Early thymectomy is the standard treatment modality for myasthenia gravis (MG) patients with thymoma. MG patients have reduced pulmonary function, and surgery is often limited to using muscle relaxants and antibiotics. Therefore, minimally invasive techniques are more commonly used to treat MG.123 However, the basis for the use of these minimally invasive techniques is the absence of thymic carcinoma, because when it is present, complete resection is important for survival.4

Thymomas [World Health Organization (WHO) types A, AB, and B] are neoplasms arising from or exhibiting differentiation toward thymic epithelial cells; they also exhibit a nonneoplastic lymphoid structure. Their malignant potential ranges from absent to low. Collaboration between the dysfunctional neoplastic thymic structure and the nonneoplastic lymphoid structure induces autoimmune diseases such as MG. On the other hand, thymic carcinomas are malignant epithelial tumors with overt cytologic atypia, almost invariable invasiveness, and a lack of "organotypic" (thymus-like) features.5 MG has been most commonly associated with WHO type A, AB, or B thymoma, but not thymic carcinoma.678910

While the WHO has classified thymoma and thymic carcinoma as different tumor types, it has been shown that thymic carcinomas (which have very poor prognoses) can actually arise after the development of the thymoma.511 Theoretically, thymic carcinoma can accompany MG after a sufficient period. MG is an early and easily detectable sign of a thymoma, and therefore thymoma with MG is generally detected at an early stage and has a better prognosis than thymoma without MG.9 Early thymectomy is the standard treatment of MG with thymoma. Whether or not thymic carcinoma can arise in thymoma with MG has yet to be established.

The medical records of patients who underwent thymectomy between January 1990 and December 2011 at the Yonsei Medical Health System, Seoul, Korea were reviewed. All cases with a pathologic diagnostic code of "thymic carcinoma" or "WHO type C" were selected. From these, all cases with MG were selected. MG was diagnosed by a positive repetitive nerve stimulation study and/or the presence of anti-acetylcholine-receptor antibody. Each case was reviewed and reclassified according to the 2004 WHO classification.5

The study protocol was reviewed and approved by the Institutional Review Board (IRB No. 2014-08-114). Informed consent was waived by the board due to the retrospective nature of the study.

A total of 297 patients had undergone thymectomy due to thymic tumor during the test period, of whom 29 (9.8%) were classified as having thymic carcinoma. Eighty-one patients were found to have a thymic tumor with MG, 10 of which were classified as either thymic carcinoma or thymoma type C. After applying the new WHO criteria, seven of the ten cases were reclassified as having well-differentiated thymic carcinoma (WHO type B3). Three cases (3.7%) of thymic carcinoma were found (one man and two women; mean age, 47.3 years).

All three cases of thymic carcinoma had a predominant B3 or B2 thymoma area with a focal, well-demarcated squamous cell carcinoma area and overt cytologic atypia; two patients had a type B3 thymoma and the other patient had a type B2+B3 thymoma (a thymic carcinoma portion was seen in the B3 area). Thymic carcinoma portions were clearly identifiable from thymoma portions, and their areas were much smaller than that of the thymoma (Fig. 1A-D). The thymic carcinoma area exhibited strong immunoreactivity for p63, which is a squamous cell differentiation marker; the conventional thymoma B3 tissue was not p63 immunoreactive (Fig. 1E and F).

All three patients are currently still alive and without recurrence, after follow-up periods of 5, 10, and 22 years. The pathologic findings are summarized in Table 1.

While no de novo thymic carcinomas were found in the present study, a small (3.7%) portion of thymomas with MG had a mixed thymic carcinoma portion. Previous studies and other reports have clearly established that large thymic carcinomas with poor prognoses can arise from a preexisting thymoma.1112

The point at which transformation to thymic carcinoma occurs is unknown. Two previously reported cases of thymic squamous cell carcinoma developed from thymomas after 10 and 14 years;12 it was unknown whether these thymic carcinomas were able to develop during the earlier stages of the thymoma. A recent study found that a large portion of a thymoma exhibited mixed histology findings.13 Moreover, additional research has shown that type B2 thymomas are genetically related to type B3 thymomas, in line with the frequent histologic observation of combinations of type B2 and B3 areas in the same tumor.1415 It has further been suggested that some type B2 thymomas are precursor lesions of type B3 tumors.15 As a part of the thymic carcinoma, thymic squamous cell carcinomas frequently show gains of chromosomes 1q, 17q, and 18, and the loss of chromosomes 3p, 6, 16q, and 17p.16 Apart from the "thymic stemness" alteration on chromosome 6q25, thymic squamous cell carcinomas share other similarities with type B3 thymomas, namely gain of chromosome 1q and loss of chromosome 6. Apart from these similarities, they are genetically distinct from thymomas, justifying their listing as a separate entity in the WHO classification.151718

A squamous cell carcinoma can theoretically develop inside a B3 thymoma. However, any type of thymic carcinoma can develop within all types of thymoma.11 We believe that this phenomenon is due to the long period before detection of malignant transformation. In addition, thymic carcinomas have been shown to develop in the necrotic portion of a thymoma.11 All of the thymic carcinomas in our case were squamous cell carcinomas and were accompanied by B3 thymomas.

The standard surgical technique for treating thymic carcinomas is median sternotomy with complete thymectomy and removal of all surrounding mediastinal fat.19 There are no published data on the use of minimally invasive surgery for thymic carcinoma.20

In conclusion, thymoma with MG had a thymic carcinoma component; this thymic carcinoma portion was small and localized within the thymoma in these patients.