in these patients may be attributed to the morphological type of RMS and a high rate of lymph node metastases. Studies have suggested that sinonasal ARMS carries a lower 5-year survival rate compared to ERMS (28-38% versus 49-57%), although these data were not stratified by age (5, 21). In our study, the majority of cases were diagnosed as ARMS, which may explain the unfavorable disease prognosis. Lymph node metastases in head and neck RMS are observed in 28% to 75% of cases and are more frequent in patients with sinonasal RMS (4, 14). In our study, 61% of patients (8/13) presented with lymph node metastases in the neck, consistent with findings in patients with sinonasal RMS.
Our findings suggest that age at diagnosis, sex, and tumor site may play significant roles in determining survival outcomes in adult patients with sinonasal RMS. The better prognosis observed in younger patients aligns with trends reported in the literature, highlighting differences in prognosis between adult and pediatric groups (6). The relationship between prognosis and sex remains unclear in existing studies. Some reports indicate no association with sex (4), whereas others demonstrated longer survival in women compared to men (22). Interestingly, in our study group, male patients had a higher chance of longer survival. However, further studies with larger sample sizes are needed to confirm and generalize these results, facilitating the development of more effective therapeutic interventions and multidisciplinary approaches for this aggressive malignancy.
Strengths and limitations of the study. The use of a retrospective cohort design allowed the inclusion of a substantial number of cases, providing a comprehensive analysis of demographic, clinical, and treatment-related factors. The application of both Kaplan-Meier analysis and Cox proportional hazards regression analysis enhanced the understanding of survival probabilities and identified potential prognostic factors in this patient population.
Limitations of the study include reliance on data from a single data source, potentially impacting generalizability. Additionally, the study’s sample size and follow-up period should be considered when interpreting the findings. Finally, as a retrospective study, the data were dependent on existing medical records, which may be subject to information bias.
Conclusion
In conclusion our findings underscore the grave nature of sinonasal RMS in adult patients and the formidable challenges that clinicians and researchers face in managing this malignancy. The high incidence of adverse outcomes underscores the urgent need for improved diagnostic tools, treatment strategies, and supportive care measures to enhance patient survival rates and quality of life in RMS.
Footnotes
Authors’ Contributions
Conceptualization: Monika Durzynska; Data curation: Irmina Maria Michalek, Florentino Caetano dos Santos; Formal analysis: Irmina Maria Michalek; Florentino Luciano Caetano dos Santos; Investigation: Monika Durzynska; Irmina Maria Michalek; Software: Irmina Maria Michalek, Florentino Caetano dos Santos; Florentino Caetano dos Santos; Writing – original draft: Monika Durzynska; Writing – review & editing: Irmina Maria Michalek; Florentino Luciano Caetano dos Santos; All Authors read and approved the final manuscript.
Funding
The Authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Conflicts of Interest
The Authors have no relevant financial or non-financial interests to disclose.
- Received July 11, 2023.
- Revision received August 2, 2023.
- Accepted August 4, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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