Grading, Staging, and Metastasis

Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. The tumor grade classifies a tumor by its histology and is part of the internationally accepted TNM staging system, which is used to characterize the extent of the disease. Metastatic disease refers to cancer that has spread beyond its primary tumor site.

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Grading is the histologic assessment of tumor cells according to their state of differentiation.

  • Microscopic examination of tumor cells after surgery or biopsy
  • Tumor cells are grouped into 4 types based on their resemblance to/difference from healthy cells (G1, G2, G3, G4):
    • Well-differentiated tumors (low grade, G1) generally have a better prognosis than poorly differentiated tumors (high grade, G4).
    • Poorly differentiated tumors are called anaplastic.
  • Tissue markers are helpful if cells of unknown origin are found:
    • Cytokeratin is expressed by carcinomas.
    • Vimentin is expressed by sarcomas.
    • CD45 is expressed by lymphomas.

Grading is performed for most types of tumors, but there are specific exceptions.

  • Prostate cancer: uses the Gleason score ranging from 2–10
    • Based on the growth pattern and degree of differentiation of tumor cells
    • A higher score is associated with disease outside the prostate.
    • A higher score indicates a greater likelihood of a worse prognosis.
  • Brain tumors: specific WHO classification
    • Uses both genotype and phenotype for some tumors
    • Immunohistochemical data for molecular genetic alterations are used in addition to histology.
  • Breast cancer: uses the Nottingham grading system
    • Based on tubule formation of the tumor, nuclear grade, and mitotic rate
    • Each category is scored between 1 and 3, and a total score is calculated.
    • Total score of 3–5 is G1 (low grade; well differentiated).
    • Total score of 6–7 is G2 (intermediate grade; moderately differentiated).
    • Total score of 8–9 is G3 (high grade; poorly differentiated).

Tumor grading:

  • Gx = grade cannot be assessed (undetermined grade)
  • G1 = well differentiated, close similarity to original tissue (low grade)
  • G2 = somewhat differentiated malignant tissue (intermediate grade)
  • G3 = poorly differentiated malignant tissue (high grade)
  • G4 = undifferentiated malignant tissue: The original tissue that gave rise to the tumor can be determined only by immunohistochemical evaluation or not at all (high grade).


Staging for cancer describes the extent of the disease and is used to help communicate with other members of the medical and surgical team for treatment decisions and prognosis. For example, with colon cancer, after surgery and pathologic staging, chemotherapy given to individuals with stage III disease eradicates micrometastases, reduces the likelihood of disease recurrence, and increases cure rates.

  • Clinical staging (“c” before the stage) happens before surgery.
    • Physical exam
    • Imaging with CT, MRI, or PET scans
  • Pathologic staging (“p” before the stage) is done after biopsy or surgical removal.
  • Stages range from localized to widespread:
    • Stage 0: carcinoma in situ (marked growth of abnormal cells that have not spread to neighboring tissue but have the potential to develop into a tumor)
    • Stage I: localized (beyond the basement membrane)
    • Stage II: early localized advanced
    • Stage III: late locally advanced
    • Stage IV: metastasized to different organs
  •  Stage is applied after a tumor is classified using the TNM system.
    • The American Joint Committee on Cancer (AJCC) updates the staging system periodically; currently, the 8th edition is being followed (effective 2018).
    • Relies on anatomic, macroscopic groupings of disease with similar prognoses
    • T = size and extent of the primary tumor:
      • Tx: Primary tumor cannot be measured.
      • T0: absence of primary tumor
      • T1–T4: assignment according to the specific type of tumor considering criteria such as size, invasive depth, and infiltration of neighboring tissue and organs
    • N = involvement of lymph nodes:
      • Nx: Involvement of neighboring lymph nodes cannot be assessed.
      • N0: no involvement of neighboring lymph nodes
      • N1–N3: number and localization of lymph nodes with cancer
    • M = status of metastases:
      • Mx: Distant metastases cannot be assessed.
      • M0: no metastases
      • M1: distant metastases observed
  • Staging is specific for each cancer; some deviate from the commonly used TNM system.
    • Lymphoma: Ann Arbor staging
    • Cervical and ovarian cancer: International Federation of Gynecology and Obstetrics (FIGO) system
    • Breast carcinoma staging uses TNM plus other factors to determine stage:
      • Grade
      • Receptor status: human epidermal growth factor receptor (HER)-2, estrogen receptor (ER), and progesterone receptor (PR)
    • Lung cancer:
      • T relates to tumor size but also to whether it has invaded nearby structures.
      • N of the TNM stage uses the number of involved nodal stations.
      • M of the TNM stage is divided according to whether metastatic disease is limited to the chest or single/multiple extrathoracic sites of metastasis.
    • Melanoma uses the TNM staging system; however:
      • Concordance with consensus reference diagnosis and reproducibility between pathologists remains low.
      • T of the TNM stage takes into account tumor thickness in mm and the presence or absence of ulceration.
      • M of the TNM stage takes into account the lab LDH levels.
    • Colon cancer staging:
      • Clinical staging is based on exam, CT results, and tumor marker carcinoembryonic (CEA) antigen levels.
      • Pathologic staging is based on TNM.
Example of T1–T4 staging for tumor in the colon-01

Example of T1–T4 staging for tumor in the colon
T1: Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria).
T2: Tumor invades the muscularis propria.
T3: Tumor invades through the muscularis propria into the surrounding tissues.
T4: Direct extension through the serosa, invading the visceral peritoneum or adhering to adjacent organs

Image by Lecturio. License: CC BY-NC-SA 4.0



Metastasis is the spread of a tumor from its primary site to nearby or distant places.

Routes of metastasis

  • Local spread: through infiltration in adjacent healthy tissues
  • Seeding: through cavities such as the peritoneum, pleura, and CSF
    • Ovarian cancer
    • Gastric cancer
    • Mesothelioma
    • Glioblastoma multiforme (type of brain cancer)
  • Lymphatic spread: through regional lymph nodes and lymph vessels
    • Seen with carcinomas, such as breast cancer
    • Some exceptions: colon cancer, which spreads through the portal vein
  • Hematogenous spread: through blood vessels, such as with sarcomas


  • Invasion of the extracellular matrix and basement membrane is facilitated by proteases and hyaluronidases.
  • Malignant cells are transported through the lymph and blood vessels forming a tumor cell embolism.
  • Cells invade other tissues and organs through extravasation:
    • Initially, they lie dormant and excrete signal complexes → angiogenesis
    • Blood vessels form → deliver nutrients

Sites of metastasis

  • Depending on the location of the primary tumor, there are different types of metastases according to blood flow.
  • The most common sites are the bones, lungs, liver, and brain.
  • GI tumors spread through the portal system to the liver and lungs.


  1. Telloni, S.M. (2017). Tumor staging and grading: A primer. Methods Mol Biol. 1606, 1–17.
  2. Rosen, R.D., Sapra, A. (2021). TNM Classification. StatPearls. Retrieved May 9, 2021, from
  3. Brierley, J., Gospodarowicz, M., O’Sullivan, B. (2016). The principles of cancer staging. Ecancermedicalscience, 10, ed61.
  4. Burstein, H.J. (2020). Tumor, Node, Metastasis (TNM) staging classification for breast cancer. UpToDate. Retrieved July 22, 2021, from
  5. Yang, X.J. (2021). Interpretation of prostate biopsy. UpToDate. Retrieved July 22, 2021, from
  6. Thomas, K.W., Gould, M.K. (2019). Tumor, Node, Metastasis (TNM) staging system for lung cancer. UpToDate. Retrieved July 22, 2021, from
  7. Keung, E.Z., Gershenwald, J.E. (2018). The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: Implications for melanoma treatment and care. Expert review of anticancer therapy, 18, 775–84.

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