Thymomas are rare tumors (incidence 1–4 per 10⁶ per year) without clear gender bias. Although they rarely occur in children, their incidence peaks between 40 and 60 years of age [1, 2]. Thymic carcinomas are even rarer (incidence 0.1–0.4 per 10⁶ per year), more common in men and occur with increasing frequency from adolescence onward [1, 2].

The etiology of thymomas and thymic carcinomas is unknown. Rare familial [8] and syndromal thymoma cases (e.g., HNPCC) have been reported [9]. Thymoma patients show a higher frequency of nonthymic solid and hematopoietic cancers than the general population [10]. Since almost all thymomas show medullary and cortical differentiation [11] they are thought to arise from a bipotent thymic epithelial stem cell. In TCs, the (stem) cell of origin is enigmatic.

TETs show recurrent genetic gains and losses that increase from type A to B3 thymomas and further to TCs [12]. Genetic alterations in thymomas and TCs overlap partially [13]. Overlap with other cancers is limited [12]. The commonest chromosomal deletion of thymomas and TCs concerns the 6p25 region that contains the FOXC1 tumor suppressor gene [14]. The most common gains are at 1q23 (PBX1) and 8q24.3 (GLI4) [14, 15]. The commonest alteration overall is a point mutation in the GTF2I oncogene that is most prevalent in type A and AB thymomas (~80%), less common in type B thymomas (20–40%), rare in TCs (5–10%) and apparently absent in other cancers [16]. The only predictive biomarkers identified so far are activating KIT exon 11 gene mutations in 5% of TCs that correlated with transient responses to imatinib [17]. Markers predicting the response of many TCs to multikinase inhibitors are elusive [18].

Thymoma and TC can cause pain, respiratory distress, vena cava superior syndrome or be fortuitous findings. Myasthenia gravis, pure red cell aplasia, acquired hypogammaglobulinemia (Good syndrome), and mucocutaneous candidiasis are “indicator autoimmune diseases” of thymomas but not of other cancers [3]. Therefore, their diagnosis should prompt a search for thymoma and their detection prior to surgery of a mediastinal mass makes the diagnosis of TC, lymphoma, germ cell, or mesenchymal tumor unlikely. Other thymoma-associated autoimmune diseases are not thymoma-specific, e.g., thyroiditis, type I diabetes, hepatitis, encephalitis, and SLE [19]. Autoimmune diseases in TCs (e.g., polymyositis) are very rare and not specific. Enlargement of mediastinal lymph nodes in association with a mediastinal mass argues against thymoma (see staging) and is in favor of a diagnosis of TC, lymphoma, or germ cell tumor (GCT).

Biopsies of mediastinal masses are indicated if there are nonsurgical treatment options, e.g., in neoadjuvant settings or if lymphomas and germ cell tumors are differential diagnostic possibilities. Biopsies are usually dispensable in myasthenic patients, since thymoma is the only likely diagnosis and surgery is the curative therapy. Although small biopsies help to guide treatment [20], reporting of diagnoses based on small biopsies should be cautious for the following reasons:

Epidemiology and stage distribution of type A thymoma are summarized in Table 5.1. This usually indolent tumor has been delineated from “atypical type A thymoma”, i.e., a rare variant that infiltrates extensively, metastasizes, and shows histologic features of aggressiveness [1, 2].

Macroscopy Type A thymomas are usually encapsulated or well circumscribed (stage I or II). The cut surface is gray to white and usually shows a fascicular texture, few fibrous septae, and small cysts. Atypical type A thymoma may be poorly circumscribed, extend into adjacent organs, and exhibit necrotic areas and distant metastasis [21–23].

Histology and immunohistochemistry Type A thymoma can show fascicular, storiform, glandular/adenoid, glomeruloid, solid, rosette-forming, hemangiopericytoma-like, and “pseudoendocrine (paraganglioma-like)” patterns, often within a single tumor. Bland spindle or oval cells with small, spindly, or oval nuclei with fine chromatin und without prominent nucleoli accompanied by thin-walled hemangiopericytomatous vessels are encountered at least focally in almost all properly sampled cases (Fig. 5.1a, b). Polygonal tumor cells are an optional and sometimes predominant feature (Fig. 5.1c–d). By definition, lymphoid cells are scarce (Fig. 5.1e, f). Mitoses, apoptotic cells, and perivascular spaces are uncommon. Coagulation necrosis (e.g., of comedo type) is usually restricted to “atypical type A thymomas” (Fig. 5.2). Hassall corpuscles are absent.

Immunohistochemistry Type A thymomas [1, 2] harbor no or rare immature T cells as identified by staining for TdT (recommended), CD1a, or CD99. Any dense (“crowded“) accumulation of immature T cells or moderate numbers of immature T cells (Fig. 5.1e, f) in >10% of the evaluable tumor area implies a diagnosis of type AB thymoma. Epithelial cells of type A thymoma consistently stain for CK19 und p63/p40, commonly for CD20 (focally) but not for CK20, CD5, and CD117.

Molecular pathology Recurrent structural genetic alterations are rare [13], while hot spot point mutations in the GTF2I gene show the highest prevalence (80%) among all thymomas [16].

If only lymphocyte-poor (TdT−) areas of type AB thymomas and micronodular thymoma with lymphoid stroma (MNT) are sampled in a small biopsy, an erroneous diagnosis of type A thymoma may be inevitable. Fortunately, this is rarely of clinical relevance. Focal spindle cell areas in rare type B3 thymoma can be challenging: prominent perivascular spaces and Hassall corpuscles argue for B3 thymoma, while epithelial expression of CD20 and a ki67 index <2% [24] in epithelial cells are in favor of type A thymoma, leaving quite some tumors that may defy classification in small biopsies. While spindle cell (sarcomatoid) carcinoma is usually easily recognized by striking atypia, brisk proliferative activity and common CD5 and CD117 expression, spindle cell carcinoids, mesenchymal neoplasms (e.g., synovial sarcoma, solitary fibrous tumor, inflammatory myofibroblastic tumor, nerve sheath tumor), desmoplastic melanoma, various dendritic cell neoplasms [1] and even reactive changes (e.g., sclerosing mediastinitis, thymic fibrosis [25], inflammatory spindle cell tumors [26]) may need immunohistochemical analysis for recognition.

Therapy and prognosis Complete surgical removal is the only definite treatment and usually achievable due to the circumscription and low tumor stage of most classical “type A” thymomas. Removal may be challenging in “atypical” and metastatic cases [22, 27]. The 10-year survival rates reach 80–100% [5, 28, 29]. Survival rates for atypical type A thymomas have not been reported.

Epidemiology and stage distribution of this commonest thymoma subtype (up to 40%) [28–30] are summarized in Table 5.1.

Clinical peculiarities Myasthenia gravis (occurring in 20–40%) and other paraneoplastic autoimmune diseases [1, 19] are frequent in this usually indolent tumor [27].

Macroscopy Most cases are well circumscribed [28]. On the cut surface, a nodular architecture and biphasic pattern with firm, whitish (lymphocyte-poor) areas separated by coarse septae from lymph node-like gray (lymphocyte-rich) regions is typical. “Atypical cases” with features that are analogous to those of “atypical type A thymoma” (i.e., advanced stage and necrosis) are rare (<5%) [23].

Histology and immunohistochemistry Fibrous septae that separate large tumor lobules are more common than diffuse and fibrosclerotic variants. The type A areas can exhibit the broad spectrum of type A thymoma morphologies, while tumor cells in the B-like areas are typically spindly, oval, or rarely polygonal with small nuclei and inconspicuous nucleoli and, thus, look different from tumor cells in type B1, B2, and B3 thymomas (Fig. 5.3a). Rarely, light staining medullary islands can occur in type AB thymomas. Type A and B-like areas may be sharply separated or show gradual transition. The proportions of type A and B-like areas are variable. Rarely, type AB thymomas are immature T-cell-rich throughout, i.e., type A areas and a biphasic pattern with lymphocyte-poor regions are not absolutely required for the diagnosis. Spindle-shaped tumor cells and a typical immunohistochemical profile (e.g., CD20 expression; see next) are helpful to recognize these challenging cases.

Immunhistochemistry reveals that type AB thymomas are epithelial-rich tumors that show a dense but delicate network of tumor cells expressing various keratins (Fig. 5.3b) and p63/p40. Focal epithelial expression of CD20 occurs in 30–50% of cases (Fig. 5.3c), and spindle cells in septal structures often stain for EMA [31]. Complex expression of cortical and medullary markers is typical [11]. Lymphocytes mainly consist of immature, highly proliferative CD3+ TdT+ T cells (ki-67 index >90%) (Fig. 5.3d), but in medullary islands mature CD3+ TdT− Ki67^low T cells prevail.

Molecular pathology Structural genetic alterations are more common in type AB than type A thymomas [15, 16, 32], while GTF2I mutations occur at the same high frequency (74–80% of cases) [16].

Problems with small biopsies in type AB thymoma. The commonest challenge is the distinction between lymphocyte-rich type AB, B1, and B2 thymomas. In type AB thymomas epithelial cells and their often oval or elongated nuclei are smaller and less conspicuous than in type B1 and B2 thymomas. Even minor spindle cell areas favor a diagnosis of type AB thymoma. While medullary islands occur in all lymphocyte-rich thymomas, Hassall corpuscles almost never occur in type AB thymomas but are frequent in B1 and not uncommon in B2 thymomas. Keratin stains highlight the consistently dense epithelial network in AB (and B2) thymomas, as compared to the delicate network in B1 thymomas. Epithelial CD20 expression is restricted to AB (and type A) thymomas. For the distinction between lymphocyte-poor type AB from type A thymoma and its mimics, see Fig. 5.1e, f. To separate biphasic AB thymomas from micronodular thymomas with lymphoid stroma (MNT), one has to recognize that the complex lymphoid component of MNTs (see below) is localized outside the epithelial component. Of note, heterogeneous tumors featuring type A or AB thymoma and an MNT component are quite common.

Therapy and prognosis. Complete resection is usually achieved and curative due to the common low tumor stage. The 10-year overall survival rates are over 80% [29, 33]. The impact of exceedingly rare metastases on survival has not been studied [22].

Epidemiology and stage distribution of this infrequent thymoma subtype are given in Table 5.1.

Clinical peculiarities Myasthenia gravis is frequent (−45%), while other paraneoplastic autoimmune diseases, e.g., hypogammaglobulinema (Good syndrome) are rare (5%). “Pure” B1 thymomas usually follow an indolent clinical course and show stages I and II in over 80% of cases [5, 28, 33].

Macroscopy Most cases are well circumscribed and may reach large diameters due to late infiltration [28]. While the capsule may be firm, the cut surface is usually soft, and large tumor nodules may be separated by delicate or coarse fibrous septae.

Histology and immunohistochemistry In H&E stained sections, type B1 thymomas usually show little or no lobulation on low power. Dark cortical regions almost always dominate massively over lighter “medullary islands (MIs)” (Fig. 5.4a). In contrast to normal childhood medulla, MIs are not consistently “burried” in cortical areas but are commonly misplaced to the periphery of tumor lobules or along fibrous septae. Hassall corpuscles are common but not obligatory constituents of MIs. By definition, the frequency of epithelial cells must be similar to that of the normal thymus and must not show epithelial cell clustering (i.e., 3 or more contiguous tumor cells) as can be highlighted by p63 stain (Fig. 5.4b). Tumor cell nuclei resemble those of normal thymus, exhibiting round contours, vesicular chromatin, and variably prominent nucleoli. Keratin stains highlight a delicate epithelial network that is attenuated in MIs (Fig. 5.4c). In cortical regions, immature TdT+ T cells may obscure tumor cells. MIs are dominated by CD3+/TdT(−) mature T cells (Fig. 5.4d) and CD20+ B cells, and may harbor desmin-positive myoid cells and AIRE-positive epithelial cells.

Molecular pathology Genetic gains and losses are less frequent than in the more aggressive B2 and B3 thymomas [12, 34, 35]. The GTF2I mutation occurs in 32% of cases [16].

In small biopsies, distinction of B1 thymomas from normal thymus, post-chemotherapeutic rebound hyperplasia, true thymic hyperplasia, B-like areas of AB thymoma, and T-lymphoblastic lymphoma (T-LBL) may be challenging or even impossible—requiring cautious reporting. In contrast to non-neoplastic thymus, excess of cortical over medullary areas, irregular and misplaced medullary islands (MIs), and lack of Hassall corpuscles may be clues to the diagnosis of B1 thymoma, while immunohistochemistry (ki67 index close to 100%; delicate epithelial cell network) is usually not helpful. Lymphocyte-rich areas of AB thymomas may be another challenge, particularly when MIs are present: spindle cells, a denser than normal keratin(+) epithelial cell network and epithelial CD20 expression hint to the diagnosis of AB thymoma (Fig. 5.3). As to T-LBL, the clinical setting, i.e., dramatic local and systemic symptoms and absence of Myasthenia gravis, is usually different. Atypical blastic infiltrates that destroy/attenuate keratin-positive epithelial networks and infiltrate (epithelial-free) mediastinal fat are characteristics of T-LBL. Immunohistochemistry in T-LBL may reveal antigen loss (e.g., of CD1a) or abnormal expression of Notch1 and/or LMO2 [36] in TdT+ lymphoblasts. However, in many T-LBLs, the immunohistochemical profile is normal. Clonality analyses may help to clarify such cases. Rarely, T-LBL develops in thymoma [37].

Therapy and prognosis Over 90% of type B1 thymomas are resectable. Recurrences and metastasis are rare [1]. The 10-year and 20-year survival rates is 85–100% [29, 33].

Definition Type B2 thymomas are immature T-cell-rich tumors with a content of polygonal and dendritic neoplastic epithelial cells that is higher than in B1 thymomas and normal thymus. Spindle tumor cells are absent. Cortical differentiation is slightly reduced and medullary features are often strongly attenuated in B2 compared to B1 thymomas [11].

Epidemiology and stage distribution are given in Table 5.1. Occurrence in children is rare [11].

Clinical peculiarities Myasthenia gravis (MG) occurs in up to 50% of cases [5, 28], pure red cell aplasia and hypogammaglobulinemia (with or without accompanying MG) in 5%. Pleural effusions and the SVC syndrome are more common than in A, AB, and B1 thymomas.

Histology and immunohistochemistry Fibrous septae typically delineate small tumor lobules, and dominant lymphocytes impart a dark or blue impression (Fig. 5.5a, b). Tumor cell nuclei have distinct membranes, vesicular chromatin, and prominent nucleoli (Fig. 5.5b). Perivascular spaces with palisading of tumor cells (Fig. 5.5c) and pale medullary islands (MIs) with or without Hassall corpuscles are optional findings. Intratumorous lymphoid follicles are common in MG-associated cases (Fig. 5.5d). Neoplastic epithelial cells are either dispersed but more numerous than in normal thymus or B1 thymoma, or occur in clusters of at least three contiguous epithelial cells that can be highlighted by p63 immunohistoochemistry (Fig. 5.5e). Fourty percent of B2 thymomas show a minor B3 or B1 thymoma component (Fig. 5.5e). Tumor cells express many keratins (e.g., CK5/6 and CK19) and p40/p63 but are negative for CK20. Most lymphocytes are immature, highly proliferative CD3+ CD5+ CD4+ CD8+ TdT+ T cells (Fig. 5.5f).

Molecular pathology The number of genetic alterations in B2 thymomas is intermediate between AB thymomas on the one hand, and B3 thymomas on the other hand. B2 and B3 thymomas share losses of 6q25.2–q25.3 and 3p and gains of 1q [12, 34, 35, 38]. 22% show GTF2I mutations [16].

Problems with small biopsies in B2 thymomas Type B2 thymomas must be distinguished from the less aggressive B1 thymomas and from T-LBL. Small tumor lobules, more abundant than normal and clustered polygonal epithelial cells, and a dense keratin(+), p63(+) epithelial network are hints that the diagnosis is type B2 but not B1 thymoma. Cytologically atypical, TdT+ lymphoblasts that destruct and efface the normal thymic epithelial cell network is the hallmark of T-LBL. A pitfall in this respect is the rare (usually partial) loss of keratin expression in B2 thymomas [39]. Since epithelial expression of p40/p63 is almost always maintained in keratin(−) thymomas, it is recommended to stain for p40/p63 whenever the differential diagnosis between thymoma and T-LBL is problematic.

Therapy and Prognosis Complete surgical removal is achieved in 70–90% of cases [29, 34, 40]. The 10-year recurrence rates reach 32 and 41% in completely resected Masaoka stage II and III B2 thymomas, respectively, arguing for adjuvant radiotherapy in stage III thymomas [41, 42]. Postoperative radiotherapy is also used for incompletely resected thymomas, although it is usually not curative [43]. Nonresectable thymomas may be successfully treated by multimodal concepts [44]. The 10-year survival rates of B2 thymoma patients reach 70–90% [5, 28, 29].

Definition Type B3 thymomas are epithelial-predominant tumors that harbor a minor number or (rarely) no immature T cells. Neoplastic epithelial cells have largely lost cortical differentiation and medullary features are generally missing [11].

Epidemiology and stage distribution are given in Table 5.1. Occurrence in children is rare [45].

Clinical peculiarities Myasthenia gravis occurs in 40–50% of cases, other paraneoplasias are rare [28]. Since advanced tumor stages occur in 50% of cases, thoracic pain and superior vena cava syndrome are common at presentation.

Histology and immunohistochemistry Fibrous septae separate tumor lobules that are composed of sheets of polygonal neoplastic epithelial cells. The sheets of tumor cells impart a pink impression on low power (in contrast to the blue hue that is one of the hallmarks of B2 thymomas) (Fig. 5.6a). Plump, sharply delineated lobules of tumor cells form the invasion front of B3 thymomas (Fig. 5.6a), while single-cell infiltration and prominent desmoplasia are more common in thymic carcinoma. Tumor cell nuclei can be varied: bland looking with inconspicuous nucleoli or moderately atypical with anisonucleosis and prominent nucleoli. Sheets of tumor cells are usually sprinkled with few lymphocytes (Fig. 5.6b). Rarely lymphocytes are absent. Perivascular spaces surrounded by palisades of tumor cells are usually conspicuous (Fig. 5.6b). Hassall corpuscles occur rarely. Focal occurrence of spindle cells and clear cell features may occur (Fig. 5.6c, d). Diffuse epithelial expression of keratins (e.g., CK19, CK5/6, CK8/18) (Fig. 5.6e) and p40/p63, and focal expression of GLUT1 and EMA are typical [1], while CD20 is absent (in contrast to many type A and AB thymomas). Focal CD5 and CD117 expression has been described as rare exception. The lymphocytes are mainly TdT+ immature T cells (Fig. 5.6f). Perivascular spaces may harbor mature and immature T cells and plasma cells.

Molecular Pathology Type B3 thymomas show the highest prevalence of genetic alterations among thymomas [12, 15, 34, 35]. Changes that are largely restricted to B3 thymomas comprise losses of 13q, 16q, and 17p and gains of 4p and 17q [15, 16, 34, 35, 46]. GTF2I mutations occur in 21% of cases [16].

Problems with small biopsies Distinction of a relatively lymphocyte-rich (but still pink appearing) B3 thymoma from a relatively lymphocyte-poor (but still blue appearing) B2 thymoma is inevitably subjective (but clinically of minor relevance). Tumors showing both B3 and B2 patterns are more common than pure B3 thymomas, and small biopsies often fail to sample this tumor heterogeneity. Therefore, we comment on this possibility if we encounter pure B3 and B2 thymomas in small biopsies. Rare B3 thymomas can show focal spindle epithelial cells, raising the differential diagnosis of type A thymoma. This distinction may be impossible if the focal and inconsistent CD20 expression of type A thymomas, or prominent perivascular spaces of B3 thymomas are missing in small biopsies. The distinction of B3 thymomas from thymic squamous cell carcinomas (TSQCC) is clinically relevant and difficult since well-differentiated TSQCC may have perivascular spaces, and small biopsies may fail to sample the single cell or finger-like infiltration pattern at the invasion front. Prominent intercellular bridges, strong and usually extensive expression of CD5 and CD117 (in 80% of TSQCCs), and absence of TdT+ immature T cells favor a diagnosis of TSQCC [1]. Whenever a suspected “B3 thymoma” shows unusual features, alternative diagnoses should be seriously considered (e.g., melanoma; seminoma; carcinoid; synovial sarcoma; parathyroid adenoma).

Therapy and Prognosis Therapeutic principles are the same as in B2 thymomas (see above). 30% of B3 thymomas recur within 10 years [28]. The 10-year overall survival rates are 50–70% [5, 29]. MG-associated cases may have a better prognosis due to earlier detection [40, 47].

TSQCC make up 80% of TCs, are more common in males, and typically present in patients over 50 years of age [53, 63]. If Myasthenia gravis is present, this usually hints to a rare thymoma component [65]. 90% of cases are in advanced tumor stages at presentation [66]. Histology can be quite varied (Fig. 5.9). Morphological peculiarities of TSQCCs are: (i) structures resembling perivascular spaces; however, optically empty spaces around central vessels that are typical of thymomas are often effaced by fibrosis; (ii) plump instead of infiltrative invasion in many well-differentiated cases; (iii) epithelial cells expressing CD5 in 60% and CD117 (Fig. 5.10) and FOXN1 in 70–80%; (iv) frequent expression of neuroendocrine markers in a minority (<50%) of tumor cells; (v) rare fully encapsulated (stage I) “cystic well-differentiated TSQCCs” with excellent prognosis [67]. A molecular peculiarity is “targetable” KIT mutations in 5–10% of cases [13]. The 10-year survival rate is 60–65% [53, 68].

TSQCC can be accompanied by dense lymphoid and plasma cell-rich infiltrates, raising the possibility of lymphoepithelioma-like carcinoma (LELC). Since both cancer types can be CK5/6+, CD5+, and CD117+, negativity on EBER in situ hybridization (ISH) and solid instead of syncytial tumor complexes would support diagnosis of TSQCC.

Poorly differentiated carcinomas resembling TSQCC should routinely be checked for EBV association using EBER-ISH. By definition, EBER+ carcinomas are counted among LELCs, even if they resemble SQCCs and completely lack lymphoid stroma (see below) [1].

TSQCCs that show transition to undifferentiated or small-cell carcinoma components should be stained for neuroendocrine markers to exclude “combined large-cell neuroendocrine carcinoma” or “combined small-cell carcinomas” of the thymus; and for NUT protein to exclude the aggressive “NUT carcinoma” [69]. In biopsies the poorly differentiated component of NUT carcinoma can be missed. Therefore, in young patients, centrally located tumors and/or TSQCCs in small biopsies should be tested for NUT expression. To distinguish poorly differentiated TSQCC from undifferentiated carcinoma, staining for CK5/6, p63, and CD5 is required. By definition, all these staining are negative in undifferentiated carcinomas of the thymus [1].

Distinguishing TSQCC from metastases of pulmonary or head-and-neck SQCCs is straightforward in small biopsies, if the TSQCC is CD5+ CD117+ FOXN1+. In SQCCs that are negative for these markers (20% of TSQCCs) imaging studies are needed to resolve this differential diagnostic problem.

Basaloid thymic carcinomas (BTCs) make up 5% of TCs, are more common in males, and typically occur in elderly patients. 60% show stage III and IV disease at presentation [1]. Striking palisading of tumor cells at the periphery of tumor infiltrates is the hallmark of BTCs and necrosis is common (Fig. 5.11a–c). Large, cystic tumors with papillary, nested, or “cylindromatous” growth patterns are frequent. Tumor cells usually are quite monotonous giving a blue or clear cell impression. Keratinization and transition to sarcomatoid components may occur [70]. Like TSQCC most BTCs express CK5/6, p63, CD5, and CD117 (Fig. 5.11d) and are TTF1(−) [70]. The prognosis is similar as in TSQCC.

Problems with small biopsies and differential diagnoses Distinction of BTC from poorly differentiated TSQCC may be difficult in small biopsies. Atypia in TSQCCs is usually more striking. NUT carcinoma needs consideration and staining for NUT protein in cases with sharp transition between keratinizing and small-cell areas, particularly in young patients [69] might be helpful. Adenoid cystic carcinoma-like tumor usually shows some cribriform areas, less palisading than BTC and is usually CD117(−) [71].

Thymic LELCs make up 5% of TCs, are more common in males and often occur in children and young adults. 70% are in stage III or IV at presentation. Syncytial growth of poorly delineated cells with large nuclei, vesicular chromatin, and prominent nucleoli in a lymphoid and plasma cell-rich stroma with no or little desmoplasia is typical (Fig. 5.12). Keratinization is rare [53, 72]. 50% of classical, lymphocyte-rich cases are EBV-associated, particularly those in patients under 30. By definition, EBV(+) carcinomas without lymphoid stroma are also called LELCs, even if they look like TSQCC or undifferentiated carcinoma (Fig. 5.13a) [1, 2]. EBV detection needs EBER in situ hybridization (EBER-ISH) due to insensitivity of LMP1 immunohistochemistry. Tumor cells typically express keratins, p63, CD5, and CD117 (Fig. 5.13b–d). Lymphocytes are mature, TdT(−) T and B cells. Plasma cells are polyclonal. The prognosis is similar as in TSQCC.