Introduction
The chondrosarcoma family represents a heterogeneous group of malignant osseous neoplasms which, by definition, produce a cartilaginous (chondroid) matrix and most commonly occur in the pelvis, femur, humerus, and ribs. Overall, chondrosarcoma accounts for approximately 4% of all sarcoma cases [
1,
2] and 11% of all primary bone malignancies [
3]. Chondrosarcoma of the head and neck is rare, comprising only 1–12% of all human chondrosarcoma tumors, and shows a slight predilection for men in their fourth-to-sixth decade [
2,
4]. Sites of involvement within the head and neck include the sinonasal tract, gnathic bones, larynx, and base of the skull, while pain, swelling and nasal obstruction represent the most common clinical findings [
3,
5]. Several histopathologic subtypes of head and neck chondrosarcoma are recognized including conventional, periosteal, dedifferentiated, and clear cell, with the conventional subtype predominant in the maxillofacial bones [
2,
5,
6]. At the molecular level, hot spot mutations of the isocitrate dehydrogenase 1 and 2 genes (
IDH1/2) generally characterize approximately 65% of head and neck chondrosarcoma tumors [
4].
Also, tumors with chondrosarcomatous differentiation have been reported rarely in relationship to somatic malignant transformation developing in testicular germ cell tumors (TGCTs) [
7‐
10]. Somatic-type malignancy (STM) occurs in 2.5 – 8% of TGCTs, exclusively in postpubertal individuals aged 15–68 years (mean age: 33 years) [
11,
12]. These most commonly arise in association with a concomitant or prior teratoma, or mixed GCT with a teratomatous component [
7,
13,
14]. A smaller subset of STMs appear to derive from non-teratomatous TGCTs including yolk sac tumor [
15,
16], and rarely, seminoma [
13,
17]. STM can develop within primary testicular malignancies or metastatic tumors to lymph nodes, commonly retroperitoneal and mediastinal, or other organs following cisplatin-based chemotherapy treatment [
18,
19]. Development of STM in metastatic GCT severely affects prognosis and patient survival, while the prognostic significance of STM occurring within the primary tumor is less understood. Deciphering whether a metastatic STM originates from TGCT or represents
de novo malignancy involving other organs or tissues may be challenging, particularly when conventional GCT is not identified within the biopsy specimen [
14].
Examples of primary or metastatic TGCT with STM exhibiting overt chondrosarcomatous features are exceedingly rare in the English literature [
7‐
10] and, to the best of our knowledge, involvement of the head and neck region has not been previously documented. Herein, we report the clinicopathologic, immunohistochemical (IHC) and molecular characteristics of a skull base chondrosarcoma which strongly support the diagnosis of STM arising from a metastatic TGCT.
Discussion
We report the clinicopathologic, immunophenotypic and molecular characteristics of a diagnostically challenging case of chondrosarcoma involving the nasal cavity and skull base of a man with previously undiagnosed malignant TGCT and extensive lymph node metastases. Several lines of evidence strongly indicate that the skull-based cartilaginous neoplasm represents a STM from metastatic TGCT. As we have shown, radiographically and histopathologically, the patient presented with widespread left metastatic nodal disease involving retroperitoneal, retrocrural, periaortic, mediastinal and, even, supraclavicular lymph nodes. Metastasis to the left supraclavicular (Virchow’s) node from infradiaphragmatic primary malignancies is, overall, considered uncommon [
20,
21] and exceedingly rare in the case of TGCTs [
22]. Therefore, intracranial and/or sinonasal TGCT metastasis is strongly favored given the presence of metastatic seminoma in supradiaphragmatic, including supraclavicular, lymph nodes.
Histopathologic diagnosis of STM arising within a primary or metastatic TGCT may be problematic. According to the most recent W.H.O. classification, criteria for the diagnosis of STM include an expansile overgrowth comprising a pure population of atypical mesenchymal or epithelial cells that occupy at least one low-power field (×4 objective, 5 mm in diameter) and show an infiltrative pattern [
23]. Microscopically, STMs derived from TGCTs exhibit a markedly broad spectrum of histopathologic types lacking morphologic resemblance to TGCTs, including sarcomas (approximately 50% of all cases), carcinomas (20%), embryonic-type neuroectodermal tumor (10%), nephroblastoma and, even, myeloid neoplasms and undifferentiated tumors [
14,
23,
24]. Notably, carcinomas and sarcomas occurring as TGCT STMs show divergent clinical characteristics, with the former developing later in the course of disease (median: 108 months post TGCT diagnosis) and the latter usually presenting earlier (median: 20 months) [
13,
23]. Among the sarcoma subgroup, rhabdomyosarcoma accounts for greater than 50% of reported STM cases [
11,
14,
18,
23].
Well-documented examples of TGCT with conventional chondrosarcoma as STM are sparse in the English literature and have been published either in the form of single case reports [
9,
10] or as part of large-scale clinicopathologic cohorts [
7,
8]. In the latter, STMs with chondrosarcomatous features account for just 3.7% [
8] – 5% [
7] of all TGCTs with STM. In all previously reported cases of STM chondrosarcoma (
N = 5, age range = 19–53 years; age mean = 32.2 years), chondrosarcoma was discovered either within the primary testicular tumor [
7,
9], or during retroperitoneal lymph node dissection [
8], or both [
10]. The present case is the first reported example of STM chondrosarcoma occurring in an extratesticular and extranodal anatomic location. Similar to most previous cases of TGCT with STM, chondrosarcomas arose within a pure teratoma [
8,
10], mixed GCT with a teratomatous component [
7,
9], or yolk sac tumor [
7]. Even after extensive sampling, STMs may be lacking a recognizable GCT component [
10,
14,
18,
25,
26], adding to the diagnostic complexity of such cases. In our patient, the primary testicular tumor and lymph node metastasis demonstrated features of seminoma with syncytiotrophoblastic cells, although no seminomatous component was identified in the vicinity of the chondrosarcoma. On rare occasions, STMs have been associated with “pure” seminomas [
13,
17]. A plausible explanation for the above would be a sampling error during evaluation of the primary testicular tumor or foci of teratoma that escaped histologic detection due to their small size [
17].
Another interesting finding regarding this chondrosarcoma, which further supports its etiopathogenesis as a STM from a metastatic TGCT, is its unique IHC properties. Although the overall histomorphologic characteristics of the tumor were unequivocally consistent with the diagnosis of chondrosarcoma, lesional cells showed strong and diffuse immunoreactivity for S100 and EMA, as well as focal staining with CAM 5.2 and CK AE1/AE3. Given that overt expression of epithelial differentiation markers is not anticipated in conventional chondrosarcoma [
5,
27,
28], the observed S100 and EMA positivity raised suspicion for the diagnosis of chondroid chordoma. However, brachyury stain, a highly sensitive and specific marker for notochordal neoplasms [
28,
29], was uniformly negative. Negativity was also observed for the GCT markers OCT3/4 and SALL4, which were strongly positive in the metastatic seminomatous cells. As reported previously [
10,
14,
25], STMs commonly demonstrate a divergent immunoprofile compared to the TGCT of origin.
Genomic inactivation and loss of nuclear expression of SMARCB1, a core subunit of the SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, characterizes a plethora of mesenchymal neoplasms with, overall, diverse histopathologic appearance and biologic properties [
30,
31]. SMARCB1-deficient soft tissue neoplasms traditionally comprise of a monomorphic population of undifferentiated epithelioid cells with “prototypical” rhabdoid cytomorphology, and anaplastic large-cell or small round-cell features [
30,
32]. Multiple previous studies have shown that virtually all malignant rhabdoid tumors [
33] and poorly-differentiated chordomas [
34], 90% of epithelioid sarcomas [
35,
36], as well as a subset of epithelioid malignant peripheral nerve sheath tumors [
30,
31], myoepithelial carcinomas [
35] and extraskeletal myxoid chondrosarcomas [
37] demonstrate SMARCB1 inactivation and/or loss either by FISH or IHC. Furthermore, SMARCB1 germline mutations have been associated with familial schwannomatosis and meningiomatosis [
33,
38], in which acquired NF2 mutations synergize with SMARCB1 inactivation [
39]. Interestingly, the STM chondrosarcoma of the current patient exhibited uniform negativity for SMARCB1 by IHC in the sarcomatous cells but retained expression in non-neoplastic background cells. To the best of our knowledge, only one additional example of SMARCB1-deficient conventional chondrosarcoma has been previously reported and involved the mandible of a 13-year-old boy with a history of thoracic malignant rhabdoid tumor and an underlying germline SMARCB1 deletion [
40]. The latter raised the question whether our patient also harbored a SMARCB1 germline aberration which would render him susceptible to the development of malignancies. However, as we showed, metastatic nodal seminoma cells were strongly positive for SMARCB1 by IHC, suggesting that loss of SMARCB1 in the STM chondrosarcoma represents an acquired genetic or epigenetic phenomenon rather than a germline event.
Early genetic alterations of
IDH1/2 have been identified in 46.1% [
41] to 71.4% [
42] and, more recently, in 85.7% [
4] of skull base chondrosarcoma cases.
IDH1 mutations involving codon 132 of exon 4 predominate, with the R132C transition (CGT N TGT) detected in about 40% of the cases [
43].
IDH2 mutations are seen in 8.6% of chondrosarcomas, most of them being an R172S transversion (AGG N AGT) [
43]. This chondrosarcoma was lacking
IDH1/2 mutations. Although a fraction of skull base chondrosarcomas may be negative for
IDH1/2 aberrations, it is also plausible that as a STM arising from a metastatic TGCT, this tumor is not driven by usual genetic mechanisms that underlie conventional chondrosarcomagenesis. Detection of i(12p) or overrepresentation of 12p is a hallmark feature of TGCTs and has been confirmed in most STMs [
8,
44]. Therefore, cytogenetic studies for the identification of i(12p) by FISH [
45,
46] or quantitative PCR may be diagnostically useful in cases of STM that are not associated with conventional GCT components [
12,
46], like the current chondrosarcoma. Notably, FISH analysis confirmed abnormal duplication of 12p in the chondrosarcoma cells, as well as multiple copies of i(12p) in the metastatic seminoma cells, validating that the skull base chondrosarcoma represents STM arising from a metastatic seminoma.
Recognition of STMs arising in association with TGCTs is of utmost importance since their presence dramatically impacts prognosis and overall survival [
14,
23]. Furthermore, proper identification of STM histopathologic subtypes may harbor therapeutic implications. Although cisplatin-based chemotherapy is highly effective for conventional TGCTs conferring excellent prognosis, such therapeutic regimens are often ineffective in STMs derived from TGCTs [
13]. In agreement with that, our patient showed no signs of responsiveness to the administered cocktail of bleomycin, etoposide and cisplatin. Notwithstanding multimodality chemotherapeutic protocols, patients with STMs show cancer-specific survival rates ranging from 50 to 60% [
14,
47].
In conclusion, herein we report a rare example of skull-based conventional chondrosarcoma in a 39-year-old man presenting as chemotherapy naive STM arising from a metastatic seminoma. Unlike “typical” cases of conventional head and neck chondrosarcoma, the STM chondrosarcoma showed loss of SMARCB1 expression, focal to diffuse immunostaining for epithelial markers, including EMA, CAM 5.2 and CK AE1/AE3, and 12p duplication with absence of IDH1/2 mutations. Although exceedingly uncommon, metastasis to the head and neck region may occur in patients with testicular neoplasia. This case report also underscores the importance of high index of suspicion regarding the diagnosis of lesions that present with otherwise typical histomorphology but unexpected or uncommon IHC or molecular properties.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.