Desmoplastic small round cell tumor is a unique mesenchymal neoplasm with distinct histological features and multiphenotypic differentiation, which was first described by Gerald and Rosai in 1989 . It is a highly aggressive tumor with a predilection for adolescent males and occurs predominantly in the abdominal and pelvic cavity. Isolated cases of extra-abdominal involvement have been reported in the central nervous system, mediastinum, pleura, lung, paratesticular region, bone and soft tissue [1, 2, 4–6]. The presentation of DSRCT as a primary head and neck lesion is even extremely rare. To our knowledge, only 22 cases have been documented in previous literatures [3, 6–22, 24–26]. In this study, we present a small series of three additional cases of DSRCT in the head and neck, increasing the reported number to 25. The clinicopathological features of 25 cases are summarized in Table 1. Like classic intra-abdominal DSRCT, DSRCT of the head and neck also occurred in the second to third decade of lifetime, with a mean and median age of 26 and 25 years (range, 4 to 61 years), respectively. Compared with intra-abdominal DSRCT (male:female, 5:1) [11, 27], there was a more prominent male predilection with a male to female ratio of 24: 1. Tumors arose in the salivary glands (8 cases), brain (4 cases), orbital region (4 cases), sinonasal region (4 cases), cranium (3 cases), middle ear (1 case) and neck region (1 case). The tumor size (available in 17 cases) ranged from 1.5 to 8 cm in maximum diameter (mean, 4.1 cm). Clinically, most tumors presented as a slowly enlarging mass or swelling of soft tissue, occasionally with pain. The specific symptoms and signs of DSRCT depend on the tumor location and involved organs or tissues [6, 11, 13, 14, 17, 18, 22].
Histologically, most DSRCTs are typically characterized by sharply demarcated nests or sheets of varying size with small round or oval cells embedded in a hypervascular desmoplastic stroma. In some cases, the tumor cells may be arranged in large nests with central necrosis, tubular-like structures, trabeculas, and cord-like patterns. Other unusual features, including Homer Wright-like rosettes, papillary areas, zones that resemble transitional cell carcinoma, and myxoid background, can also be identified occasionally [2, 27, 28]. In addition, tumor cells may also show rhabdoid, spindled, pleomorphic, vacuolated, signet-ring or larger cell morphology [28, 30]. Rare cases simply consist of solid sheets of round cells without desmoplastic stroma, making identification of this rare tumor even more difficult.
DSRCT has a distinctive immunohistochemical feature. The tumor displays multiphenotypic differentiation with co-expression of epithelial (cytokeratins, EMA), mesenchymal (desmin, vimentin) and neural markers (NSE). Of note, typical examples of DSRCT usually demonstrate a unique paranuclear cytoplasmic dot-like staining pattern of desmin and vimentin. The reported cases of DSRCT in the head and neck showed variable expression of cytokeratin (95.7%, 22/23), EMA (70.6%, 12/17), desmin (91.7%, 22/24), vimentin (100%, 17/17) and NSE (76.2%, 16/21), which is almost in line with intraabdominal tumors [28, 31, 32]. More than 95 % of DSRCTs harbor a unique cytogenetic abnormality, t (11; 22) (p13; q12), which fuses the amino terminus of EWSR1 gene on 22q12 to the carboxy terminus of WT1 on 11p13 [33, 34]. All tested cases (20/20, 100%) of DSRCT in the head and neck possessed EWSR1-WT1 gene translocation. Besides, immunohistochemistry for WT1 amino terminus and carboxy terminus antibodies may be useful to identify EWSR1-WT1 transcript despite the presence of some controversies regarding the epitope specificity of WT1 antibody used . Most of previous studies revealed that DSRCT showed nuclear expression of WT1 antibody (Clone:C-19) to the carboxy terminus with positive rates 70%~100%, but no expression of WT1 antibody
(Clone:6F-H2) to amino terminus [21, 31, 37]. In this series, three cases were also negative for WT1 amino terminus antibody. However, two other studies reported that DSRCT displayed discrete nuclear or paranuclear cytoplasmic staining of WT1 antibody to the amino terminus, with positive rates of 91% (29/32) and 81.4% (22/27), respectively [3, 28]. Murphy et al. have identified that some cases have novel fusion transcripts or express full-length WT1, resulting in nuclear staining for WT1 N-terminal antibody; and they have proposed that fusion transcripts in DSRCT result in the altered immunostaining pattern for WT1. Hence, interpretation of WT1 immunostaining requires knowledge of antibody target epitopes and correlation with results of molecular testing for the EWS-WT1 fusion transcript. Among DSRCT of the head and neck, 50% (6/12) of cases were immunoreactive for WT1. However, the antibody type and immunostaining pattern were less uncertain in most cases, because these cases were mainly from isolated case reports or small series.
The histogenesis of DSRCT is still uncertain owing to few studies focused on it in the literature. Originally, DSRCT was speculated to derive from mesothelial or submesothelial cells, given that it mainly occurs in the mesothelial-lined cavities and expresses both epithelial and mesenchymal antigens . However, some tumors arising in locations not lined by mesothelial cells challenged this hypothesis. Furthermore, there is no ultrastructural features of mesothelial differentiation in DSRCT [32, 36], which also does not support the above viewpoint. Therefore, the issue of origin of DSRCT remains to be studied.
The main differential diagnosis of DSRCT embraces a variety of malignancies with small round cell morphology, especially poorly differentiated carcinoma (including neuroendocrine carcinoma), Ewing’s sarcoma (EWS) and alveolar rhabdomyosarcoma (ARMS). Due to the uncommon tumor site as well as similar histologic features and expression of epithelial markers, all three cases in this series were initially misdiagnosed as poorly differentiated carcinoma by the referring pathologists. But different from DSRCT, poorly differentiated carcinoma often lacks prominent desmoplastic stroma and expression of desmin. Moreover, it is also absent of EWSR1-WT1 fusion. In addition, EWS also needs to be differentiated from DSRCT, because both tumors have overlapping immunophenotype and cytogenetic features. However, EWS is generally positive for CD99 (membrane staining) and NKX2.2 , but usually negative for AE1/AE3 and desmin. The unique t (11; 22) (p13; q12) chromosomal translocation of DSRCT occurs at breakpoints different from that of EWS t (11; 22) (q24; q12) resulting in EWSR1-FLI1 fusion . Finally, ARMS can be confused with DSRCT. The application of myogenic markers of myogenin and MyoD1 is helpful in the separation of DSRCT from ARMS; again, the detection of FOXO1 translocation by FISH can also distinguish these two entities. Other small round cell tumors occurring in the head and neck may also enter into the differential diagnosis of DSRCT, such as malignant melanoma and neuroblastoma. The positive staining of melanotyic markers in melanoma, including S100 protein, SOX10, HMB-45 and Melan-A, helps to distinguish from DSRCT. Although neuroblastoma and DSRCT are both positive for NSE, neuroblastoma is usually negative for EMA and desmin. It is worth noting that abdominal DSRCT can develop metastases to the head and neck region occasionally . In such settings, the detailed medical history and careful clinical examinations are warranted in the distinction. All three patients reported in this study had no special clinical history.
So far, the treatment of DSRCT remains challenging. Despite a combined therapeutic strategy of surgery, radiotherapy and chemotherapy applied, the overall prognosis remains very poor, with approximately 29% for a 3-year survival and just 18% for a 5-year survival , respectively. Recently, some reports revealed that patients treated with aggressive surgery and intense alkylator therapy (P6 protocol: vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide) had a better prognosis . Besides, patients with superficial DSRCT also have a better outcome, because earlier clinical manifestations and symptoms offer a higher chance of complete surgical excision . Among DSRCT of the head and neck, 6 of 22 (27.3%) patients with follow-up information died, with five cases dead of the disease and one dead of other causes. Two patients were alive with disease, and the other 14 remained well with no evidence of disease. Due to the limited follow-up duration, the prognosis of DSRCT in the head and neck is difficult to compare with that of intra-abdominal DSRCT. Therefore, whether there is a difference in the prognosis between the two subsets still need to be elucidated in the future.
In summary, we describe three cases of extra-abdominal DSRCT arising primarily in the head and neck. Due to the unexpected occurrence of DSRCT in this unusual site and similar histological and/or immunohistochemical features, it may be easily misinterpreted as other small round cell tumors, especially poorly differentiated carcinoma (including neuroendocrine carcinoma). This study further demonstrates the importance of including DSRCT into the differential diagnosis of small round cell tumors of the head and neck, particularly those affecting the young patients and expressing of epithelial markers. In challenging cases, molecular assays of EWSR1-WT1 fusion by RT-PCR, FISH or next-generation sequencing will be helpful for establishing a correct diagnosis.