Pulmonary BNCT is extremely rare, the incidence is still unknown[4, 10]. To our best knowledge, there are only five cases have been reported so far, in the English literature via PubMed search (Table 1). The presented study is the sixth case. Of these six cases (Table 1), a similar incidence was presented in men and woman (male to female ratio 2:3), and the age range was 38 to 57 years old (median, 49 years old). Coincidentally, all the patients came from Asian countries, four patients were Japanese, and the other two came from China. Five patients were detected nodules in single lobe of the lung (four cases in the right lung and one case in the left lung), only one case presented as bilateral nodules. Six out of seven nodules were adjacent to the visceral pleura, while one nodule was revealed within the lung parenchyma. Previous reported patients remained alive and asymptomatic with no evidence of recurrence or metastasis after 1–5 years since the operation.(Table 1)
Table 1
Clinical Features of the six reported lung BNCTs
Case No. | Reference | Area | Age (y) | Sex | Tumor | Diameter (mm) | Follow-up |
Side | Location |
1 | Kikuchi Y[3] | Japan | 48 | M | Right | Within the parenchyma | 15 | 1 year |
2 | Kikuchi Y[3] | Japan | 38 | F | Right | Beneath the visceral pleura | 15 | 1 year |
3 | FY, Lee[9] | China | 53 | F | Bilateral | Beneath the visceral pleura | 10, each | 2 year |
4 | Y Takahashi[10] | Japan | 57 | F | Right | Adjacent to the visceral pleura | 10 | 5 year |
5 | M Shintaku[8] | Japan | 41 | M | Left | Subpleural | 12 | 20 months |
6 | Presented | China | 50 | F | Right | Adjacent to the visceral pleura | 7 | 4 months |
Macroscopically, the tumors were well demarcated, and with a tumor size ranging from 7 to 15 mm (median, 10 mm) in diameter. On the sectioning, the tumors were gray-white, and showed central cystic changes, except Y Takahashi et al[10]. Microscopically, the previous reported cases and our presented case shared almost identical characteristics. The cells were vacuolated with peripherally located nuclei, mimicking mature adipocytes. The nuclei were small and bland, with no atypia or mitosis, implying the benign nature of the tumors. Furthermore, our case and Y. Takahashi et al[10]’ s demonstrated a cluster of lymphocytes at the board of the tumor.
Intraosseous BNCTs are characterized by unencapsulated sheets of adipocyte-like vacuolated and less vacuolated cells. They exhibit bland round nuclei and eosinophilic cytoplasm. No mitotic figures are recognized. The tumors lack any intercellular myxoid matrix[2, 4]. These pathological features are identical to those lung BNCTs, including this presented case.
Pulmonary chordoma is extremely rare, to our knowledge, there were only three reported cases[6, 7, 11]. The pathogene sis is unclear, one possible mechanism may derive from multipotent cells in the lung parenchyma or a notochordal remnant with aberrant migration from midline[6]. Because of the aggressive behavior of chordoma, it is important to differentiate BNCT from chordoma. Lobule structure containing cords or nests of atypia notochordal cells and extracellular myxoid matrix are the important histological features of chordoma, while the BNCT lacks such structures. Intraosseous BNCT has recently been recognized to be a potential precursor of classic chordoma[2, 12], while it has not been documented that chordomas arise from BNCT in the lung, pulmonary BNCT is considered a potential precursor of classic chordoma[3, 9, 11].
Besides the chordoma, metastatic tumor should be ruled out first. The whole-body CT, bone scintigraphy, and (18)F-fluorodeoxyglucose-positron emission tomography would be helpful. Other primary pulmonary neoplasms with myxoid background and secondary clear cell tumors, such as myoepithelioma, hamartoma, pleomorphic adenoma, perivascular epithelioid cell tumor, pulmonary myxoid sarcoma with EWSR1-CREB1 fusion should be considered in the differential diagnosis[3, 8–10]. But these were easily ruled out on the basis of pathological and clinical findings and the immunohistochemistry.
Immunohistochemical staining is often used to confirm the diagnosis of BNCT. Typically, BNCT constantly express brachyury, a key transcription factor involved in the early stage of posterior mesoderm development of hemangioblasts and notochord[3, 5, 13, 14]. In the previous literatures, there two different brachyury-positive pattern. Four nodules showed strong immunoreactive for Brachyury, only one nodule was focally positive[10]. In their study, Takahashi et al analyzed the differences in Brachyury-positive expression between BNCTs and chordomas. They found the ratio was dramatically lower than chordomas[10]. According to Shen et al[15], those brachyury negative parts might be bound up with the fetal notochordal cells, as they reported that brachyury staining was negative in the BNCT component around chordomas and was negative in fetal notochordal cell rests, which are histopathologically similar to BNCTs. Jambhekar et al[16] have reported the expression rate of brachyury in chordomas was 90.2%, therefore, some other sensitive but less specific markers, including CK (AE1/AE3), EMA, S100, were usually recommended to be used in combiantion[9]. In our case, the brachyury-positive pattern was consistent with most of the literatures aforementioned, and CK (AE1/AE3), EMA, S100 were positively stained, strongly suggested notochordal differentiation. Reported skull BNCT typically had a Ki-67 index range from ༜1–3%[17–19], while the lung BNCTs was 1–5.2%[3, 8–10], which was even higher. However, the follow-up results showed that no recurrence occurred in patients with a higher Ki-67 index, indicating the benign biological behavior of this tumor[19].
To the best of our knowledge, none of the previous cases of lung BNCT mentioned the molecular features, and we firstly reported the EGFR gene changes. EGFR amplification was not detected. Du reported the EGFR amplification rate in skull base BNCT was 30.8%, much lower than that in chordoma[19]. While deletion mutation of EGFR gene exon 19 occurred, which was common in lung adenocarcinomas.
Because of the rarity of the lung BNCT, there is no consensus on treatment at present. Though the existing histological and immunohistochemical features indicate the benign nature of the tumor to some extent, surgical resection and close follow-up seem to be routine treatments. Therefore, more reports are need to explore pathological characteristics, especially the molecular characteristics, in order to better understand the nature of tumors.