Introduction to Neoplasia

Question 1

Differentiate neoplasia and dysplasia.

Answer 1

• Cancer is the number two cause of death in the USA
• The majority of cancers are epithelial in derivation (carcinomas, see below)
  
  • The most commonly diagnosed forms of cancer (aside from indolent skin cancers) are lung cancer, breast cancer, prostate cancer, and colon cancer.
• Neoplasia is an unregulated clonal proliferation of abnormal cells, often forming a mass
  
  • A Neoplasm is an abnormal clonal mass of tissue, the growth of which is uncontrolled
  • The normal physiologic checks on cell proliferation are not functioning
  • A neoplasm may be benign or malignant (see below)
  • Some, but not all, malignant epithelial neoplasms (carcinomas) are preceded by dysplasia
  • Benign neoplasms are never preceded by dysplasia
• Dysplasia means disordered growth
• Dysplasia is characterized by a variety of changes that include a loss in the maturation of the individual cells as well as the accumulation of mutations
  
  • ​The proliferation in dysplasia is dysregulated
  • Dysplasias accumulate mutations and can can evolve into a malignant neoplasm in some cases if left unchecked
  • The more advanced a dysplasia is, the less likely it is to regress
  • The line between severe dysplasia and neoplasia is hazy in some cases as both may be clonal
• Malignant neoplasms either arise de novo or arise in a background of dysplasia
  
  • Benign neoplasms almost never evolve into malignant neoplasms

Question 2

Describe the nomenclature of tumors and how it describes the types of tumors and whether or not they are benign. What is an important exception?

Answer 2

• Cancer is not one disease, but a family consisting of hundreds of morphologically, genetically, and clinically distinct entities
• **Prefix **- Refers to line of differentiation
  
  • Adeno – Glandular
  • Lipo – Fatty
  • Osteo – Bone
  • Chondro – Cartilage
• Suffix – Tells you if it’s benign or malignant
  
  • -oma – generally benign
  • -sarcoma – malignant mesenchymal tumor
  • -carcinoma – malignant epithelial tumor
  • Lymphoma – malignant lymphoid tumor
  • Melanoma – malignant melanocytic tumor
• ***Important exception: Adenomas of the GI tract are not benign, but rather dysplastic lesions that can evolve into invasive malignant neoplasms (carcinomas)
• Note that in general, >95% of malignant neoplasms are carcinomas (by far the most common), sarcomas, lymphomas, or melanomas.

Question 3

What are general principles in differentiating between benign and malignant tumors?

Answer 3

• The biological distinction of benign and malignant neoplasms are complex but can be simplified into differences in the following 4 general properties:
  
  • differentiation
  • growth rate
  • local invasion
  • metastasis
• While a very few benign tumors may show loss of differentiation and an accelerated growth rate, invasion and (especially) metastatic spread are only seen in malignant neoplasms for all practical purposes
• **Important Point: Benign neoplasms, in general, do not evolve into malignant neoplasms
• Malignant neoplasms either arise de novo or (in the case of some epithelial malignant neoplasms) from a background of dysplasia

Question 4

How does differentiation of tumor cells compare between benign and malignant tumors?

Answer 4

• Well differentiated tumors closely resemble their tissue of origin, poorly differentiated tumors do not
• Compared to benign neoplasms, malignant neoplasms are generally more poorly differentiated and demonstrate:
  
  • Pleomorphism: Both cells and nuclei display marked pleomorphism (variation in size and shape)
    
    • Cells may be present which are many times larger than neighboring cells, and other cells may be very small
    • Anaplasia: Tumor cells lose their resemblance to tissue of origin
      
      • squamous tumors will stop making keratin
      • cartilage tumors will stop making chondroid
      • glandular tumors will stop forming glands

Question 5

How does the growth rate differ between benign and malignant tumors?

Answer 5

• In general, benign tumors tend to be slow growing and malignant tumors tend to grow rapidly
• The growth rate may be approximated by looking for mitotic activity

Question 6

What are the important processes involved in local tumor invasion?

Answer 6

• Tumor invasion is defined as active migration of neoplastic cells from the primary tissue of origin (also from secondary sites) into the contiguous or adjacent tissues
  
  • This is an active process involving tumor cells, extracellular matrix, and normal host tissue responses - defenses
  • The biochemical/molecular mechanisms responsible for tumor invasion include the tumor cell-extracellular matrix (ECM) interactions
• Local invasion is a complex process involving:
  
  • Changes (“loosening up”) of tumor cell-cell interactions
  • Degradation of the extracellular matrix (ECM)
  • Changes in attachment of tumor cells to ECM proteins
  • Locomotion, migration – is final step of invasion

Question 7

What is metastasis, and what are the sequential steps involved?

Answer 7

• Metastasis is defined as the spread/transfer of cancer cells from one organ or part to another site not directly connected with it
  
  • The formation of metastases is a cardinal property of malignant tumor growth
  • One should be able to enumerate the routes/pathways by which tumors spread; and know the various steps involved in metastasis
• Metastasis is a step-wise progressive process:
  
  • A metastatic subclone of cells in the primary tumor invades the basement membrane:
    
    • Detachment/attachment to basement membrane and extracellular matrix by receptors
    • Destruction of basement membranes.
  • Migration through ECM: This invasion may be due to various intrinsic factors of tumor cells:
    
    • motility
    • loss of cell-cell adhesion
    • collagenolytic and proteolytic enzyme (proteinases) secretion (e.g. Type IV collagenase)
    • Tissue inhibitors of metalloproteinases (TIMP-1,2)
    • Matrix metalloproteinases (MMPs) include collagenases Type I and Type IV and stromelysins
  • Penetration/Invasion of the vessel wall, i.e., intravasation (lymphatic or vein) and entry of tumor cells into the lumen
  • Survival and transport via lymphatics or blood vessels
  • Arrest in target organs (e.g., lymph node in case of lymphatic spread; liver, lung etc., with hematogenous spread)
  • Extravasation in secondary sites
  • Survival and growth at metastatic site

Question 8

What are the various routes of spread for malignant tumors?

Answer 8

• Lymphatic spread: Transport through lymphatics is the most common pathway for initial dissemination of carcinomas
  
  • Lymphatic invasion and embolization to lymph nodes:
    
    • Tumor cells enter into lymphatics and are carried away to the regional lymph nodes without getting arrested along the passageway (typical of carcinomas)
• Hematogenous spread: Tumor cells enter the thin-walled vessels (veins) and naked sinuses in highly vascular tumors; detach and embolize to other sites/organs, ie lungs, liver, etc.
  
  • Arteries with their thicker walls are less readily penetrated than are veins
  • Some cancers invade veins and grow as solid propagating tumor masses within the lumen (typical of sarcomas).
• Seeding of body cavities and surfaces: Peritoneal cavity, pleural cavity; pericardial, and cerebrospinal membranes (typical of some carcinomas, ie ovarian)

Question 9

Describe the grading and staging of tumors.

Answer 9

• Once a given neoplasm is diagnosed as malignant (carcinoma or sarcoma), it is imperative to determine the grade [degree of histologic differentiation] and the stage [extent of spread] of the malignant tumors
  
  • It is important to know that the tumors, although clonal in origin (every tumor is derived from a single mutated cell), contain heterogeneous populations of cells with different degrees of differentiation
• **Grading of cancer **depicts the degree of histologic differentiation
  
  • This is a reflection of how closely tumor cells reflect their benign counterparts
  • The degree of anaplasia and mitotic activity are also factors
  • Grading systems are subjective and vary among organ systems
• Staging of cancer is based on the extent of tumor spread:
  
  • size of the primary tumor
  • lymph node involvement
  • distant metastatic spread
• Tumor (T), lymph node (N) and metastases (M) classification (TNM) or O to IV staging are used
• Staging has clinical implications – staging has assumed a critical role in deciding the best therapeutic approach

Question 10

What is the role of immunohistochemistry in the pathologic examination of tumors?

Answer 10

• Immunohistochemistry (IHC) – Oftentimes, the site of origin or lineage of differentiation of a tumor is unclear based on the morphology and clinical findings. In these cases, IHC is employed to demonstrate which proteins a tumor is making. This information can point to a line of differentiation or site of origin of a tumor. For example, if a metastatic tumor is found to produce thyroglobulin, it is likely of thyroid origin. An undifferentiated tumor expressing desmin is likely to be a smooth muscle neoplasm (leiomyosarcoma).
• Without going into too much detail, a slide with the tumor in question is treated with an antibody directed against the protein of interest. These antibodies are conjuaged to peroxidase or another enzyme that, when the slide is treated with a substrate, will produce a visual signal. (IE, if the protein of interest is present the cells will turn brown).

Question 11

What is the role of molecular diagnostics in the evaluation of a tumor?

Answer 11

Molecular diagnostics – Molecular techniques are increasingly used in the diagnosis of tumors and to predict response to therapy. Certain tumors have pathognomonic genetic lesions whose demonstration facilitates the diagnosis. For example, in a patient with leukocytosis, demonstration of a t(9;22) translocation via RT-PCR is virtually diagnostic of CML. When confronted with a pediatric “small round blue cell” tumor, the cytogenetic finding of a t(11;22) is diagnostic of Ewing’s sarcoma.

Driver mutations are early inciting events in tumorigenesis that confer a growth advantage upon cells harboring them. Common driver mutations found in solid tumors include things like EGFR, KRAS, BRAF, and PTEN lesions. Tumors of a given site harboring different driver mutations are often clinically and pathologically distinct from one another. For example, lung adenocarcinomas harboring KRAS point mutations tend to be poorly differentiated and occur in smokers while those with EGFR mutations tend to be well differentiated and occur in non smokers. While multiple driver mutations have been described for most tumor types, typically only one is seen in any given tumor.

Identifying driver mutations is of increasing importance in determining prognosis, and more importantly, predicting response to newer drugs which target certain driver mutations (ie, EGFR inhibitors for patients with EGFR mutated lung cancer, BRAF inhibitors for patients with BRAF mutated melanoma).