ZHAO Luo，ZHU Rong-Rong，LIANG Nai-Xin，LI Shan-Qing

（Department of Thoracic Surgery，Peking Union Medical College Hospital，Chinese Academy of Medical Science，Beijing 100730，China）

·腫瘤治療與轉(zhuǎn)化醫(yī)學(xué)·

Advances in diagnosis and treatment strategies of thymic carcinoid

ZHAO Luo，ZHU Rong-Rong，LIANG Nai-Xin，LI Shan-Qing

（Department of Thoracic Surgery，Peking Union Medical College Hospital，Chinese Academy of Medical Science，Beijing 100730，China）

Thymic carcinoid is a rare neuroendocrine tumor with unclear risk factors and controversial classifications．Its clinical manifestations vary from asymptomatic to many nonspecific symptoms，among which endocrine abnormality seems to be associated with poor prognosis．Quantitative and qualitative analysis of ACTH and prognosis could become a topic in the future．Image studies show no specificity both in CT and PET／CT，but are of great value in clinical staging of thymic carcinoid．Ki67 has been found to be a powerful tool for grading neuroendocrine tumors and further studies should be made．The diagnosis of thymic carcinoid mainly depends on pathology and immunohistochemistry plays a key role in differential diagnosis at present．Radical resection is the first choice in treatment，and target therapy becomes possible with the development in molecular pathology．However，since the rarity of thymic carcinoid，there is no practical clinical staging or standard guideline to instruct clinical practice．Thus，support of International Thymic Malignancy Interest Group（ITMIG）seems to be of great significance in case collection and resource sharing of thymic diseases．In this paper，we are going to put forward a strategy available in clinical application for diagnoisis and treatment of thymic carcinoid by using a new clinical staging system．

thymic carcinoid；clinical staging；treatment strategies；Ki67

Introduction

As an uncommon variantofthymicepithelial tumors，thymic neuroendocrine tumor（TNET）or neuroendocrine carcinoma（TNEC）only accounts for 2%to 4%of all the tumors localized within the anterior mediastinum［1］．This group of neoplasms was first identified from other thymic epithelial tumors and named as thymic carcinoid tumor by Rosai and Higa in 1972［2］．The term‘carcinoid’ indicates that the neoplasms show more benign features than the conventional carcinomas．However，thymic carcinoid has been noticed to behave more aggressively than its foregut counterpart in most studies［3］．With more cases and research，people come to realize that thymic NET is composed of a continuum from one end of poor differentiation to the other end of well differentiation．However，the classification of thymic NET is still under debate and continues to be controversial．

In this paper，we are going to review the latest WHO classification， epidemiology， clinical features，treatment strategies and prognosis of thymic NET，especially thymic carcinoid，and try to put forward a strategy available in clinical application for diagnosis and treatment of thymic carcinoid．

Definition and pathological classification

Neuroendocrine neoplasm is defined as epithelial tumor with either exclusive or predominant neuroendocrine differentiation．The epithelial origin can be identified from keen observation on cell morphology of histopathology specimens，whereas the neuroendocrine features are not going to be displayed with conventional light microscope．Either specific immunohistochemistry（IHC）panel（basically including chromogranin，synaptophysin，neuron-specific enolase and CD56）or ultrastructure such as neurosecretory granules defined by electromicroscope is required to confirm the neuroendocrine differentiation［4］．

While as an important part of thymic NET，carcinoid tumor of the thymus，according to ICD10，is defined as a primary thymic neuroendocrine neoplasm，often associated with Cushing’s syndrome．Two morphologic subtypes are recognized：typical and atypical carcinoid tumors．Atypical carcinoid tumors have a more aggressive clinical course．Moran and Suster suggested that the terms carcinoid and atypical carcinoid were outmoded and neuroendocrine carcinomas of well or poorly differentiated types should be used［3］．However，as the term thymic carcinoid remains the one most commonly used，we will continue to use‘carcinoid’in the following texts．

NET can be divided into two mutually exclusive groups，functioning tumors and nonfunctioning ones according to clinical symptoms．The functioning masses produce and excrete excess hormone which elicits significant endocrine symptoms， while the nonfunctioning ones predominantly present with symptoms and signs associated with mass effect．This classification is mainly based on symptoms and has nothing to do with histopathological features or immunohistochemistry profiles［5］．In another word， the positive expression of ACTH with IHC does not necessarily indicate the tumor is a functioning one．The presentation of associated endocrinopathy is a predictor of poor prognosis［6］．

Thymic NET can also be classified according to histopathological features of tumors，but the criteria are still controversial．This criterion used by the 2015 version of WHO classification of tumor is the same as that applied to NET of the lung due to lack of data on thymic counterparts．The well-differentiated tumors are known as carcinoid with relatively greater similarity with the original normal tissue．They are further subdivided into typical carcinoid with fewer anaplastic features（＜2 mitoses／2mm2，no necrosis） and atypical ones with more prominent necrosis and mitosis（2-10 mitoses／2 mm2，and／or necrosis，including comedonecrosis）［7］．

However，mitotic count might be inaccurate or even not feasible when it is a biopsy sample，for which is usually of limited tissue．Ki67 index，in that circumstance，provides an alternative evaluation of the proliferative rate and becomes a new tool for grading［8-9］．To date，there is no evidence proving which of the two measures is superior to the other one or that Ki67 index adds valuable information to mitoses in assessing proliferative status．McCall et al．have mentioned that the two measures may yield conflicting results sometimes and they recommend assigning the higher grade under that situation［9］．Many more data and studies are required before we reach agreement on which single index or the combination of the two is best for the grading purpose．At the same time，caution should be taken that this grading system itself is not specific for thymic NET and the cut-off values might not be the optimal ones of greatest accuracy．

In the contrast of the idea of grading to clearly divide tumors into different groups，a clinicopathologic and immunohistochemical study conducted by Moran raises the possibility that the tumors are in a single big family of a broad continuous spectrum，and it is not necessary to classify them into various histologic subtypes［3］．Foci of varied differential levels are found within the same tissue sample and the transition zone［10］．

Epidemiology

Thymic neuroendocrine tumor（TNET） isan extremely rare condition，and the overall age-adjusted incidence of thymic carcinoids is estimated to be around 0．01／100 000 per year［11］．It accounts for only approximately 2%to 4%of all anterior mediastinal neoplasms．In a relatively large scale study of carcinoid tumors，thymus is the origin in about 2%of cases．Male predominance has been noticed to be significant in all types of thymic neuroendocrine neoplasms other than the small cell subtype which shows no preference for gender．TNET associated with MEN-1 nearly occurs exclusively in heavysmoking male［12］．Most TNETs are atypical carcinoids but the accurate percentage has not been confirmed due to limited data．

Hormone secretion is an important feature of TNET and the most common endocrinopathies encountered in cases of TNET are ectopic ACTH syndrome and MEN-1 syndrome．Ectopic ACTH syndrome has been reported in approximately 20%to 35%cases of thymic NET while MEN-1 is concurrent with TNET in about 25%of cases．Interestingly，both of these endocrine disorders are combined only with carcinoids，but not the poorly-differentiated counterpart．Maybe the less differentiated cells are further from maturation to be of function．On the other hand，TNET is responsible for 10%of ectopic ACTH syndrome and develops some time during the course of 8%cases of confirmed MEN-1．

Clinical manifestation

A large portion of TNETs are first detected on chest X-ray or chest CT scan as routine exam or for another questionable medical issue．It is reported that 28%to 71%patients show no significant clinical manifestations at the time of diagnosis［13］．As for symptomatic patients，they might present with separated local symptoms，neuroendocrine disorders， paraneoplastic syndrome or a mixture of them．

Local symptoms due to mass effect are the most common reason leading to admission of patients．Mostpoorly differentiated and some well differentiated thymic NETs exhibit local symptoms mainly due to mass effect．Chest pain， cough， dyspnea， superiorvena cava syndrome have been reported widely．

Endocrine disorders resulted from the autonomous secretion of hormones from tumor cells are another setting of clinical findings which leads to the final correct diagnosis．Cushing syndrome due to ectopic ACTH excretion occurs in about 20%to 35%of patients with TNET［12，14］．TNETs associated with MEN-1 rarely secret hormone themselves， and endocrine disturbance is usually due to the functioning status of MEN-1 tumors，most often hyperparathyroidism［15］．SIADH and acromegaly due to tumor secretion of GHRH are uncommon findings with TNET，and carcinoid syndrome is extremely rare．Thymic carcinoid causing Zollinger-Ellison and Cushing’s syndromes due to ectopic ACTH and gastrin secretion has also been reported［16］．

Paraneoplastic syndrome is most commonly associated with neuroendocrine neoplasms．A case reported by Lowenthal and colleagues in 1974 is the first NET case with probably thymic origin and a variety of systemic features of the non-metastatic type，including polyarthritis，finger clubbing，peripheral neuropathy and proximal myopathy［17］．In 2003，Li et al．reported a case of thymic carcinoid related tumor-induced osteomalacia（TIO）presenting with bone pain，fracture and muscle weakness．This is probably the first case of TIO associated with underlying thymic NET in the world［18］．Davis et al．reported a case in 2008 of TNET presenting initially with short term memory loss and behavior changes and this is the first case of TNET heralded by paraneoplastic limbic encephalitis［19-20］．Liu added another line to the list of TNET associated paraneoplastic features by reporting a case presenting with Churg-Strauss syndrome［21］．Myasthenia gravis and pure red aplasia have been also reported to be associated with TNET．

Other miscellaneous manifestations include massive anterior mediastinal hemorrhage and dysgeusia．

Radiographic manifestation

The imaging approaches can be roughly divided into two groups，the general methods and the functional images．The former includes chest X-ray，computed tomography（CT）and magnetic resonance（MR）imaging，while the latter mainly indicates octreotide scintigraphy and positron emission tomography（PET）．However，there is no defined optimum imaging strategy yet．

Chest X-ray can frequently detect the tumor as an anterior mediastinal mass，but with very limited diagnostic and prognostic information．When thymic carcinoid is suspected，chest CT is often recommended as the initial investigation and contrast-enhanced CT is preferred．Specific contrast pattern of the lesion increases the likelihood of malignancy and brightening of vessels and makes it easier to evaluate lymph node invasion．Thymic carcinoid often appears as round，ovoid or lobulated mass of soft tissue density located in the anterior mediastinum．It is usually heterogeneous with hypodensity of cystic degeneration or necrosis and hyperdensity of calcification．The heterogeneity is more likely to exist in atypical carcinoid．With bolus injection of contrast agent，the tumor appears to be slightly or moderately heterogeneous enhancement．Lymph node metastasis might be revealed with contrast CT scan．These imaging manifestations are not specific of thymic carcinoid，but they raise the possibility that the lesion is malignant．With great resolution of soft tissue，MRI is the preferable strategy to detect small tumors，metastases，pericardial or large vessel involvement and thereby to assess surgery indication．Overall，chest CT is more cost-effective compared with other methods［22］．

Functional imaging such as octreotide scintigraphy［23］and PET／CT，is an additional option and can be of extreme diagnostic value in the cases where NET is highly suspected but prior study is negative．However，the relatively lower sensitivity is the disadvantage of octreoscan．In a prospective study of patients with MEN-1 combined thymic NET，bone metastases were detected early only on MRI，not octreoscan．In a small-scale case series study（only 12 cases），octreotide scintigraphy shows no positive result neither with the primary tumor nor the metastatic lesion in the lung in one case．On the other hand，patients with positive result are very likely to benefit from the treatment with somatostantin and its biological analogues．FDG PET has high sensitivity to tumors with active metabolism and thymic carcinoid is FDG-avid tumor as well．According to a case report of recurrent thymic carcinoid，F(xiàn)DG PET is useful for recognition of multiple bone metastases while（201）Tl-whole body scintigraphy and（99）mTc-methylene diphosphonate［（99）mTc-MDP］bone scintigraphy donot reveal the metastases［24］．But FDG will lose its advantage in some NET which are relatively well-differentiated and with lower metabolic rate．

Diagnosis and differential diagnosis

According to the typical clinical manifestation and typical imaging features，thymic carcinoid should be considered．However，pathological study such as fineneedle aspiration specimen or biopsy is still the gold standard of diagnosis and grading of malignant lesions and of great value in staging［25］．Histopathology is required to confirm that the mass is a malignant neoplasm and of neuroendocrine origin［26］．Loss of the normal morphology and presence of pleomorphism are the signs of malignancy．Necrosis and proliferation rate are evaluated to determine the grade of the tumor as reviewed above．Immunohistochemistry stain contributes a lot to the diagnosis of thymic carcinoid at least from two mutually supportive aspects，to confirm the status of neuroendocrine differentiation and to exclude the possibility of origination from other sites．The commonly used markers include CAM 5．2 low-molecular weight cytokeratin，broad-spectrum keratin cocktail，chromogranin，synaptophysin，and Leu-7．

The most important consideration in the differential diagnosis of thymic carcinoid is a metastatic NET from other sources such as the lung，intestine and pancreas．Positive stain for neuroendocrine markers of a lesion in the thymus is not enough for a definite diagnosis of thymic carcinoid．Metastatic NETs from other anatomic sites may manifest as neuroendocrine marker positive masses in the thymus as well．However，such metastatic NETs can be easily recognized through their clinical history and imaging studies combined with markers．Markers of primary origin now exist for excluding the most common metastatic NETs．For well-differentiated NETs，thyroid transcription factor-1（TTF1）labeling usually favors pulmonary origin，while CDX2 expression is typical of intestinal or pancreatic primaries，and PDX1 or Isl1 are most commonly expressed in pancreatic NETs．The most important and difficult differential diagnosis in this setting is thymoma．Immunohistochemical markers can play a role in such instances：although both of them have strong CAM 5．2 positivity，thymomas will be negative for neuroendocrine markers such as chromogranin or synaptophysin．Others can also be distinguished by immunohistochemical stains［27］．

Staging

At least four different staging systems have been proposed，Yamakawa-Masaoka system，NCCHJ system，WHO system and NCII system．A study of 1320 patients reveals that for thymus epithelial tumor，Yamakawa-Masaoka staging is an excellent prognostic factor and‘N’and‘M’factors influence the prognosis more significantly than‘T’factor［4］．But a remarkable majority of cases involved in this study are thymoma and only 41 cases are carcinoid．A tentative version largely based on Masaoka system is used in the recent WHO classification of tumors．Although tumor size is not a parameter for determining T-category in the current TNM staging system，it has been reported that tumor size is of great impact on the overall survival．However，more studies are required to define the critical values of tumor size．And largescale studies including the resectable and unresectable tumors are necessary．What’s more important，all this staging system are all applied to thymus epithelial tumors among which only a small portion are of neuroendocrine origin，therefore caution should be taken when using them for evaluation．

Treatment

Three conventional approaches（surgery，chemotherapy and radiotherapy）for malignancy management are commonly applied to thymic carcinoid．

However，thymic carcinoid does not respond well to either chemotherapy or radiotherapy，and radical resection is of primary importance［28］．For all localized cases，the best chance for a cure seems to be complete surgical excision plus adjuvant radiotherapy．Even if the primary tumor is unresectable，debulking is still the first choice．For metastatic cases，surgery plus chemotherapy should be chosen．Surgery plays a role also in managing recurrence．Several reports indicate satisfactory long-term survival after resection of the recurrent disease and they suggest that an aggressive approach might be indicated［29］．

Considering the relatively high risk of local recurrence，radiotherapy is recommended for local lesions，especially after incomplete resections．Despite a lack of evidence，adjuvant radiotherapy may improve local control without significant increased morbidity and mortality．The optimal radiation dose has not been determined，but doses similar to those employed for thymic epithelial tumors represent a reasonable choice．

Chemotherapy should be taken into consideration given the high incidence of distal recurrence．The poorly differentiated tumors have a high proliferation index and can be treated with chemotherapy，although there is not yet a standard combination regimen．Cisplatinum-based regimens have shown some value and temozolomidebased treatment is also reported to give some benefit［30］．Cisplatin plus etoposide and streptozotocin in combination with 5-fluorouracil and doxorubicin are frequently employed．Recently a new combination chemotherapy with doxorubicin， 5-fluorouraciland dacarbazinehas demonstrated its activity in the treatment of NETs［31］．Patients with locally advanced disease unable to achieve R0 resection may benefit from neoadjuvant chemotherapy and radiation．Optimal agents have not been elucidated，but platinum／etoposide is reasonable．

Targeted therapy is becoming popular and developing its role in TNET management［32］．For functional tumors with low proliferating activity，treatment with somatostatin analogs and α-interferons might be an option．Peptide receptor radiotherapy（PRRT）might be a choice for patients with a high content of somatostatin receptors［29］．Tyrosine kinase inhibitor（TKI）such like imatinib may induce good response in cases with CD117（KIT）overexpression［33］．And after the PROMID study indicating antitumor efficacy by octreotide in small intestinal NETs，it is now widely accepted the use of somatostatin for non-functioning tumors．However，all these treatment evidences are for bronchial NET．While for the thymic carcinoid，somatostatin analogs can be used to control the Cushing’s syndrome related to thymic NETs．PRRT is promising in thymic carcinoid but more studies are needed［11］．Results support further research into Hsp90，IGF1R and EGFR as targets for developing new anticancer therapeutics for some NETs［34-35］．Although tumors of thymic origin only account for a small portion of NETs，and the exact number of TNET cases involved in this study is unknown，it raised the potential therapeutic targets and research strategy since TNET shares many common features with other NETs．

Prognosis

Prognostic factors for thymic carcinoid have not been clearly identified yet to date，probably due to lack of data［36］．A recent retrospective study involving 28 patients showed that high proliferative rate，absence of macroscopically radical primary resection and no surgical resection are three negative prognostic factors in patients with TNETs．Fukai and colleagues confirmed that neither histologic grading nor TNM classification is a good predictor for the prognosis of thymic carcinoid tumors，in contrast to thymoma and thymic carcinoma［37］．It is possible that this lack of predictive power is at least partially due to the deficiency in specificity．

With the high risks for local invasion， distant metastasis and recurrence，the general prognosis is poor for thymic carcinoid．However，typical carcinoid shows a better prognosis than the atypical one［38］．Metastatic rates range from 40%to 82%and the relapse rate is as high as 60%．The most frequent metastatic sites are lymph nodes，lung and bone．Overall 5-year survival rate is 28%to 31%，and overall 10-year survival is as low as 10%despite aggressive treatments according to some large series［5］．Accompanied with endocrine disorder is a negative prognostic factor，which leads to the significant difference in overall 5-year survival between patients with endocrinopathy and those without（35%vs 70%）．But evidence is further required to demonstrate whether there is proportional relationship between the pre-treatment ectopic hormone level and prognosis．

Conclusion

In conclusion，with the discovery of more and more cases，thymic carcinoid as a rare neoplasm has arrested people’s attention．There are still many problems and challenges for us to explore，especially the diagnosis and treatment．In recent research， scientists have found Ki-67 may be a reliable and reproducible marker for grading of NETs，hoping it to be a powerful tool to predict the prognosis and direct the treatment．However，the rarity of thymic carcinoid has become the restriction of further research．The WHO classification of thymic NET is the same as that applied to NET of the lung just due to lack of data on thymic counterparts．Only by formulating unified diagnostic and therapeutic criteria，collecting more patient data and making overall analysis can we get more information of this disease．And International Thymic Malignancy Interest Group（ITMIG），as an international organization，plays an important role in providing the basic information of patients and promoting the advancement of clinical and basic science pertaining to thymic and other mediastinal malignancies．

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2095-6894（2017）05-55-06

2017-04-01；接受日期：2017-04-19

北京協(xié)和醫(yī)院中青年科研基金（PUMCH-2016-2．25）；教育部博士點(diǎn)優(yōu)秀青年教師科研基金（20131106120063）；北京市科委“首都特色”臨床專項(xiàng)（Z151100004015157）

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