We searched the Pubmed database and found 23 case reports thus far(1–13) (Table 1). Patients range in age from 33 to 84 years, with a median of 55 years. The male-to-female ratio is 14:9. The median survival time is 13 months (range, 4 months to 2 years).
Table 1
Summary of thymic clear cell carcinoma reported on Pubmed
Literature | Age/gender | Chief complaint | Immunohistochemistry and special stain | Treatment | DFS | MS |
Snover et al | 42/M | Asymptomatic | PAS (+) | TT CR | 108 | WS |
Wolfe et al | 33/M | Fever Fatigue Weight loss | PAS (+) Muci (-) | CR | 0.5 | Buttock |
Stephens et al | 72/M | Asymptomatic | LMK (+) Muci, PAS, CEA (-) | TT CR | 12* | |
Kuo et al | 64/M | Dyspnea | PAS, LMK (+) | None | 3 | DOD |
Truong et al | 69/M | Chest pain | LMK, EMA (+) Muci, Vim, PLAP (-) | TT RT | 36 | Lung |
Hasserjian et al | 36/M | Asymptomatic | PAS, LMK, HMK, Vim (+) Muci, EMA, CEA, PLAP (-) | TT CR | 24 | DOD |
58/F | Asymptomatic | PAS, LMK, HMK, PLAP (+) Muci, Vim, EMA, CEA (-) | TT RT | 20 | DOD |
52/F | Chest pain | PAS, LMK, HMK (+) Muci, Vim, EMA, CEA, PLAP (-) | TT CR | 12 | Spine |
84/F | Asymptomatic | PAS, LMK, HMK (+) Muci, Vim, EMA, CEA, PLAP (-) | TT | 1.5 | DOD |
37/F | NA | Muci (-) | TT RT | 72* | |
50/M | Chest pain | PAS (+) Muci, EMA, CEA, PLAP (-) | CR | 4 | DOD |
62/M | NA | PAS, LMK, HMK, EMA, CEA (+) Muci, Vim, PLAP (-) | TT RT | 7* | |
36/F | Dyspnea Chest pain | PAS, LMK, HMK, EMA, PLAP (+) Muci (-) | CR | 7 | DOD |
Okuda et al | 59/M | Dyspnea | CK, EMA (+) | CR | 6* | |
Nakano et al | 42/M | Asymptomatic | CK, CEA (+) Vim, PLAP (-) | TT CR | 12 | Brain |
Lale et al | 66/F | Chest pain Dyspnea | CK7, EMA, PAS (+) CK20, Muci, P63 (-) | RT TT | NA | NA |
Bertocchi et al | 36/M | Asymptomatic | CK, AE/AE3 (+) CK5/6, p63, EMA, PLAP (-) | TT CR | 24* | |
Dai et al | 50/F | Asymptomatic | CK, PAS, p63, CK19 (+) CK7, Vim, PLAP, Pax-8, PTH, (-) | TT CR | 12* | |
Porubsky et al | 66/M | NA | P40(+) HMK, PAX8 (-) | NA | NA | NA |
| 52/F | NA | P40, PAX8 (+) HMK, (+)/(-) | NA | NA | NA |
| 64/M | NA | P40, PAX8 (+) HMK (-) | NA | NA | NA |
Salgueiro et al | 61/F | Chest pain Dyspnea | AE1/AE3, CK5/6, CK7 (+) | None | 2 | DOD |
Present case | 45/M | Chest tightness | AE1/AE3, CK18, EMA, PAX8, Vimentin (+) CK19 (-) | TT RT CR | 20 | Adrenal gland |
*: Disease Free Survival up to the last follow-up; |
DFS: Disease Free Survival; MS: Metastasis site; M: Male; F: Female; NA: Not available; TT: Thymectomy; CT: Chemotherapy; RT: Radiotherapy; DOD: Dead of disease; WS: Widespread |
PAS: Periodic acid Schiff; LMK: Low molecular weight keratin; HMK: High molecular weight keratin; EMA: epithelial membrane antigen; CK: Cytokeratin; Vim: Vimentin; PLAP: Placental alkaline phosphatase; CEA: Carcinoembryonic Antigen; PAX8: Paired box protein pax-8. |
Clinically, most chief complaints are asymptomatic (34.7%) and chest pain (26.1%) (Table 2).
Table 2
Descriptive statistics of the data from the case reports
Item | Mean/ frequency | Percentage (%) |
Cases | 23 | / |
Age | 55 | / |
Sex | | |
Male | 14 | 60.9 |
Female | 9 | 39.1 |
Chief complaint | | |
Asymptomatic | 8 | 34.7 |
Dyspnea | 5 | 21.7 |
Chest pain | 6 | 26.1 |
Chest tightness | 1 | 4.3 |
Fever | 1 | 4.3 |
NA | 5 | 21.7 |
Treatment | | |
TT + CT | 7 | 30.4 |
TT + RT | 6 | 26.1 |
TT | 1 | 4.3 |
CT | 4 | 17.4 |
None | 2 | 8.7 |
NA | 3 | 13.0 |
DFS | | |
<12months | 6 | 26.1 |
≥12months | 11 | 47.8 |
NA | 6 | 26.1 |
NA: Not available; TT: Thymectomy; RT: Radiotherapy; CT: Chemotherapy; DFS: Disease Free Survival. |
Clinically, the detections of mediastinal tumors mainly rely on the imaging examination, and the major method is chest CT or MRI, especially the enhanced chest CT. It can precisely show the tumor location, density, internal structure, and the relationship with the surrounding structure. MRI is easier to identify the foramen or spinal canal invasion of the tumor. Most patients underwent thymectomy with chemotherapy (30.4%) or thymectomy with radiotherapy (26.1%). Data improves patients underwent thymectomy or chemotherapy after thymectomy have longer disease free survival (≥ 12months) than patients with thymectomy alone. Different organ metastases may occur, but the adrenal metastasis in our case is firstly reported.
Microscopically, it composed of sheets, islands, and trabeculae of predominantly or exclusively of cells with optically clear cytoplasm. The nuclei are small to medium-sized with or without small nucleoli. Fibrous stroma can present, Lymphocyte infiltration is rare(14). Hyalinizing stroma in some cases has been mentioned in 5th WHO Classification of Thoracic Tumor. It may be related to EWSR1 translocation(15). Immunohistochemically, there is not a certain diagnostic biomarker. Tumor cells is typically positive for and PAS staining. At least one cytokeratin markers such as Low- and high- molecular-weight cytokeratin and EMA is positive. PAX8 and P40 are positive in some cases(13).
For differential diagnosis, metastasis from other organs like kidney and ovary should be excluded first. Abdominal and pelvic imaging is helpful for that. After excluding distant metastasis of other sites, primary mediastinal tumors characterized by clear cytoplasmic tumor cells included parathyroid adenoma/carcinoma, thymoma with clear cell components, and mediastinal seminoma, among others.
The tumors mentioned above have some characteristic clinical symptoms and serological laboratory test results, which are of great help to the differential diagnosis. Parathyroid adenoma/carcinoma can have increased PTH and abnormal serum calcium and phosphorus(16). Mediastinal seminoma can have increased β-HCG(17). Patients with thymoma may be accompanied by systemic sclerosis(18). Histologically, tumors mentioned above all have the features that composed of sheets, islands, and trabeculae of clear cytoplasmic tumor cells. Seminoma can have obvious nucleoli and inflammatory cell infiltration(17). Parathyroid adenoma / carcinoma can have fine capillary network with small nucleoli(16). Transparent components of thymoma B3 often migrate with typical thymoma regions, and bleeding and necrosis are rare(18). There are also some characteristic immunohistochemical and molecular changes in these tumors (Table 3).
Table 3
Differential diagnosis of primary mediastinal tumors
| Thymic clear cell carcinoma | Thymoma with clear cell component | Mediastinal seminoma | Parathyroid carcinoma with clear cell component |
Median age | 55 | 58 | 40 | 56 |
Clinical features | - | Accompanied with systemic sclerosis | Abnormal Β-hCG level | Abnormal PTH, serum calcium and phosphorus |
Histopathology | Common points | Islands and trabeculae of carcinoma cells with clear cytoplasm. |
Different points | Sclerotic stroma often present | Transition with typical thymoma region | Large nucleoli and prominent lymphocyte infiltration | Invasive growth pattern with abundant vessels |
Essential IHC results | CK (+) | TdT (T cell+) | OCT3/4, PLAP, CD117, SALL4 (+) | PTH, CK, Syn, ChrA (+) |
Molecular changes | EWSR1-ATF gene infusion | - | Isochromosome 12p, 12q amplification | - |
CK: Cytokeratin; OCT3/4: Octumer-binding transcription factor 3/4; SALL4: Spalt like transcription factor 4; PLAP: Placental alkaline phosphatase; |
In summary, clear cell carcinoma is a rare type of carcinoma in the mediastinum. Most patients are young or middle-aged. Imaging examination, tumor markers and hormone levels are helpful for differential diagnosis. We recommend thymectomy with chemotherapy or with radiotherapy as treatment. Histologically, tumor cells with a clear cytoplasm show an infiltrating growth pattern. Immunohistochemically, it is positive for we think epithelial markers. PAS staining, CK, EMA, P40, PAX8 and exclusive markers (TdT, OCT3/4, PLAP, CD117, SALL4, PTH) can be used as a diagnostic combination. Adrenal metastasis can occur, and imaging examination should focus on this site during postoperative follow-up.