Standardized pathologic reporting of epithelial malignancy of the thymus has been difficult for several reasons. First, some may consider the most common neoplasm of thymic epithelium, the thymoma, to be a benign neoplasm and, therefore, excluded from the “cancer” rubric. While the majority of thymomas behave in a benign manner, some clearly exhibit malignant behavior. Given this, we believe thymomas should be considered epithelial neoplasms of at least low malignant potential and should be pathologically assessed as malignant neoplasms. Second, contrasting nomenclature used in several histologic categorization schemes has made uniformity in reporting difficult in the clinical practice setting and in the research arena.1–4 Finally, pathologic staging of thymic epithelial tumors can be difficult in practice. The commonly used modified Masaoka staging system requires integration of preoperative imaging, intraoperative findings, pathologic gross findings, and pathologic microscopic findings to arrive at an accurate clinical-pathologic stage relevant to patient management.5,6 Unfortunately, imaging and intraoperative findings are often not readily available to pathologists, which can lead to inaccurate staging, particularly understaging, of these tumors.

Given these difficulties, we have generated a global checklist to be used in the pathologic evaluation of thymic epithelial tumors. The ultimate goal of the guidelines and checklist is to enable pathologists to provide a clinically meaningful surgical pathology consultative opinion that can be used by oncologists and surgeons alike in the care of patients with this tumor type. This information and background material incorporate key evidence-based determinants of prognosis in thymoma: histology, stage, and completeness of resection.

Reporting Guidelines

  • Clinical information

    • Mechanism of discovery of thymic mass

      1. Incidental radiographic finding

      2. Workup of thoracic problem/complaint

      3. Workup of systemic disorder (if applicable; see part B below)

    • History of myasthenia gravis, pure red cell aplasia, or other autoimmune or paraneoplastic process

    • History of thoracic surgery for neoplastic disease

  • Gross description

    • Specimen

      1. How the specimen was labeled and manner of receipt (fresh, fixed)

      2. Weight (g) and size (cm) in 3 dimensions

      3. Anatomic orientation (if any) as provided by surgeon

        • Ink identifiers by pathologist (specify color and anatomic correlation)

      4. Condition of the capsule (intact, ruptured)

      5. Attached tissues (mediastinal fat, pleura, lung, chest wall, pericardium)

        • Ink identifiers by pathologist (specify color and anatomic correlation)

        • Correlation with imaging studies

        • Correlation with intraoperative findings per surgeon

    • Tumor

      1. Size (cm) in 3 dimensions, largest dimension listed first

        Note: Size (greatest linear dimension) has been reported to correlate with resectability and prognosis.7

      2. Tumor gross description (color, texture, nodularity, necrosis, fibrous bands)

      3. Relationship of tumor to capsule, attached tissues, and surgical margins

        Note: Consultation with the surgeon during the gross exam is optimal to determine the completeness of surgical resection. Encapsulated or minimally invasive tumors (Masaoka stage I and II, respectively) with negative surgical margins do not generally require adjuvant therapy, and demonstrate very low risk of recurrence.7–9

      4. Gross description of nonneoplastic thymus and/or attached tissues

        Nonneoplastic thymus, if not involuted, will be soft, golden yellow, and lobulated. Involuted thymic tissue may be indistinguishable from adipose tissue. In cases that are involved by marked follicular thymic hyperplasia, the nonneoplastic gland may take on a gray-tan, vaguely nodular appearance similar to lymph node.

      5. Sampling: At least 5 sections; 1 section per 1 cm of greatest tumor dimension for tumors larger than 5 cm10

        Note: Accurate histologic classification requires adequate sampling. Moran and Suster10 suggest that 5 sections of tumor is a reasonable starting point, and increasing the number of sections increases the likelihood of detecting microscopic transcapsular invasion. Gross extracapsular extension should be directly sampled.

      6. Intraoperative consultation (frozen section)

        Thymoma shares the mediastinum as a primary site with other malignancies, including mediastinal Hodgkin lymphoma, non-Hodgkin lymphomas, and mediastinal germ cell tumors.1 If a preoperative pathologic diagnosis is not obtained, the surgeon may elect for intraoperative pathology consultation to determine the need for complete resection. Frozen section and cytologic preparations (smear and/or touch imprint) may be useful in this setting and may assist with triage of the tissue for special studies before further handling.11,12 The most difficult issue at stake for pathologists is distinguishing lymphoma from thymic epithelial tumors. If a definite diagnosis cannot be made, a portion of tissue should be saved fresh frozen and in tissue culture media in case molecular, flow cytometric, and/or cytogenetic studies are needed.

    • Lymph nodes

      Note: Lymph node dissections are not performed routinely in thymectomy for thymoma. However, lymph node dissections may be performed in cases in which other malignancies have not been comfortably excluded before resection of mediastinal tumor.

      1. Anatomic location(s) and number of pieces/nodes per location

      2. Presence or absence of grossly viable tumor

  • Diagnostic information

    • Histologic type of thymic epithelial neoplasm

      1. Thymoma

        The histologic classification of thymoma is outwardly complex owing to the various existing classification schemes in clinical use. Each classification scheme has its merits and drawbacks. For the sake of uniformity and clinical relevance, we propose that the World Health Organization (WHO)1 and/or Suster-Moran2 systems be used in reporting of thymoma.

        The 2004 modification of the WHO classification was built on the histogenetic/functional classification of Müller-Hermelink (MH).3 The WHO system uses alphabetic and numerical designations (ie, A, AB, B1, B2, B3) in an attempt to facilitate clinically relevant communication and comparison of thymoma histology across clinical studies and among pathologists. This classification scheme, like the MH scheme, is prognostically significant13,14; however, reproducibility is an issue, particularly for those who may not encounter many thymomas in routine practice.

        Suster and Moran2 proposed a simplified schema in 1999 that essentially condensed thymic epithelial tumors into 3 histologic groups based on architectural morphologic and epithelial cytologic features: thymoma, atypical thymoma, and thymic carcinoma. The Suster-Moran2 thymoma includes WHO sub-types A, AB, B1, and B2, and atypical thymoma corresponds to WHO subtype B3. This simplified scheme has been shown to have good reproducibility and, more important, carries adequate prognostic power with regard to survival and recurrence.15

        Whether one chooses to use the WHO1 or Suster-Moran2 system (or both) is a matter of local standard of practice; ie, one must pick a classification that best suits the needs of local surgeons and oncologists. Other classification systems may be used; however, we recommend that the WHO1 or Suster-Moran2 nomenclature (or both) be parenthetically added to the report if another classification system is used.

        Note: A brief histologic synopsis of each thymoma subtype follows each category in the following listing; WHO1 and/or Suster-Moran2 provide detailed histologic descriptions and differential diagnosis.

      2. Classification of thymoma according to WHO1 and Suster-Moran2

        • Thymoma, type A (WHO)/thymoma (Suster-Moran)

          Type A thymoma is characterized by bland appearing spindled to ovoid epithelial cells that recapitulate the appearance of involuted thymus and demonstrate few intraepithelial lymphocytes, if any. Many architectural patterns have been described, including solid sheets, rosettes, glands, and hemangiopericytoma-like patterns. This type of thymoma best corresponds to the medullary thymoma of the MH system.

        • Thymoma, type B1 (WHO)/thymoma (Suster-Moran)

          Type B1 thymoma is characterized by sheets and lobules of small round (cortical-like) thymic lymphocytes with single thymic epithelial cells scattered in the background; identification of these may be facilitated by cytokeratin staining. This thymoma has been referred to as lymphocyte-rich thymoma and corresponds to the cortical or organoid thymoma in the MH system.

        • Thymoma, type B2 (WHO)/thymoma (Suster-Moran)

          Type B2 thymoma is similar to B1 in that small lymphocytes dominate the histology, but in B2, the relative proportion of epithelial cells is increased, and individual cells appear more prominent, showing larger nuclei and easily discernible nucleoli, compared with type B1. The epithelial cells may be found in small clusters, and perivascular palisading may be prominent. This thymoma has been referred to as mixed lymphoepithelial thymoma and corresponds best to the pure cortical-type thymoma of the MH system.

        • Thymoma, type AB (WHO)/thymoma (Suster-Moran)

          Type AB thymoma demonstrates a mixture of type A and type B histologic features. There is usually abrupt transition from spindle cell areas (type A) to cortical-like areas (B1, B2).

        • Thymoma, type B3 (WHO)/atypical thymoma (Suster-Moran)

          Type B3 thymoma is characterized by increased numbers of large, round to polygonal epithelial cells with far fewer numbers of lymphocytes in comparison with types B1 and B2. The epithelial cells may be present in large clusters or sheets and display mild nuclear irregularities, if any. Intraepithelial lymphocytes will be present, and this is a helpful finding in distinguishing type B3 thymoma from thymic carcinoma. This thymoma has been referred to as epithelial rich and coresponds to well-differentiated thymic carcinoma in the MH system.

        • Other (specify)

      • 2. Thymic carcinoma

        Thymic carcinoma is rare, and the reported histology of thymic carcinoma is representative of carcinomas seen outside the thymus, including squamous cell carcinoma (most common), adenocarcinoma, neuroendocrine carcinoma (NEC), and special morphologic variants.1 Nonneuroendocrine thymic carcinoma is differentiated from type B3 thymoma (atypical thymoma) by the presence of the following: (1) overt cytologic atypia, (2) solid growth pattern, and (3) paucity or absence of intraepithelial lymphocytes. The histologic appearance of neuroendocrine thymic carcinoma generally mirrors that of pulmonary NEC: carcinoid, atypical carcinoid, small cell carcinoma, and large cell NEC. The principal difficulty with any thymic carcinoma is determining whether the carcinoma arising at the site of the thymus is primary or metastatic. This distinction may not be possible on histologic examination alone and is best done clinically by excluding other primary cancer sites, particularly the lung. Immunohistochemical analysis may be helpful in select cases. Thymic carcinoma (non-NEC types) may express CD5 and/or CD117 (c-kit), markers that are not typically seen in carcinomas of the lung.16,17 Thyroid transcription factor-1 may be helpful in distinguishing NEC of pulmonary origin.1

        • Squamous cell carcinoma

          1. Keratinizing

          2. Nonkeratinizing

        • Adenocarcinoma

        • Undifferentiated carcinoma

          1. Other (specify)

        • NEC

          1. Carcinoid (well differentiated neuroendocrine carcinoma)

            • Typical

            • Atypical

          2. Small cell carcinoma

          3. Large cell NEC

    • Angiolymphatic invasion

      1. Present or absent

    • Invasion of nearby structures

      1. Mediastinal fat

      2. Mediastinal pleura

      3. Pericardium

      4. Lung

      5. Chest wall

      6. Other

    • Lymph nodes

      1. No lymph nodes submitted

      2. Lymph nodes submitted by site/station

        • Number positive by site/station

    • Stage

      1. Modified Masaoka Stage6

        Note: There is no formal TNM staging system for thymic epithelial neoplasms in the sixth edition of the staging manual of the American Joint Committee on Cancer/International Union Against Cancer. One may choose to adopt a TNM style of staging based on the Masaoka staging system.1

        • Stage I: Tumor completely encapsulated, grossly and microscopically; nontransmural capsular invasion included in stage I

        • Stage II: Complete transmural (transcapsular) invasion

          1. IIA: Microscopic transmural (transcapsular) invasion only

          2. IIB: Macroscopic invasion into extracapsular soft tissue or tumor grossly adherent to mediastinal pleura or pericardium without invasion through these structures

            Note: The biologic and prognostic significance of distinguishing between IIA and IIB may be of little value given that most stage I and stage II tumors show excellent long-term survival.7 However, this distinction may be helpful for a surgeon to under stand the nature of extracapsular disease that may or may not have been visually apparent at the time of surgery.

        • Stage III: Macroscopic invasion into neighboring organs

          1. IIIA: Invasion spares great vessels

          2. IIIB: Invasion includes great vessels

        • Stage IV: Locally advanced thoracic disease or metastasis

          1. IVA: Pleural or pericardial dissemination

          2. IVB: Lymphovascular metastasis

  • Optional information

    • Ancillary studies

      1. Immunohistochemical analysis

        Note: Immunohistochemistry analysis is not required routinely for the diagnosis of thymoma but may be helpful in the following circumstances:

        • Confirmation of thymic epithelial cells for diagnosis and histologic subtyping1

        • Excluding other potential primary sites of origin from thymic carcinoma.16–18 Although best done clinically, the exclusion of metastatic carcinoma to the mediastinum may be facilitated by the use of immunohistochemical stains for CD5 and c-kit (CD117). These markers are expressed in a high percentage of thymic carcinomas and only rarely in the common tumors of the lungs and head and neck region.

Thymic Epithelial Tumors Checklist

Accession No.: Part No. Date: 

 
Patient Name:
 
Organ Site Operation  
Thymus Other: Mediastinum Thymectomy  
A. Primary Tumor Diagnosis (Required
Thymoma 
  Histologic classification 
  World Health Organization Classification (2004)/Suster-Moran (1999) 
    Thymoma, type A/thymoma 
    Thymoma, type AB/thymoma 
    Thymoma, type B1/thymoma 
    Thymoma, type B2/thymoma 
    Thymoma, type B3/atypical thymoma 
    Other (specify)
 
Thymic Carcinoma 
Note: Primary thymic carcinoma is one of exclusion of other primary sites. 
  Squamous cell carcinoma 
    Keratinizing 
    Nonkeratinizing 
  Adenocarcinoma (specify if special type) 
  Undifferentiated carcinoma 
  Other nonneuroendocrine carcinoma (specify) 
  Neuroendocrine carcinoma 
    Carcinoid (typical vs atypical) 
    Small cell carcinoma 
    Large cell neuroendocrine carcinoma
 
Size of Tumor 
  3 dimensions, greatest dimension listed first
 
Invasion and Extent of Disease 
  No transcapsular invasion (encapsulated thymoma) 
  Transcapsular invasion 
    Limited to mediastinal adipose tissue (minimally invasive) or Involvement of adjacent structures (widely invasive) 
      Tumor invades (circle all that apply
        Mediastinal pleura 
        Lung parenchyma 
        Pericardium 
        Chest wall tissue 
        Other (specify)
 
Completeness of Resection 
  Tumor completely resected 
  Tumor resection incomplete 
    Gross residual disease present or 
    Microscopic residual disease only 
      Location of positive margins (specify) 
  Cannot assess completeness of resection (specify reason(s))
 
Additional Tumor Features 
  Angiolymphatic vessel invasion: Identified ___ Not identified ___ 
Ancillary Tumor Studies (Optional) 
  Immunohistochemical studies are performed, and the immunophenotype is as follows: 
    Positive markers (tumor cells): 
    Negative markers (tumor cells): 
    Indeterminant markers: 
    Nontumor-associated markers: 
    Interpretation:
 
Nonneoplastic Findings 
  Thymic involution 
  Thymic follicular hyperplasia 
  Thymic cyst 
  Other (specify) 
  No nonneoplastic findings
 
B. Lymph Nodes 
Note: Lymph node dissections may not routinely accompany thymic resections. 
Anterior mediastinal,specify station(s) 
  1. Positive or negative for tumor: __________ 
  2. Comment: __________ 
Intrathoracic,specify station(s) 
  1. Positive or negative for tumor: __________ 
  2. Comment: __________ 
Scalene and/or supraclavicular 
  1. Number examined: __________ 
  2. Number positive: __________ 
  3. Comment: __________
 
C. Stage (Modified Masaoka Stage) (Required) 
  Stage I 
    Tumor completely encapsulated, grossly and microscopically; nontransmural capsular invasion included in stage I 
  Stage II 
    Complete transmural (transcapsular) invasion 
    IIA: Microscopic transcapsular invasion only 
    IIB: Macroscopic invasion into extracapsular soft tissue or tumor grossly adherent to mediastinal pleura or pericardium without invasion through these structures 
  Stage III 
    Macroscopic invasion into neighboring organs 
    IIIA: Invasion spares great vessels 
    IIIB: Invasion includes great vessels 
  Stage IV 
    Locally advanced thoracic disease or metastasis 
    IVA: Pleural or pericardial dissemination 
    IVB: Lymphovascular metastasis 
Accession No.: Part No. Date: 

 
Patient Name:
 
Organ Site Operation  
Thymus Other: Mediastinum Thymectomy  
A. Primary Tumor Diagnosis (Required
Thymoma 
  Histologic classification 
  World Health Organization Classification (2004)/Suster-Moran (1999) 
    Thymoma, type A/thymoma 
    Thymoma, type AB/thymoma 
    Thymoma, type B1/thymoma 
    Thymoma, type B2/thymoma 
    Thymoma, type B3/atypical thymoma 
    Other (specify)
 
Thymic Carcinoma 
Note: Primary thymic carcinoma is one of exclusion of other primary sites. 
  Squamous cell carcinoma 
    Keratinizing 
    Nonkeratinizing 
  Adenocarcinoma (specify if special type) 
  Undifferentiated carcinoma 
  Other nonneuroendocrine carcinoma (specify) 
  Neuroendocrine carcinoma 
    Carcinoid (typical vs atypical) 
    Small cell carcinoma 
    Large cell neuroendocrine carcinoma
 
Size of Tumor 
  3 dimensions, greatest dimension listed first
 
Invasion and Extent of Disease 
  No transcapsular invasion (encapsulated thymoma) 
  Transcapsular invasion 
    Limited to mediastinal adipose tissue (minimally invasive) or Involvement of adjacent structures (widely invasive) 
      Tumor invades (circle all that apply
        Mediastinal pleura 
        Lung parenchyma 
        Pericardium 
        Chest wall tissue 
        Other (specify)
 
Completeness of Resection 
  Tumor completely resected 
  Tumor resection incomplete 
    Gross residual disease present or 
    Microscopic residual disease only 
      Location of positive margins (specify) 
  Cannot assess completeness of resection (specify reason(s))
 
Additional Tumor Features 
  Angiolymphatic vessel invasion: Identified ___ Not identified ___ 
Ancillary Tumor Studies (Optional) 
  Immunohistochemical studies are performed, and the immunophenotype is as follows: 
    Positive markers (tumor cells): 
    Negative markers (tumor cells): 
    Indeterminant markers: 
    Nontumor-associated markers: 
    Interpretation:
 
Nonneoplastic Findings 
  Thymic involution 
  Thymic follicular hyperplasia 
  Thymic cyst 
  Other (specify) 
  No nonneoplastic findings
 
B. Lymph Nodes 
Note: Lymph node dissections may not routinely accompany thymic resections. 
Anterior mediastinal,specify station(s) 
  1. Positive or negative for tumor: __________ 
  2. Comment: __________ 
Intrathoracic,specify station(s) 
  1. Positive or negative for tumor: __________ 
  2. Comment: __________ 
Scalene and/or supraclavicular 
  1. Number examined: __________ 
  2. Number positive: __________ 
  3. Comment: __________
 
C. Stage (Modified Masaoka Stage) (Required) 
  Stage I 
    Tumor completely encapsulated, grossly and microscopically; nontransmural capsular invasion included in stage I 
  Stage II 
    Complete transmural (transcapsular) invasion 
    IIA: Microscopic transcapsular invasion only 
    IIB: Macroscopic invasion into extracapsular soft tissue or tumor grossly adherent to mediastinal pleura or pericardium without invasion through these structures 
  Stage III 
    Macroscopic invasion into neighboring organs 
    IIIA: Invasion spares great vessels 
    IIIB: Invasion includes great vessels 
  Stage IV 
    Locally advanced thoracic disease or metastasis 
    IVA: Pleural or pericardial dissemination 
    IVB: Lymphovascular metastasis 

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Author notes

*
Committee members are Jamie A. Weydert, MD,1 Barry R. De Young, MD,1 and Kevin O. Leslie, MD,2 from the Departments of Pathology, 1University of Iowa Carver College of Medicine, Iowa City; and 2Mayo Clinic Arizona, Scottsdale.