Thymoma and thymic carcinoma in the target therapies era

Cancer Treatment Reviews xxx (2012) xxx–xxx

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Cancer Treatment Reviews

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Tumour Review

Thymoma and thymic carcinoma in the target therapies era

Angela Lamarca ⇑, Victor Moreno, Jaime FeliuHospital Universitario La Paz, Pso Castellana 261, 28046 Madrid, Spain

a r t i c l e i n f o s u m m a r y

Article history:Received 5 July 2012Received in revised form 14 November 2012Accepted 19 November 2012Available online xxxx

Keywords:ThymomaThymic carcinomaChemotherapyTarget therapiesRadiotherapySurgeryReview

0305-7372/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.ctrv.2012.11.005

⇑ Corresponding author. Tel.: +34 639648480.E-mail address: [email protected] (A. L

Please cite this article in press as: Lamarca A et10.1016/j.ctrv.2012.11.005

Thymic malignancies are extremely rare although usually affect young adults and continue to remain animportant health problem. Like other rare diseases, progress in thymic malignancies has been slow andthe treatment cornerstone still remains surgical resection. Next generation sequencing and otheradvances in molecular biology are shedding light onto the multiple genetic aberrations involved and haveopened a new field for research with molecularly targeted therapies such as CKIT inhibitors or anti-EGFRtherapies. In this review we will summarize the current knowledge in the pathophysiology, diagnosis,prognosis and latest advances in the management of thymomas and thymic carcinomas.

� 2012 Elsevier Ltd. All rights reserved.

Introduction

The thymus is an anterior mediastinal organ which involutesduring puberty but continues to be involved in the maturation oflymphocytes throughout adulthood. Thymic malignancies are ex-tremely infrequent and account for less than 0.13 cases per100,000 habitants per year. Like other rare diseases, progress inthe treatment of thymic malignancies has been hampered by thelack of randomized phase III clinical trials. The InternationalThymic Malignancy Interest Group (ITIMIG) is a cooperative groupfounded to promote international collaboration in clinical andtranslational research that will help to accelerate research in thepathology of thymic cancer.1 It represents the most important sci-entific achievement in the last few years in the field of thymicmalignancies.

Thymic malignancies can be divided into two major groups:thymomas (more differentiated, less locally invasive) and thymiccarcinoma (greater dedifferentiation, local aggressiveness andmetastatic capacity). Pathologic classification is essential in thesetumours to determine prognosis and proper management.Although surgery is the only curative treatment, thymomas andthymic carcinomas can be sensitive to chemotherapy and radio-therapy and these are often used in unresectable locally advancedor metastatic disease. The molecular aberrations detected bysequencing studies suggest that these tumours can be sensitive

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amarca).

al. Thymoma and thymic carcin

to targeted therapies. There are currently more than 15 clinical tri-als ongoing in this area.2

Epidemiology and risk factors

Thymic neoplasms are the most common tumors located in theanterior mediastinum (20%), however the absolute incidence is low(0.13 cases per 100,000 habitants per year). Frequency is highest inthe 30–50 year age group, with similar incidence in men andwomen.3,4 There is a predominance in Asians and Pacific Islandersfor unknown reasons.3

There are no known environmental risks factors for this neo-plasm although several case reports have described an associationbetween human foamy virus, Epstein–Barr virus, human T-celllymphotropic virus type 1 infections and thymoma.5–8 The highestincidence among Asians and Pacific Islanders also suggests a genet-ic predisposition.

Clinical findings and symptoms

Thymic neoplasms are detected in 50% of cases as an incidentalfinding in asymptomatic patients undergoing an imaging test forother reasons. In symptomatic patients, the most frequent mani-festation (50–70%) is a paraneoplastic syndrome (mainly myasthe-nia gravis). There is a relationship between histological subtypeand clinical presentation: thymic carcinomas usually present withlocal invasion and metastatic symptoms as cough, chest pain,

oma in the target therapies era. Cancer Treat Rev (2012), http://dx.doi.org/

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Table 1WHO histologic typing of tumors of the thymus.17

1. Epithelial tumors1.1 Thymoma1.1.1 Type A (spindle cell, medullary)1.1.2 Type AB (mixed)1.1.3 Type B1 (lymphocyte-rich, lymphocytic, predominantly cortical,

organoid)1.1.4 Type B2 (cortical)1.1.5 Type B3 (epithelial, atypical, squamoid, well-differentiated thymic

carcinoma)1.2 Thymic carcinoma (type C thymoma)1.2.1 Epidermoid keratinizing (squamous cell) carcinoma1.2.2 Epidermoid non-keratinizing carcinoma1.2.3 Lymphoepithelioma-like carcinoma1.2.4 Sarcomatoid carcinoma (carcinosarcoma)1.2.5 Clear cell carcinoma1.2.6 Basaloid carcinoma1.2.7 Mucoepidermoid carcinoma1.2.8 Papillary carcinoma1.2.9 Undifferentiated carcinoma2. Neuroendocrine tumors3. Germ cell tumors4. Lymphoid tumors5. Stromal tumors

2 A. Lamarca et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx

superior vena cava syndrome and shortness of breath while thy-momas are usually associated with paraneoplastic syndromes.9

Extrathoracic metastatic involvement occurs in less than 7% ofcases, predominantly in thymic carcinoma. The most common sitesof metastases are kidneys, extrathoracic lymph nodes, liver, centralnervous system, adrenal glands, thyroid and bone.10

Paraneoplastic syndromes occur more frequently in thymomathan in thymic carcinoma.11 Myasthenia gravis accounts for 70%and the rest can present with pure red cell aplasia, lupus erythe-matosus, hypogammaglobulinemia (Good syndrome) or even thy-moma-associated multiorgan autoimmunity (TAMA).12 Patientswith thymic carcinoma can present with different syndromes suchas polymyositis.13

Patients with thymic malignancies have a 3- to 4-fold increasedrisk of developing a second malignancy.14 The risk is highest fornon-Hodgkin B lymphoma, gastrointestinal tumors and soft tissuesarcomas. The reason for the increased incidence is unknown anddifferent mechanisms have been suggested: immune deregulation,chemo-radiotherapy toxicity or genetic predisposition. There areno available data concerning the role of occupation, environmentalexposures, or diet and nutrition.3

6. Tumour-like lesions7. Neck orbranchial pouch derivation tumors8. Metastatic tumors9. Unclassified tumors
Diagnosis
Computerized tomography (CT) with contrast of the chest is theimaging modality of choice to evaluate the mediastinum.11 Withthis technique, the most common finding in a patient with a thy-moma is a round or lobular and well defined mass. In cases of thy-mic carcinoma the mass is usually poorly-defined with necrotic,cystic or calcified component and local invasion.15,16 Magnetic res-onance (MRI) may be used for those cases with suspected vascularinvasion in which iodine contrast cannot be administered (allergiesand renal dysfunction). 18-Fluorodeoxy glucose (18-FDG) positronemission tomography (PET) can be useful to detect metastatic dis-ease17 and some studies suggests that the degree of differentiationcorrelates with 18-FDG uptake.11

CT-guided core needle biopsy should be performed in order toconfirm the diagnosis and histological subtype.18 The CT-guidedfine needle-aspiration (FNA) establishes the diagnosis in 69% ofcases, with a sensitivity and a specificity of 71% and 94%, respec-tively and with less side effects than core needle biopsy; it how-ever decreases the possibility of an adequate discriminationbetween thymic carcinoma and thymoma which is crucial for thecorrect management of this patients.19,20 In those patients whomthe diagnosis was not obtained with FNA or core needle biopsy, amediastinoscopy (Chamberlain procedure), videothoracoscopy(VATS) or a diagnostic and therapeutic en bloc thymectomy mightbe considered.11

However, the role of a preoperative histological or cytologicaldiagnosis when a thymic neoplasm is suspected has been recentlyquestioned. Nowadays, histological confirmation prior to surgery isusually advocated only in cases with undefined masses at CT or incases of suspected unresectable disease; while surgical completeexcision (without prior histological diagnosis) is preferred for thy-mic masses radiologically suspicious of malignancy.21 On the otherhand, the histological diagnosis previous to induction chemother-apy is mandatory.

Pathologic classification

It is considered that thymomas and thymic carcinomas are on acontinuum of different degrees of differentiation of the same dis-ease. However, some thymic carcinomas appear de novo withoutprior existence of a thymoma.

Please cite this article in press as: Lamarca A et al. Thymoma and thymic carcin10.1016/j.ctrv.2012.11.005

The WHO histological classification17 (Table 1) classifies tu-mours of the thymus into the following categories: epithelial, neu-roendocrine, germ cell tumors, lymphomas, sarcomas, metastaticand tumor-like.

Thymic epithelial tumors can be divided according to the de-gree of differentiation into22:

– Type A. Medullar thymoma: population of neoplastic thymic epi-thelial cells having a spindle/oval shape, lacking nuclear atypia andaccompanied by few or no non-neoplastic lymphocytes.– Type B. Cortical thymoma: round and polygonal tumour cells.

According to the infiltration of lymphocytes and cellular atypiaare subclassified into: B1 (large lymphocytic infiltrate with epithe-lial cells, practically indistinguishable from normal thymic cortextumour that resembles the normal functional thymus), B2 (lesslymphocytic infiltrate, the neoplastic epithelial componentappears as scattered plump cells with vesicular nuclei and distinctnucleoli, perivascular spaces are common and sometimes veryprominent with a perivascular arrangement of tumour cells), B3(epithelial cells having a round or polygonal shape and exhibitingno or mild atypia, admixed with a minor component of lympho-cytes, sheet-like growth of the neoplastic epithelial cells).– Type AB. Combined areas of A and B characteristics (foci having

the features of type A thymoma are admixed with foci rich inlymphocytes).

– Type C. Thymic carcinoma: clear-cut cytologic atypia and a set ofcytoarchitectural features no longer specific to the thymus butrather analogous to those seen in carcinomas of other organs, lackimmature lymphocytes.

According to different published series, it is estimated that sub-types B2 and AB are the most common (20–35%) while A and B1subtypes have a much lower incidence (5–10%).23

Staging of the disease

Two staging systems have been proposed: The Masaoka–Kogastaging system and The French Groupe dÉtudes des Tumeurs




Table 2The Masaoka–Koga stage classification (Adapted from Pathol Int 1994;44:359-367).30

Stage Definition

I Grossly and microscopically completely encapsulated tumorIIa Microscopic transcapsular invasionIIb Macroscopic invasion into thymic or surrounding fatty tissue, or

grossly adherent to but not breaking through mediastinal pleura orpericardium

III Macroscopic invasion into neighboring organ (pericardium, greatvessel and lung)

IVa Pleural or pericardial metastasesIVb Lymphogenous or hematogeneus metastases

Table 3GETT staging system.26

Stage Definition

Ia Encapsulated tumor, totally resectedIb Macroscopically encapsulated tumor, totally resected, but the

surgeon suspects mediastinal adhesions and potential capsularinvasion

II Invasive tumor, totally resectedIIIa Invasive tumor, subtotally resectedIIIb Invasive tumor, biopsy onlyIVa Supraclavicular metastases or distant pleural implantIVb Distant metastases

Fig. 1. Treatment algorithm in thymic malignancies (CT: chemotherapy; RT:radiotherapy; R0: complete resection; R1: microscopic residual disease and R2:macroscopic residual disease).

A. Lamarca et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx 3

Thymiques (GETT). The Masaoka–Koga staging system (Table 2) isbased on clinical and microscopic extension of disease, while theGETT system uses the extension of surgical resection as a prognos-tic factor (Table 3).24–26 A recent study on 163 patients showedthat the concordance index between these two staging systems is88%.27 Nevertheless, the most accepted staging system is theMasaoka–Koga and is the one selected for the ITMIG next editionof the international tumour staging manual. One of the reasonsfor selecting the Masaoka–Koga system over the GETT system isthat it includes the pathological examination of surgical margins,which seems to be a better predictor of five-year survival thanthe extension of surgical resection (GETT) alone.25

Although there are several TNM based classifications includingthe Yamakawa-Masaoka and the WHO TNM system, these are notusually used.28,29

Natural history and prognosis

Thymic malignancies are generally considered indolent tu-mours due to long recurrence intervals (range 4–175 months;median of 68 months). Overall, for patients diagnosed with aresectable thymic tumor, 16% of them will recur after radical resec-tion, either locally with pleural or ganglionar recurrence or withdistant metastases.31 The most common sites of distant recurrenceare lung, liver, bone, kidney, brain and bone marrow.32 The conceptthat early (stage I Masaoka–Koga) low grade (WHO subtype A) thy-momas are a ‘‘benign disease’’ underestimates the recurrencerates. Recurrence can occur even in low grade (WHO subtype A,AB or B1) thymomas in up to 15% of cases. Thymic carcinomasare highly malignant tumours with a 50% rate of local or distantrecurrence.22 Thus, aggressive treatment is recommended for themboth.

The main prognostic factors for recurrence and survival are thestage at diagnosis and whether a complete resection has beenachieved. Other prognostic factors with less impact on prognosisare the histological subtype, tumour size at diagnosis, age, genderand presence or absence of myasthenia gravis.33 One of the largestreported series of patients (1320 patients from 115 different cen-tres) shows a five-year survival rate of 98–100% in Masaoka–KogaStage I–II treated with surgery, 88% in stage III, 70% in stage IVa and


52% in stage IVb.34 A different series with a longer follow upshowed an overall survival at ten years of 90% for stage I Mas-aoka–Koga classification, 70% for stage II, 55% for stage III and35% for stage IV.35

There is a direct relationship between the histological subtype(WHO classification) and the biological behaviour (Masaoka–Kogastages). While A and AB tumours only infiltrate surrounding tissuesin 6% of the cases, B tumours are moderately invasive (rates ofneighbouring invasion: 18% for B1, 25% for B2, and 41% for B3)and thymic carcinomas infiltrate adjacent structures and demon-strate distant metastases in 89.3% of cases.22

Therapeutic approach

Treatment of thymic malignancies is summarized in Fig. 1.

Treatment of early stage tumours: localized disease

The role of surgery

Surgery is the only curative treatment and long-term survivaldepends on the ability to obtain a complete resection.36 Resectabil-ity is inversely proportional to the stage at diagnosis: the rate ofcomplete resection is 100% in stage I, 88% for stage II, 49% in stageIII and 29% for stage IV.37

A full median sternotomy is the standard open approach. Themediastinum must be thoroughly explored up to the cervical thy-mic extensions and laterally down to the phrenic nerves. Completeen bloc resection of the tumor with complete thymectomy and re-moval of the upper cervical poles and surrounding mediastinal fatis the basic surgical approach.38 When appropriate, resection mustbe extended to the pleura, pericardium, lungs, great vessels andphrenic nerves for cases with local infiltration of mediastinalorgans.39 If radical resection is considered unfeasible, close mar-gins or residual tumour areas were clipped for postoperative radi-ation therapy. Minimally invasive techniques (thoracoscopicthymectomy, video-assisted thoracoscopic thymectomy (VAT-T)and robotic surgery) are being developed.40–42

Local recurrence is much more common than distance recur-rence. The recurrence rate is higher in advanced (30% stages IIand III) than in early stages (3% stage I) Masaoka–Koga stages.Recurrences have been described 10–20 years after resection ofthe primary tumour, so long term follow up is usually advocated.43





Indications for adjuvant therapy

Due to the high rate of local recurrences after complete resec-tion, adjuvant therapy should be considered for tumours with highrisk of failure after surgery alone. This includes types B2 and B3thymomas, thymic carcinomas, Masaoka–Koga stage III as well astumours with microscopically (R1) or macroscopically (R2) resid-ual disease.

The adjuvant radiotherapy after surgery improves disease freesurvival in patients with residual disease (R1 or R2).44–46 In a retro-spective analysis of 545 thymic tumours, adjuvant radiotherapyalone after incomplete resection provides an overall disease controlrate of 20–60% after 21 years of surveillance.36 However, this benefitwas not seen in cases with no residual disease (R0) and types A, AB,and B1 thymomas (the major benefit seems to be seen in B2, B3 andthymic carcinomas). Usually a dose of 45–50 Gy is delivered within3 months after surgery. The most common toxicities of this treat-ment are pulmonary fibrosis, pericarditis, and myelitis; althoughthe development of new radiotherapy techniques such as IMRT willhopefully reduce the incidence of these toxicities.47 Other experi-mental approaches such as hemithoracic radiation are beingexplored to reduce the incidence of local recurrence.48–50

Due to the lack of clinical trials, it is currently unknownwhether adjuvant chemotherapy alone improves survival afterresection of a thymic tumor. In the retrospective series available,adjuvant chemotherapy alone does not improve the outcome ofpatients with types A, AB, and B1 thymomas or R0 resected stageII thymic malignancies. That is why current guidelines do not rec-ommend the administration of systemic chemotherapy alone,especially in patients with complete resection.51 Nevertheless, inone of the largest published series,34 survival at 5 years in 92 pa-tients studied was higher in patients treated with chemotherapy:82% in patients who received chemotherapy postoperatively, 74%in those receiving adjuvant radiotherapy, 72% in those who didnot received adjuvant therapy and 47% in those who received che-mo-radiation therapy later.

Any incompletely (R1 or R2) resected tumour or stage III com-pletely resected thymic malignancies carries a high-risk for localrecurrence when treated by adjuvant radiotherapy alone. Adjuvantsystemic chemo-radiotherapy within 3 months after surgery is beingincreasingly considered.51 The chemotherapy regimens adminis-tered in these cases are the same as those used in locally advanceddisease (Tables 4 and 5).

Management of locally advanced disease

There are a high percentage of cases where local invasion of themediastinum and great vessels increases the complexity and risks

Table 4Induction chemotherapy regimens.

Chemotherapy regimen N Study Re

CEE 7 Phase II 10CVAC 6 Phase II 83CVAC 16 Retrospective 10CEE 15 Retrospective 66CVAC or PE 25 Retrospective 72CAPP 22 Phase II 77CEE 36 Retrospective 67CAP 5 Retrospective 75CAPM 14 Retrospective 93CODE 21 Phase II 62CAP or VIP or CP or PE 18 Retrospective 67CeCAP 28 Going on –

CEE (cisplatin, epirubicin, etoposide), CVAC (doxorubicin, cisplatin, vincristine, cyclophosprednisone), CAP (cisplatin, doxorubicin, cyclophosphamide), CAPM (CAP-prednisolonacisplatin), CP (carboplatin and paclitaxel) and CeCAP (Cetuximab-CAP).


of surgery. However, achieving free margins remains essential. Instages III and IVa, total resection improves 5 year disease-free sur-vival and overall survival. Among patients who underwent totalresection, recurrence-free survival is better than in the patientswith subtotal resection (60% versus 40% at 3 years; 20% versus0% at 5 years; p = 0.009).66 That is why a total resection shouldbe the aim even in locally advanced disease (stages III and IVa).

For cases where free margins are not achievable, induction ther-apy can be considered. The most active chemotherapy regimensare those based on cisplatin and anthracyclines, with responserates of approximately 70–80%. The recommended treatmentplan51,67 involves the administration of two to four cycles of induc-tion chemotherapy (Table 4) and subsequent re-evaluation withCT. According to the response, surgery will be considered within8 weeks after the last cycle of chemotherapy. This scheduleachieves free surgical margins in approximately 50% of cases ini-tially considered not amenable to complete resection.

Radical concomitant chemo-radiotherapy can be considered forincomplete responders or patients with poor performance statusthat are not candidates for radical surgery (Table 5). Finally, pa-tients with progressive disease during induction treatment withchemotherapy or radical chemo-radiotherapy will be only likelyto benefit from further systemic chemotherapy if appropriate(Table 6).

Metastatic thymoma and thymic carcinoma

Patients with extrathoracic disease, extensive bilateral pulmon-ary involvement, and significant involvement of the anterior medi-astinum, trachea, great vessels or heart disease are consideredunresectable and systemic chemotherapy should be the treatmentof choice. Multiple monotherapy and combination schedules havebeen designed based on cisplatin and anthracyclines (Table 6).Although prolonged disease stabilization is possible, tumour erad-ication is usually not expected. Overall survival improvement isdifficult with polychemotherapy regimens.51 As can be seen in Ta-ble 6 there are several phase II studies with systemic chemother-apy. Response rates ranges between 10% and 17% formonotherapy to 90% for more intense polychemotherapy regi-mens. A phase II trial with 21 patients treated with three-weeklycisplatin provided clinical benefit in 50% of patients (40% stabledisease and 10% partial response) with a median overall survivalof 19 months.68 On the other hand, a phase II trial with 32 patientstreated with polychemotherapy (CVAC schedule)71 yielded a re-sponse rate of 90% (47% had complete clinical response, 33% ofthem with complete pathologic response), 44% had a partial re-sponse and only 6.5% and 3% stable and progressive disease respec-tively. Nevertheless the overall survival was similar than with

sponse rate (%) Complete resection (%) References

0 57 5217 53

0 69 54- 5544 5672 5778 5825 5914 6043 6167 62– NCT01025089

phamide), PE (cisplatin-etoposide), CAPP (cisplatin, doxorubicin, cyclophosphamide,), CODE (cisplatin, vincristine, doxorubicin, etoposide), VIP (etoposide, ifosfamide,




Table 5Concomitant chemo-radiotherapy schedules.

Chemotherapy regimen N Study Response rate (%) Complete resection (%) References

CAP 23 Phase II 70 0 63CVAC 16 Phase II 81 56 64PE or CVAC or CAP or CEE 10 Retrospective 40 80 65PE 30 Goingon – – NCT00387868

CEE (cisplatin, epirubicin, etoposide), CVAC (doxorubicin, cisplatin, vincristine, cyclophosphamide), PE (cisplatin-etoposide) and CAP (cisplatin, doxorubicin,cyclophosphamide).

Table 6Systemic chemotherapy used in advanced disease.

Chemotherapy regimen N Study Response rate (%) References

Single-agent chemotherapyCisplatin 21 Phase II 10-62 68Ifosfamide 15 Retrospective 46-54 69Pemetrexed 27 Retrospective 17 70

Combination chemotherapyCVAC 32 Retrospective 85-92 71CAP 30 Phase II 51 72PE 16 Phase II 56-60 73VIP 34 Phase II 32 74CP 46 Phase II 33 75Irinotecan-cisplatin 7 Retrospective 23 76Gemcitabine-capecitabine 15 Phase II 40 77

CVAC (doxorubicin, cisplatin, vincristine, cyclophosphamide), PE (cisplatin-etoposide), CAP (cisplatin, doxorubicin, cyclophosphamide), VIP (etoposide, ifosfamide, cisplatin)and CP (carboplatin, paclitaxel).


cisplatin monotherapy: 17 months. Thus, although polychemo-therapy provides higher response rates, it is not known if it hasan impact on overall survival and the appropriate selection of pa-tients fit enough for these treatments is crucial.

Besides classical chemotherapy, different systemic therapeuticapproaches could be useful for thymic malignancies. Some tu-mours express somatostatin receptors and administration of octre-otide can provide benefit in them. In a multicentre phase II trialwith 36 patients treated with octreotide and prednisone, a re-sponse rate of 21% was reported.78 Also corticosteroids are usefulin this pathology. Similar to the physiological effects of ageingand stress, steroids increase thymic fat and connective tissue anddecrease corticomedullar differentiation.79 Therefore in WHO sub-types A and B thymoma, corticosteroids produce tumour sizereduction due to lymphocyte depletion. In a phase II clinical trialcomparing octreotide with or without prednisone, the combinationarm provided a higher response rate (38% versus 11%). Higherdoses than 0.5 mg/kg/day of prednisone may enhance antitumoreffect.78,80

Management of recurrent disease

Overall, it is estimated that after optimal treatment, 10–30% ofall resectable and unresectable thymic malignancies will recur orprogress on treatment. The prognosis of recurrent disease is verypoor (overall response rate of chemotherapy in recurrent diseaseis around 20–30%), however recurrence-free survival can be longerthan 40 months. Mediastinal recurrence and achieving a secondcomplete resection are factors associated with a better progno-sis.81,82 Therefore, after recurrence is established it is essential toassess the feasibility of a second curative surgery, to improve thesurvival of these patients.83 In cases of unresectable disease, che-motherapy and radiation (Tables 4–6) are the two considerations.

The concept of ‘‘rebound thymic hyperplasia’’ is an apparent re-growth of the mediastinal mass after therapy withdrawal that his-tologically corresponds to thymic hyperplasia, without increase inthe number of lymphoid follicles or tumour cells.51 It is usually


seen 2–14 months after the last dose of therapy and can be seenup to 24 months later. The final diagnosis should be confirmedhistologically.84

New therapies

Thymomas and thymic carcinomas also differ in functional,clinical, genetic and molecular characteristics. Besides their differ-ent morphology, types A, AB and B thymomas also differ in theirexpression of immunohistochemical markers, such as MHC classII or AIRE (autoimmune regulator) and as there are different histo-logic maturational stages of a thymic ephitelial progenitor cellthere are different capacities for maturation of intratumorallymphocytes.85

Formerly, the only technique available for the analysis of genet-ic alterations was tumour cell karyotyping. This technique was notable to identify specific aberrations with the exception of translo-cation between chromosomes 15 and 19 (t15,19) which had beendescribed in three undifferentiated thymic carcinomas.62 Withthe development of newer techniques such as comparative geno-mic hybridization (CGH), new aberrations have been described:multiple losses of genetic material and microsatellite instabilityin different chromosomes (3p22-24.3, 3p14.2 (FHIT gene locus),5q21 (APC gene), 6p21, 6p21-22.1, 7p21-22, 8q11.21-23, 13q14(RB gene) and 17p13.1 (p53 gene)).85,86 From all of these aberra-tions described, the most significant ones are the loss of heterozy-gosity (LOH) on chromosome 5 (5q21) (APC gene) and losses in thelong arm of chromosome 6.87–89

The percentage of aberrations in chromosome 6 varies withWHO histological subtype (Type A 10%, AB 12%, B 20-26%, C 35%)and with clinical stage at diagnosis (Stage I7%; II 27%; III 21%; IV24%). Chromosome 6 aberrations were studied with CGH and fivehot spots were found: 6q25.2, 6q25.2-25.3, 6q21.31, 6q 14th-14.3, 6q21.86 Apparently some of these loci code for major histo-compatibility protein (MHC), so their loss may explain the autoim-mune component that exists in this disease. It is suspected that theregion 6q25 contains a tumour suppressor gene whose mutation is





a yet to be identified ‘‘gate-keeper’’ mutation that is thought tohave great importance in the evolution of these tumours.

The existence of microsatellite instability (MSI) has also beendescribed mainly on chromosome 6 and reported in 10% of thymo-mas, especially in type B. However the way it influences in thymo-magenesis is unknown.

Molecular biology study for the use of targeted therapy in thy-mic tumors.

The finding that thymic tumors harbour specific genetic aberra-tions (Table 7) has encouraged the use of targeted therapies.

KIT pathway

KIT is overexpressed by inmunohistochemistry in 2% of thymo-mas and in 79% of thymic carcinomas. This expression has beenassociated with activating mutations in exons 9, 11, 13 and 17.However, mutations are found in only 7% of all thymic carcinomas.Interestingly, not all KIT mutations in these tumours will respondwith a high sensitivity to KIT inhibitors (such as imatinib and nil-otinib).90–93 Consistent with this, in the largest published series,11 patients were treated with 600 mg of imatinib once daily in21 days-cycles. The median duration of disease stabilization was6 weeks, with a median of 2 (range 1–6) cycles administered. Theauthor concluded that despite KIT overexpression in thymic malig-nancies, imatinib did not have substantial activity.91–93

However, case reports of patients treated with sorafenib andsunitinib in KIT mutated thymic tumours suggest some activity.One patient with a KIT D820E mutation (mutation in exon 17 asso-ciated with imatinib resistant GIST), treated with sorafenibachieved a partial response in all metastatic sites and progressionfree survival of at least 15 months.94 Recently, an in vitro study hasidentified a specific mutation in exon 14 of KIT (H697Y) associatedwith sensitivity to sunitinib compared to imatinib.95

Epidermal growth factor pathway

Immunohistochemistry studies found that EGFR was overex-pressed in 70% of thymomas and in 53% of thymic carcinomas, withhigher percentage of overexpression in more advanced stages.96

EGFR mutations are extremely rare in thymic tumours, withoutany correlation seen between EGFR overexpression and mutation.Single case responses were documented with erlotinib, gefitiniband cetuximab.97,98

In a phase II trial with 18 patients, erlotinib (150 mg daily) andbevacizumab (15 mg/kg every 3 weeks) was administered.99 Sixtypercent of the patients had stable disease, without any partial orcomplete responses seen. Authors concluded that the combinationof erlotinib and bevacizumab has limited activity in thymic malig-nancies, but a well tolerated side effect profile.

Another EGFR tyrosine kinase inhibitor has also been used inthymic malignancies. Twenty-six patients were treated with250 mg of daily gefitinib. The median time to progression (TTP)was 4 months (range, 1–17), with stable disease in 14 patients,and one partial response.100

Table 7Molecular aberrations in thymic malignancies.

Molecular change Thymoma (WHO A, B) Thymic carcinoma (WHO C)

Cr 6 aberrations 10-26% 35%KIT overexpression 2% 79%KIT mutation – 7%EGFR overexpression 70% 53%EGFR mutation – –IGF-1R expression 4% 37%VEGF serum levels – Elevated


The publication of case reports97,98 describing objective re-sponses with cetuximab in patients with chemo-refractory thy-moma, has led to a phase II trial of neoadjuvant chemotherapywith cetuximab in patients with clinical Masaoka stage II–IVA thy-moma (NCT01025089) and it is currently recruiting patients.2

IGF-1R pathway

The insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R)system’s activation is related to cross-resistance to EGFR inhibitorsand it is also involved in the development of the thymus. In aretrospective analysis of 111 samples of thymic malignancies,expression of IGF-1R was found in 4% of thymomas and in 37% ofthymic carcinomas.101 Moreover, activity of IGF-1R inhibitors asfigitumumab and cixutumumab has been described in thymic tu-mors. In a figitumumab phase I clinical trial, a patient with a met-astatic thymoma experienced a 10% reduction in tumor size byresponse evaluation criteria in solid tumors (RECIST) criteria andhad prolonged stable disease for longer than 1 year.102 Howevera phase II trial in 13 patients treated with cixutumumab 20 mg/kg every 21 days did not find any objective response.103

VEGF pathway, angiogenesis

Angiogenesis plays an important role in thymomagenesis.VEGF-A, VEGFR-1 and VEGFR-2 are overexpressed in thymomasand thymic carcinomas. In assays of 37 patients with thymoma,6 with thymic carcinoma, and 23 healthy volunteers, serum VEGFlevels were significantly (P < 0.05) elevated in the patients withthymic carcinoma compared to controls. However, serum VEGFand bFGF levels did not significantly differ between patients withthymoma and the healthy volunteers.2,104 The upregulation of thispathway has been related to tumor invasion and advanced clinicalstage, predominantly in thymic carcinomas. Unfortunately, lowresponse rates have been observed with bevacizumab99 and aflib-ercept.105 Sunitinib and sorafenib are multi-tyrosine kinase inhib-itors with antiangiogenic and direct antitumour activity. Partialresponses and disease stabilisation have been reported in case re-ports and phase I trials with sunitinib106,107 and sorafenib.108

Other targeted therapies

Other drugs with different mechanisms of action such ashistone deacetylase inhibition (belinostat109), src inhibitors(saracatinib110) and cyclin-dependant kinases (PHA-848125-AC(NCT01011439)) have been studied with low response rates.

Conclusion

Despite multiple efforts to improve the prognosis of thymicmalignancies in the past 20 years, treatment still relies on surgicalresection. Adjuvant chemoradiotherapy can be offered after resec-tion although no prospective randomized trials support its use.Systemic chemotherapy for locally advanced unresectable andmetastatic disease based on platinums and anthracyclines can pro-vide high response rates but surgical resection for fit patients re-mains a priority in this patient population. The advances in theunderstanding of the molecular biology of this disease have in-creased the number of targeted therapies tested in clinical trialsalthough results have so far been disappointing. It is however ex-pected that new and more potent targeted drugs will be developedand tested in clinical trials. The low incidence of thymic malignan-cies is a big hurdle for clinical research in this pathology and thedevelopment of reference centres for multidisciplinary manage-ment is highly recommended.





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Thymoma and thymic carcinoma in the target therapies era

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