Primary mesenchymal chondrosarcoma of the lung

Abbreviations

CT

computerized tomography

MC

mesenchymal chondrosarcoma

mRNA

messenger ribonucleic acid

PCR

polymerase chain reaction

To the Editor,

Mesenchymal chondrosarcoma (MC) is a rare, high‐grade sarcoma that can arise in a variety of anatomic sites, most commonly the craniofacial bones and bones of the axial skeleton. Primary MC arising in the viscera is exceedingly rare. While MC most commonly affects adolescents and young adults, it can occur across a wide range of ages and there is no strong predilection for either sex. ¹ , ² Radiologic findings are often described as a destructive, lytic lesion with ill‐defined margins when arising in bone or a well‐circumscribed, lobulated mass with areas of ring‐and‐arc calcifications when arising in extraosseous sites. The tumor is characterized histologically by a biphasic morphology consisting of undifferentiated small round cells admixed with islands of neoplastic hyaline cartilage. Most MCs show a recurrent HEY1::NCOA2 gene fusion, resulting in an mRNA product with in‐frame fusion of HEY1 exon 4 to NCOA2 exon 13.

We report a case of primary pulmonary MC. The project was approved by an institutional ethics committee and was conducted in accordance with the Declaration of Helsinki of 1975. The patient was a 52‐year‐old female who presented to the emergency department with hypertensive crisis. During the course of evaluation, she was discovered to have a 6.3 × 6.3 × 2.6 cm lobulated anterior mediastinal mass with areas of coarse calcification (Figure 1a). She had no prior history of malignancy. The patient underwent laparoscopic robotic excision of the mass. During intraoperative exploration, the surgeon found that the mass was originating from the left upper lobe of the lung and a lung wedge resection was performed (Figure 1b).

Figure 1.

Radiologic, intraoperative, and histologic features. Lobulated anterior mediastinal mass (arrows) with coarse calcifications arising from the left upper lobe of the lung on CT imaging (a) and intraoperative photography (b). Tumor composed of large hypercellular nests infiltrating adjacent lung parenchyma (c). Occasional dilated hemangiopericytoma‐like vessels throughout the tumor (d). Biphasic morphology with transition from undifferentiated small round cells to mature‐appearing hyaline cartilage (e). Nests and cords of undifferentiated round cells with conspicuous mitotic activity (f).

Grossly, the specimen was fragmented and lobulated with variably tan‐pink and fleshy to white‐tan, firm, and partially calcified cut surface. Histologic evaluation showed a proliferation of atypical small round blue cells with scant to vacuolated cytoplasm arranged in small, densely packed nests and cords. Occasional irregularly shaped, dilated (hemangiopericytoma‐like) vessels were identified throughout this component of the tumor. Interspersed between the areas of undifferentiated small round blue cells were islands of neoplastic hyaline cartilage with occasional calcification. Mitotic figures were readily identified throughout the small round blue cell component and were essentially absent in the areas reminiscent of mature hyaline cartilage. Several foci of necrosis were present, accounting for approximately 5% of the overall tumor volume. The tumor showed invasion of the lung parenchyma and no mediastinal structures were identified (Figure 1c–f).

Immunohistochemical stains showed neoplastic cells were negative for cytokeratin AE1/AE3, CAM5.2, synaptophysin, chromogranin, TTF‐1, napsin A, and p40. A custom anchored multiplex polymerase chain reaction (PCR) assay targeting select sarcoma‐related gene fusions and rearrangements was performed on formalin‐fixed, paraffin‐embedded tissue. This assay was positive for a HEY1 exon 4 to NCOA2 exon 13 gene fusion and negative for all other gene rearrangements and fusions evaluated.

A subsequent positron emission tomography scan performed approximately 6 weeks after resection of the pulmonary tumor revealed a 2.5‐cm, hypermetabolic lesion in the uncinate process of the pancreas. The initial preresection imaging had shown no pathology throughout the upper abdomen. Biopsy of this lesion showed metastatic MC. The patient was initiated on systemic therapy with vincristine, doxorubicin, and cyclophosphamide, and has received three cycles of this regimen to date.

Due to the characteristic biphasic morphology of this resected tumor, the differential diagnosis for this case was relatively limited, but included sarcomatoid carcinoma with heterologous differentiation, a diagnosis excluded by the results of immunohistochemistry and multiplex PCR. However, small biopsies may have a broader range of diagnostic considerations, including Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, and even small cell carcinoma, as well as histologic variants of synovial sarcoma, solitary fibrous tumor, and osteosarcoma with small round cell morphology. Perhaps most problematic of these entities is the small cell variant of osteosarcoma, which often shows scant osteoid formation and can uncommonly contain areas of chondroid differentiation. ³ While immunohistochemical studies have utility in excluding several of the entities mentioned above, molecular testing may be required to establish a definitive diagnosis on small biopsies. Molecular testing employing PCR or next generation sequencing are preferred for detecting the HEY1::NCOA2 fusion as the close proximity of the HEY1 and NCOA2 genes on chromosome 8 makes this fusion difficult to detect via conventional cytogenetic studies.

Mesenchymal chondrosarcoma is an aggressive neoplasm with significant metastatic potential. Five‐year and 10‐year overall survival rates are estimated at 60%–70% and 40%–50%, respectively. ¹ , ² Although there are no established guidelines for the treatment of MC, complete surgical resection with adjuvant chemotherapy is currently considered the standard of care. ⁴

To the best of our knowledge, this is the ninth case of primary pulmonary MC lung reported in the literature and the first in the United States. The present case is not dissimilar to these eight previously reported cases, summarized in a case report and literature review by Kaihu Li and colleagues. ⁵ This cohort was predominantly female with median age at diagnosis of 45 years old and a median tumor size of 4.25 cm in greatest dimension. The histomorphologic findings in each of the previous cases were identical to those described above in this case. Follow‐up information was available for three patients. Two patients were alive with metastases 3 and 8 years after diagnosis, and one patient was alive with no evidence of metastasis 1 year after diagnosis.

In summary, we present a very rare case of primary pulmonary MC. Identifying the unique combination of undifferentiated small round cells admixed with islands of mature‐appearing hyaline cartilage is key to establishing the diagnosis on morphologic grounds. Ancillary testing including immunohistochemistry and/or molecular testing is often required when limited tissue is available for histologic evaluation.

AUTHOR CONTRIBUTIONS

Conception and design of the study: William R. Perry and Kristine E. Konopka. Acquisition and interpretation of data: William R. Perry and Kristine E. Konopka, Jonathan B. McHugh. Drafting the manuscript: William R. Perry and Kristine E. Konopka.

CONFLICT OF INTEREST STATEMENT

None declared.