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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Grading

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 Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. 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 Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. 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

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 Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix 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 Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). 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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. 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 Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix
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 Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum or adhering to adjacent organs

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Metastasis

Definition

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 Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum, pleura Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. Pleura, and CSF
    • Ovarian cancer
    • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
    • Mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma
    • Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme is a high-grade astrocytoma, an aggressive brain tumor arising from astrocytes, with an unknown cause and a poorly understood link to risk factors. There are two main types: primary, a more aggressive form seen more commonly in older patients, and secondary, developing from lower-grade astrocytomas and seen more commonly in younger patients. 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 Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix cancer, which spreads through the portal vein
  • Hematogenous spread: through blood vessels, such as with sarcomas

Mechanism

  • 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 Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, and brain.
  • GI tumors spread through the portal system to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs.

References

  1. Telloni, S.M. (2017). Tumor staging and grading: A primer. Methods Mol Biol. 1606, 1–17. https://pubmed.ncbi.nlm.nih.gov/28501990/
  2. Rosen, R.D., Sapra, A. (2021). TNM Classification. StatPearls. Retrieved May 9, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK553187/
  3. Brierley, J., Gospodarowicz, M., O’Sullivan, B. (2016). The principles of cancer staging. Ecancermedicalscience, 10, ed61. https://pubmed.ncbi.nlm.nih.gov/28101141/
  4. Burstein, H.J. (2020). Tumor, Node, Metastasis (TNM) staging classification for breast cancer. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/tumor-node-metastasis-tnm-staging-classification-for-breast-cancer
  5. Yang, X.J. (2021). Interpretation of prostate biopsy. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/interpretation-of-prostate-biopsy
  6. Thomas, K.W., Gould, M.K. (2019). Tumor, Node, Metastasis (TNM) staging system for lung cancer. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/tumor-node-metastasis-tnm-staging-system-for-lung-cancer
  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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652033/

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