Neoplasm

CLINICAL FEATURES OF TUMORS: Neoplasm is essentially a parasite. All tumors (benign & malignant) may cause morbidity & mortality. Almost all tumors (benign &malignant) present as mass.

Every mass (new growth) needs careful evaluation lest it be cancerous. Accurate diagnosis of a mass (whether benign or malignant) achieved by histopathological study (after excision), although occasionally such distinction can be achieved by clinical judgment e.g. subcutaneous lipoma.

EFFECTS OF TUMOR ON THE HOST: Neoplasm (benign & malignant) can cause problems because of:

Location & pressure on adjacent structures.eg Functional activity. e.g. Bleeding & secondary infection. e.g. Initiation of acute symptoms caused by either rupture or infarction of neoplasm. e.g. Malignant tumors may be responsible for cachexia &/or paraneoplastic syndromes. Psychological

Definition: The occurrence in many cancer patients of progressive loss of body fat & lean body mass, accompanied by profound weakness, anorexia & anemia. Severity of cachexia correlate with the size of cancer & the extent of spread.


Origin of cachexia: The origin of cachexia is obscure. Is cachexia caused by the nutritional demands of the tumor?


Current evidence indicates that cachexia may result from the action of soluble factors such (TNF-α, IL-1, interferon-γ, proteolysis-inducing factor and a lipid-mobilizing factor) produced by the tumor or host cells. The effect of such factors include: Causing abnormalities in the central control of appetite leading to anorexia & decrease food intake. Increase basal metabolic rate.- Increase the catabolism of muscle and adipose tissue.

Treatment of cachexia: There is currently no satisfactory treatment for cancer cachexia other than removal of the underlying cause, the tumor. However, cachexia clearly hampers effective chemotherapy, by reducing the dosages that can be given. Furthermore, it has been estimated that a third of deaths of cancer are attributable to cachexia, rather than directly due to the tumor burden itself

Definition: Refers to symptoms that appear in cancer patient that cannot be explained by the local effect, distant spread nor by the elaboration of hormones indigenous to the tissue of origin of the tumor. Incidence: They occur in about 10% of patients with cancer.


Is it important to recognize paraneoplastic syndrome? They may precede the diagnosis of the neoplasm & may give a clue to the presence of occult CA. In affected patients, they may represent significant clinical problems & may even be fatal. They may mimic metastatic disease & therefore affect treatment.


Hypercalcemia is probably the most common paraneoplastic syndrome; overtly symptomatic hypercalcemia is most often related to some form of cancer rather than to hyperparathyroidism. Two general processes are involved in cancer-associated hypercalcemia: (1) osteolysis induced by cancer, whether primary in bone, such as multiple myeloma, or metastatic to bone from any primary lesion, and (2) the production of calcemic humoral substances by extraosseous neoplasms. Hypercalcemia due to skeletal metastases is not a paraneoplastic syndrome

- Endocrinopathies are common paraneoplastic syndromes. Results from ectopic hormone production. Cushing syndrome is the most common endocrinopathy. Approximately 50% of individuals with this endocrinopathy have carcinoma of the lung, chiefly the small-cell type. It is caused by excessive production of corticotropin or corticotropin-like peptides

Paraneoplastic syndromes

Example
Mechanism
Syndrome
Lung (oat cell) carcinoma
ACTH-like substance
Cushing's Syndrome
Lung (squamous cell) carcinoma
Parathormone-like substance
Hypercalcemia
Lung (oat cell) carcinoma
Inappropriate ADH secretion
Hyponatremia
Renal cell carcinoma
Erythropoietin-like substance
Polycythemia
Various carcinomas
Hypercoagulable state
Trousseau's Syndrome
Various carcinomas and sarcomas
Insulin-like substance
Hypoglycemia
Metastatic malignant carcinoid tumors
5-hydroxy-indoleacetic acid (5-HIAA),serotonin
Carcinoid Syndrome


Causal Mechanism
Major Forms of Underlying Cancer
Clinical Syndromes
Endocrinopathies

Small-cell carcinoma of lung Pancreatic carcinoma Neural tumors

Antidiuretic hormone or atrial natriuretic hormones
Small-cell carcinoma of lung; intracranial neoplasms
Syndrome of inappropriate antidiuretic hormone secretion
Parathyroid hormone-related protein (PTHRP), TGF-α, TNF, IL-1 Squamous cell carcinoma of lung Breast carcinoma, Renal carcinoma Adult T-cell leukemia/lymphoma
Hypercalcemia

Ovarian carcinoma Fibrosarcoma

Bronchial carcinoid. Hepatocellular & Pancreatic carcinoma
Carcinoid syndrome

Gastric, Renal, Hepatocellular carcinoma. Cerebellar hemangioma

Polycythemia

Nerve and muscle syndromes

Immunological
Bronchogenic carcinoma
Myasthenia

Breast carcinoma

Disorders of central & peripheral nervous system
Dermatologic disorders
Immunological; secretion of epidermal growth factor
Gastric, Lung &Uterine carcinoma
Acanthosis nigricans
Immunological
Bronchogenic, breast carcinoma
Dermatomyositis
Osseous, articular, and soft-tissue changes
Unknown
Bronchogenic carcinoma
Hypertrophic osteoarthropathy and clubbing of the fingers



Vascular and hematologic changes
Tumor products (mucins that activate clotting)
Pancreatic, Bronchogenic carcinoma Other cancers
Venous thrombosis (Trousseau phenomenon)
Hypercoagulability
Advanced cancers
Nonbacterial thrombotic endocarditis
Unknown
Thymic neoplasms
Red cell aplasia
Others
Tumor antigens, immune complexes
Various cancers
Nephrotic syndrome


Staging and grading schema have been devised for malignant neoplasms to quantify the probable clinical aggressiveness of a given neoplasm and its apparent extent and spread in the individual patient. They are also necessary for making an accurate prognosis and for comparing end results of various treatment protocols In general, the higher the grade & the higher the stage, the larger a neoplasm is and the farther it has likely spread.


GRADING: Attempts to determine the aggressiveness of the tumor. Grading schema are based upon the microscopic appearance of a neoplasm with H&E staining (i.e the degree of differentiation). In some cancer on no. of mitosis


In general, a higher grade means that there is a lesser degree of differentiation and the worse the biologic behavior of a malignant neoplasm will be. A well-differentiated neoplasm is composed of cells that closely resemble the cell of origin, while poorly differentiated neoplasms have cells that are difficult to recognize as to their cell of origin.


Grading schema have been devised for many types of neoplasms, mainly carcinomas. Most grading systems have three or four grades (designated with numbers or roman numerals).

In the diagram below utilizing an adenocarcinoma as an example, the principles of grading are illustrated:

Grading of Malignant Neoplasms

Definition
Grade
Well differentiated
I
Moderately differentiated
II
Poorly differentiated
III
Anaplastic
IV

STAGING: Determine the extent of spread of a malignant tumor. It is based on: a- Size of primary tumor. b-Extent of spread to regional L.N. c- Presence or absence of distant mets. There are 2 major staging systems: 1- AJC (American Joint Committee) system: Divide the tumor into 4 stages (0-IV). 2- TNM system


TNM system: The most common employed staging system. "T" score is based upon the size and/or extent of invasion of the primary tumor. "N" score indicates the extent of lymph node involvement. "M" score indicates whether distant metastases are present or not.


Staging forms have been devised for each organ or site that a malignant neoplasm can occur, and the criteria listed on the form. The forms are filled out using clinical and pathologic criteria and aid in determination of therapy, estimating the prognosis, and developing statistics useful for determining outcomes.

In the diagram below utilizing a lung carcinoma as an example, the principles of staging are illustrated:

Staging of Malignant Neoplasms

Definition
Stage
In situ, non-invasive (confined to epithelium)
Tis
Small, minimally invasive within primary organ site
T1
Larger, more invasive within the primary organ site
T2
Larger and/or invasive beyond margins of primary organ site
T3
Very large and/or very invasive, spread to adjacent organs
T4
No lymph node involvement
N0
Regional lymph node involvement
N1
Extensive regional lymph node involvement
N2
More distant lymph node involvement
N3
No distant metastases
M0
Distant metastases present
M1


Survival:5 year 10year
Stage I : 5 year survival 87% Stage II : 5 year survival 75% Stage III : 5 year survival 46% Stage IV: 5 year survival 13%

1-History and Physical Examination

A clue to the presence of a neoplasm can be obtained from talking to the patient and through direct examination. Signs and symptoms such as weight loss, fatigue, and pain may be present. A mass may be palpable or visible.

2-Radiographic Techniques

The use of plain films (x-rays), computed tomography (CT), magnetic resonance imaging (MRI), mammography, and ultrasonography (US) may be very helpful to detect the presence and location of mass lesions. The findings from these methods may aid in staging and determination of therapy.

This computed tomographic (CT) scan with contrast of the abdomen in transverse view demonstrates multiple mass lesions representing metastases from a colonic adenocarcinoma. A normal spleen appears at the lower right in the image (on the patient's left).

3-Laboratory Analyses

Every year the approach to laboratory diagnosis of cancer becomes more complex, more sophisticated, and more specialized.

General findings such as anemia, enzyme abnormalities (such as an increased alkaline phosphatase), and hematuria or positive stool occult blood are helpful to suggest further workup

4-Tissue Biopsy and Surgery

Clinical data are invaluable for optimal pathologic diagnosis, but often clinicians underestimate its value. Radiation changes in the skin or mucosa can be similar to those associated with cancer. Sections taken from a healing fracture can mimic an osteosarcoma. Moreover, the laboratory evaluation of a lesion can be only as good as the specimen made available for examination. It must be adequate, representative, and properly preserved.


Sample small pieces of tissue (biopsy) from a particular site, via surgery or endoscopic techniques (such as colonoscopy, upper endoscopy, or bronchoscopy) can often yield a specific diagnosis of malignancy. Several sampling approaches are available Types of biopsy: At surgery, portions of an organ or tissue can be sampled, or the diseased tissue(s) removed and examined in surgical pathology to determine the stage and grade of the neoplasm.

Note: Some times we need to do frozen section, which is valuable in: Rapid determination of the nature a lesion during operation. Evaluation of the margins of an excised cancer. This method permits histologic evaluation within minutes. In experienced, competent hands, frozen-section diagnosis is highly accurate

5-Cytology

Methods that sample cells can be simple, easy to perform, cost-effective and minimally invasive. There are 2 types: Fine needle aspiration (FNA) cytology: Exfoliative cytology:

FNA cytology: using small bore needle. can be used to sample a variety of palpable mass lesions. Modern imaging techniques permit extension of the method to lesions in deep-seated structures, such as pelvic lymph nodes and pancreas (image guided FNA)


Exfoliative cytology: Here the sample represents cells that exfoliate from epithelial or serosal surfaces and this include: A good example is the Pap smear for diagnosis of cervical dysplasia and neoplasms. Cells exfoliated into body fluids may also be examined.

This is a Pap smear. The cytologic features of normal squamous epithelial cells can be seen at the center top and bottom, with orange to pale blue plate-like squamous cells that have small pyknotic nuclei. The dysplastic cells in the center extending to upper right are smaller overall with darker, more irregular nuclei

6-Special tests

Such as immunohistochemistry , flow cytometry& electron microscopy. Used to identify specific surface (& cytoplasmic) molecules, for better characterization of undifferetiated tumor.
7-Molecular diagnosis
Genetic study used for the diagnosis & in determination of the prognosis. E.g. p53 mutation, ch. translocation….etc.



By electron microscopy, features of a carcinoma can be seen. This adenocarcinoma demonstrates several features typical of a neoplasm of epithelial origin, including the junctional complex (tight junction at the asterisk and the desmosomes at crosses). The mucin granule (M) and lumenal microvilli at the upper right are also typical for an adenocarcinoma.

8-Tumor markers

Definition: Refers to molecules (whether antigens, proteins, enzymes, or hormones) that are produced by the tumor and can be detected in the blood.

Uses: They are NOT used as a primary method for the diagnosis of cancer (low sensitivity & specificity), instead they are used for: - As lab test to support the diagnosis. e.g. - They are of value in determining the response to treatment. HOW? - Also they are used for follow up of patients. HOW?

Hormones

Trophoblastic tumors, nonseminomatous testicular tumors
Human chorionic gonadotropin
Medullary carcinoma of thyroid
Calcitonin
Pheochromocytoma
Catecholamine and metabolites
See "Paraneoplastic Syndromes"
Ectopic hormones
Oncofetal antigens
Liver cell cancer, nonseminomatous germ cell tumors of testis
α-Fetoprotein Carcinomas of the colon, pancreas, lung, stomach, and heart
Carcinoembryonic antigen (CEA)
Isoenzymes
Prostate cancer
Prostatic acid phosphatase
Small-cell cancer of lung, neuroblastoma
Neuron-specific enolase

Specific proteins

Multiple myeloma
Immunoglobulins
Prostate cancer
Prostate-specific antigen (PSA)
Mucins and other glycoproteins
Ovarian cancer
CA-125
Colon cancer, pancreatic cancer
CA-19-9
Breast cancer
CA-15-3
New molecular markers
Colon cancer
p53, APC, RAS mutants in stool and serum
Pancreatic cancer
p53 and RAS mutants in stool and serum
Lung cancer
p53 and RAS mutants in sputum and serum
Bladder cancer
p53 mutants in urine