T-lymphoblastic lymphoma after previous thymoma: how NGS helps establishing the diagnosis and procures new insights

Confronted with a case in our daily practice, we recalled a highly relevant article published in this journal by Ertel et al. in 2013 [1]. They described a conversion/development of a thymoma into T-lymphoblastic leukemia (T-LBL) and showed a transition from polyclonality/biclonality of the T-cells in the thymoma to monoclonality in the T-LBL. As stated in this article, additional molecular investigations should be performed in order to ascertain a possible link in such enigmatic occasions. In 2008 a 46-year old male patient was admitted to our hospital because of pleural effusion and paratracheal compression, which was clinically highly suspicious for malignancy. A CT scan showed a mediastinal mass with invasion of the arteria pulmonalis, the right atrium and the right ventricle. At that time six small endomyocardial biopsies were retrieved from the right atrium. They were mainly composed of subendocardial hypocellular connective tissue and myocardial muscle tissue. However in three fragments an atypical proliferation, constituting of two distinctive cell populations, was seen. On one hand there was a lymphoid like population, consisting of small blue cells without cytoplasm and with uncleaved nuclei. While on the other hand a larger, epitheloid cell population with round-oval nuclei and a variable amount of eosinophilic cytoplasm was observable. Further ancillary studies showed that the lymphoid component consisted of thymocytes (CD3þ, CD5þ, CD20-, TdTþ), while the epithelioid component was epithelial (CK5/6þ, EMAþ, CD68-, CD117-) and constituted a network interlacing the aforementioned thymocytes (Figure 1(A)). No corpuscles of Hassall were present. The amount of epithelioid cells equaled the amount of thymocytes and qualified this lesion for the diagnosis of B-type thymoma, (at least) type B2 according to the current WHO classification. Clonality analysis by polymerase chain reaction (PCR) showed a polyclonal (Band T-cell) pattern [2]. Treatment consisted of chemotherapy (five cycles of cis-platinum/ adriamycin/cyclophosphamide), followed by radiotherapy (48.6Gy in total), leading to clinical and radiological remission lasting until 2010. By then multiple pleural nodules were observed, which histologically proved to be metastases of the previous thymoma, at that time fulfilling criteria of a B3 type (Figure1(B)). Additional radiotherapy was given (39.6Gy in total), which led to clinical remission. In early 2018 the general clinical condition of the patient worsened and a generalized lymphadenopathy was discovered (Figure 2(A)). A cervical lymph node was excised and showed a total architectural effacement, infiltrated in a diffuse pattern by a small to medium size lymphoid cells. Focally there were relatively well demarcated nodular structures with – on low magnification – quite distinctive dual cellular populations, one smaller and darker and one larger and paler, which were demarcated from each other. The lymphocytes displayed a fine granular chromatin with mostly singular inconspicuous nucleoli and a brisk mitotic activity. This histological pattern beard some resemblances with the cortico-medullar differentiation seen in thymic tissue and some thymic epithelial tumors, yet no distinct epithelial cells were seen on the H&E slide. Immunohistochemically there were no epithelial cells within this lymph node, neither by cytokeratin staining, nor by p63 staining [3]. The lymphoid cells displayed an immature pre-T-cell phenotype (CD1a , CD2þ, CD3dim, CD4 , CD5 , CD7þ, CD8dim, TdTþ) and pathologically expressed LMO2 [4] and NOTCH1 [5] (Figure 2(C–D)). Thus, the provisional diagnosis of pre-T LBL was established. An additional clonality essay [2] showed no clonal T-cell receptor-Gamma rearrangements, and seriously challenged the diagnosis. In order to ascertain the malignant nature of this lesion a next generation (NGS) sequencing was performed, applying the Oncomine TM Comprehensive Panel Version 3 (135 genes) and a customized lymphoma panel (68 genes) [6]. The following pathogenic mutations were detected: JAK1 p.Y652H (44%; Exon 14), JAK3 p.M511I (44%; Exon 11), NOTCH1 p.S2467 (44%, Exon 34). Since these mutations are commonly