Thymic Tumors Guidelines

Updated: Feb 22, 2021
  • Author: Dale K Mueller, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Guidelines

Guidelines for Thymic Neuroendocrine Tumors

The following organizations have released guidelines for the management of thymic neuroendocrine tumors (NETs):

  • National Comprehensive Cancer Network (NCCN) [11]
  • North American Neuroendocrine Tumor Society (NANETS) [18]
  • European Society of Medical Oncology (ESMO) [19]

Grading and staging

Grading schemes for gastroenteropancreatic NETs use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. However, for NETs of the lungs and thymus, the WHO includes only mitotic count and assessment of necrosis. [20]  

Under the 2015 WHO grading scheme, tumors fall into one of the following three grades [20] :

  • Low-grade tumors, < 2 mitoses per 10 high power fields (HPFs; or 2 mm 2) and no necrosis
  • Intermediate tumors, 2-10 mitoses per 10 HPFs/2 mm 2 and/or foci of necrosis
  • High-grade tumors, >10 mitoses per 10 HPFs/2 mm 2

Whereas NCCN recommends use of the WHO scheme for grading, it also recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. [11] Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results.

ESMO uses only mitotic count in determining tumor grade, as follows [19] :

  • Low-grade tumors, < 10 mitoses/10 HPFs
  • Intermediate tumors, 10-20 mitoses/10 HPFs
  • High-grade tumors, >20 mitoses/10 HPFs

The ESMO guidelines recommend staging according to the seventh edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual [19] ; the NCCN guidelines follow the eighth edition. [11]  TNM staging of thymic NETs follows the general rules for tumors of the thymus. [9]

NANETS concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage. For NETs of the thorax (including the lungs and thymus) resection margins should be indicated, measuring the distance from the tumor edge to guarantee radical excision on surgical specimens. [18]

NCCN recommendations include the following [11] :

  • Localized disease (stage I/II) - Surgical resection
  • Locoregional disease (stage IIIA/B) - If the lesion is resectable, surgical resection with clean margins; if resection is incomplete or margins are positive, follow with radiation therapy (RT) and/or chemotherapy; if the lesion is locally unresectable, consider observation or RT with or without cytotoxic chemotherapy

The NANETS guidelines include the following recommendations [18] :

  • Locoregional disease - Surgical resection including mediastinal lymphadenectomy
  • Recurrent localized disease - Surgical resection of localized disease
  • Metastatic or unresectable disease - Options include RT (for unresectable disease), everolimus, interferon alfa, or temozolomide

The ESMO guidelines note that a protracted follow-up should always be performed after surgical resection because of the high rates of recurrence. For metastatic disease, although the available chemotherapy regimens have not demonstrated good effects, cisplatin-based regimens have been of value and temozolomide-based treatment gives some benefit. [19]

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Guidelines for Thymoma and Thymic Carcinoma

NCCN guidelines have been developed for management of thymoma and thymic carcinoma. [10]

Initial management

Recommendations for initial management include the following [10] :

  • Surgically resectable lesion - Total thymectomy with complete excision of tumor
  • Locally advanced disease, unresectable lesion - Core needle biopsy (CNB) or open biopsy

Locally advanced, advanced, or recurrent disease

Recommendations for locally advanced, advanced, or recurrent disease include the following [10] :

  • Locally advanced disease - If unresectable, concurrent chemoradiation; if potentially resectable, chemotherapy, with computed tomography (CT) of the chest with contrast or fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT to assess resectability; if resectable, surgical resection of primary tumor and isolated metastases, with consideration of postoperative RT; if unresectable, RT ± chemotherapy
  • Solitary metastasis or ipsilateral pleural metastasis - If potentially resectable, chemotherapy, followed by chest CT or PET/CT and subsequent therapeutic approach as for locally advanced disease; alternatively, surgery, with consideration or postoperative chemotherapy or RT
  • Evidence of extrathoracic metastases - Chemotherapy

Surgical resection

Principles of surgical resection include the following [10] :

  • Surgical resection should be performed on carefully evaluated by board-certified thoracic surgeons; locally advanced (unresectable) and resectable stage ≥II cases should be evaluated by a multidisciplinary team
  • Surgical biopsy should be avoided if a resectable thymoma is strongly suspected
  • Biopsy of a possible thymoma should not be done transpleurally
  • Before surgical resection, patients should be evaluated for myasthenia gravis (MG) and should be medically controlled
  • Goals - Complete excision of the lesion with total thymectomy and complete resection of contiguous and noncontiguous disease
  • Complete excision may require resection of adjacent structures; bilateral phrenic nerve resection should be avoided
  • Surgical clips should be placed at the time of resection to help guide RT (when indicated)
  • During thymectomy, pleural surfaces should be examined for metastases, which should be resected if possible to achieve complete gross resection
  • Minimally invasive procedures currently are not routinely recommended but may be considered for stage I/II lesions if (1) all oncologic goals can be met and (2) they are performed in specialized centers by surgeons with relevant experience

Radiation therapy

General principles of RT include the following [10] :

  • RT recommendations should be made by a radiation oncologist with experience in managing thymomas and thymic carcinomas
  • Definitive RT should be provided to (1) patients with unresectable disease that progresses on induction chemotherapy, (2) patients with incompletely resected thymoma or thymic carcinoma, or (3) to patients with locally advanced disease as adjuvant therapy after chemotherapy and surgery
  • Radiation oncologists must communicate (1) with surgeons, to review operative findings and help determine target volume at risk; and (2) with pathologists, to assess detailed pathology, disease extent, and surgical margins
  • Definition of treatment volumes is facilitated by review of preoperative imaging and coregistration of preoperative imaging into the planning system

Chemotherapy

First-line combination chemotherapy regimens include the following [10] :

  • CAP (cisplatin-doxorubicin-cyclophosphamide; preferred for thymoma)
  • Carboplatin-paclitaxel (preferred for thymic carcinoma)
  • CAP + prednisone
  • ADOC (cisplatin-doxorubicin-vincristine-cyclophosphamide)
  • PE (cisplatin-etoposide)
  • Etoposide-ifosfamide-cisplatin

Second-line systemic therapies include the following [10] :

  • Sunitinib (thymic carcinoma only)
  • Pembrolizumab (thymic carcinoma only)
  • Lenvatinib (thymic carcinoma only)
  • Pemetrexed
  • Everolimus
  • Paclitaxel
  • Octreotide (including LAR) ± prednisone
  • Gemcitabine ± capecitabine
  • 5-Fluorouracil (5-FU) + leucovorin
  • Etoposide
  • Ifosfamide
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