GENERAL ONCOLOGY

 GENERAL ONCOLOGY

NOMENCLATURE:

Metaplasia

Metaplasia means replacement of one mature cell type with another. It is non-neoplastic. For example, squamous metaplasia

- most common type; seen in endocervix and bronchial mucosa.

Glandular metaplasia is seen in Barret’s esophagus.

Dysplasia

Dysplasia is a loss in the uniformity of the individual cells and a loss in their architectural orientation. It is encountered principally in the epithelia. It is non-neoplastic with maximum potential for malignant change.

Carcinoma In Situ When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ. It is a preinvasive stage of cancer.

Anaplasia

Loss of differentiation of cells is known as anaplasia. It is the hallmark of malignancy.

Features of anaplastic cells:

1. Pleomorphism (variation in size and shape).

2. Nuclei are hyperchromatic and large.

3. The nucleus : cytoplasm ratio of normal 1:4 or 1:6 may approach 1:1.

4. Anaplastic nuclei are variable and bizarre in size and shape.

5. Mitoses are often numerous and distinctly atypical.

Desmoplasia

Tumors with dense, abundant fibrous stroma are called desmoplastic or scirrhous carcinoma

Tumors

Malignant tumors:

• Sarcoma - that arises from mesenchymal tissue.

• Carcinoma - that arises from epithelial tissue.

Features of malignancy:

1. Anaplasia or lack of differentiation.

2. Rate of growth erratic and rapid.

3. Locally invasive.

4. Metastases to distant sites - most characteristic of neoplasm.

Mixed tumors: Tumors composed of a single type of parenchymal cells that differentiate towards more than one cell line are called mixed tumors.

For example, pleomorphic adenoma of parotid gland.

Teratoma: Tumors composed of a number of parenchymal cell types arising from totipotent cells derived from more than one germ cell layer.

Choriostoma: Congenital anomaly defined as ectopic rests of normal cells.

Hamartoma: It is a congenital malformation defined as a mass of disorganized but mature cells of tissues

indigenous to the particular site.

METASTASIS

Routes

1. Lymphatic spread: Carcinomas spread via lymphatics.

Sarcomas that spread via lymphatics

1. Synovial sarcoma

2. Clear cell sarcoma

3. Angiosarcoma

4. Rhabdomyosarcoma

5. Fibrosarcoma

6. Epithelioid sarcoma

7. Malignant fibrous histiocytoma

2. Hematogenous spread: Hematogenous route is favored by sarcomas, but carcinomas also spread by this route especially those of lungs, breast, kidney, thyroid and prostrate.

3. Seeding within body cavity: e.g. peritoneal deposits in colonic carcinoma.

4. Other routes:

• Spread along epithelium-lined surfaces.

• Spread via CSF.

• Direct implantation by surgeon’s instruments.

Most common metastasis:

TO FROM

Brain - melanoma, lung

Bone - prostrate (male), breast (female)

Lungs - liver

Liver - GI tract, neuroblastoma in children, adrenals,

melanoma, and lungs.

Overall most common sites of metastasis are lymph nodes and liver.

EPIDEMIOLOGY:

Incidence

Most common sites of cancer in male are prostrate (world wide) and oral cavity (in India). Most common sites of cancer in female are breast (worldwide) and cervix (in India). Maximum mortality is from lung cancer.

Most common cancer in children is leukemia (ALL).

Heredity

I. Inherited cancer syndrome (autosomal dominant):

1. Familial retinoblastoma

2. Familial adenomatous polyposis of the colon

3. Multiple endocrine neoplasia (MEN) syndrome

4. Neurofibromatosis type 1 and 2

5. von Hippel-Lindau syndrome.

II. Familial cancers:

1. Breast carcinoma

2. Ovarian carcinoma

3. Colonic carcinoma

III. Autosomal recessive syndroms of defective DNA repair (chromosomal breakage syndrome):

1. Xeroderma pigmentosa

2. Ataxia telangiectasia

3. Bloom syndrome

4. Fanconi’s anemia

CELL CYCLE AND REGULATION

Phases

• G0 : Resting phase.

• G1 : First gap phase during which the cell determines its readiness to commit to DNA synthesis.

• S : Phase of DNA synthesis (replication).

• G2 : Second gap phase during which the fidelity of DNA replication is determined and errors are corrected.

• M : Phase of mitosis.

Interphase Regulator

G1 - S Product of retinoblastoma gene (pRB) and cyclin D along with CDK 4 and 6

S - G2 Cyclin A along with CDK 1 and 2

G2 - M Cyclin B along with CDK 1

• CDK inhibitors:

p15, p16, p18, p19 inhibit CDK 4 and 6 (G1 - S interphase). p21, p27, p57 inhibit all the CDKs.

• RB protein is regulated by four genes – RB gene CDK4, Cyclin D and CDKN2A (p16)

• Transforming growth factor b (TGF-b): has antiproliferative effects by cell arrest at G1 phase.

Mutation of TGF-b is associated with pancreatic carcinoma (100%) and colonic carcinoma.

CANCER GENETICS:

Proto-oncogenes

Genes that promote normal cell growth are called protooncogenes.

Activation of such genes converts them to oncogenes which produce oncoproteins. Their production

or function is independent of any external regulator.

Oncogenes transferred to in vitro animal cells turn them neoplastic.

Mechanism of activation of proto-oncogenes:

a. Point mutation:

i. RAS gene: RAS gene is associated with

Neurofibromatosis type 1. RAS is activated by binding to GTP and inactivated by conversion of

GTP to GDP by guanosine triphosphatase (GTPase). GTPase activity is controlled by GTPase

activating protein (GAPs). Thus, GAPs prevent uncontrolled activation of RAS gene and control

cell growth.

Disabling mutation of neurofibrin 1 (NF 1), a GAP is associated with neurofibromatosis type 1.

ii. Ret gene:

• Gain of function in the protooncogene Ret on chromosome 10 is associated with Multiple

Endocrine Neoplasia (MEN) syndrome type 2.

• Loss of function of Ret causes Hirschsprung’s disease.

b. DNA amplification: Over expression of these genes cause growth autonomy by binding to nucleus and increasing transcription of DNA.

i. erbB gene:

• erbB1 is associated with squamous cell carcinoma of lung.

• erbB2 (Her2/neu) is associated with breast cancer, adenocarcinoma of lung.

ii. MYC genes:

• N-MYC gene is associated with neuroblastoma.

• L-MYC gene is associated with small cell Ca of lung.

• C-MYC gene is associated with familial polyposis coli.

c. Chromosomal alterations:

i. Translocation:

• t (8:14) causes dysregulation of MYC gene and produces Burkitt’s lymphoma.

• Balanced translocation between ABL gene on chromosome 9 and BCR gene on chromosome

22 produces Philadelphia chromosome in chronic myeloid leukemia.

• t (14:18) causes follicular B cell lymphoma.

ii. Deletions:

• 13q14 deletion is associated with retinoblastoma.

• 18q deletion is associated with colorectal Ca.

• 3p deletion is associated with small cell Ca of lung.

• 11p13 deletion is associated with WAGR syndrome.

Tumor Suppressor Genes:

Genes that normally restrain cell growth are called tumor suppressor genes. They usually regulate at the G1 - S interphase.

Majority of inherited autosomal dominant traits are due to suppression of function of tumor suppressor genes.

Examples:

• RB gene (on chromosome 13) - retinoblastoma, osteosarcoma.

• BRCA 1 (on chromosome 17) - breast, ovary, colon, prostatic Ca.

• BRCA 2 (on chromosome 13) - breast, ovary (lower risk), male breast Ca.

• WT 1 - Wilm’s tumor, WAGR syndrome.

• NF 1 - neurofibromatosis type 1 (neurofibromas, neurofibrosarcomas, brain tumor).

• NF 2 - neurofibromatosis type 2 (acoustic neuroma, meningioma).

• p16 (CDKN2A) - melanoma, pancreatic Ca.

• p53 - sarcoma, breast, colon, lung Ca.

• APC - intestinal polyposis, colorectal Ca (loss of APC gene causes decreased degradation of b-catenin and increased WNT signaling). p53 gene:

• It is a 53 kD protein

• It is located on short arm of chromosome 17.

• It blocks cyclins and CDK and prevents cell to enter

G1 phase transiently and allows DNA repair.

• The wild type is normal and acts as a tumor supressor gene.

• p53 gene plays a major function in –

1. Antiproliferative effect

2. DNA repair

3. Apoptosis

That is why it is called ‘guardian of genomes’. Mutations in p53 gene causes Li-Fraumeni syndrome

where affected individuals may develop a variety of sarcomas, brain tumors and leukemia.

Mutations in p53 gene are the most common genetic alteration in human cancer.

DNA Repair Genes

i. Hereditary nonpolyposis colon cancer (HNPCC or Lynch’s syndrome): due to mutation of one of four

DNA mismatch repair genes.

ii. Autosomal recessive disorders:

• Xeroderma pigmentosa - nucleotide excision repair defect.

• Ataxia telangiectasia - mutation of ATM protein.

• Bloom syndrome.

• Fanconi’s anemia.

iii. BRCA 1 and BRCA 2 genes: defective repair of double stranded break.

Genes Regulating Apoptosis

Genes that promote apoptosis:

• p53, BAD, BAX, BID.

• All these genes favor cytochrome C release and promote apoptosis.

Genes that inhibit apoptosis:

• BCL 2 and BCL-XL.

• They prevent release of cytochrome C.

CARCINOGENESIS

Chemical Carcinogens

1. Alkylating agents such as anticancer drugs.

2. Acylating agents.

3. Aromatic hydrocarbons.

4. Aromatic amines (azo dyes) - bladder Ca.

5. Others-

– Vinyl chloride - liver Ca (angiosarcoma).

– Asbestos - Ca lung, pleura (mesothelioma) and peritoneum.

– Arsenic - Ca lung, skin.

– Benzene - acute myelocytic leukemia.

Hormones

1. Androgens - prostatic Ca.

2. Diethylstilbestrol (prenatal exposure) - vaginal Ca (clear cell Ca) in female offspring.

3. Estrogen - carcinoma endometrium, liver (adenoma), breast.

Viruses:

1. Human T cell lymphotropic virus type 1 (HTL V 1)- adult T cell leukemia/lymphoma.

2. Human papilloma virus (HPV) - benign squamous papillomas (warts), squamous cell Ca of cervix and

anal canal, perianal, vulvar and penile Ca.

3. EB virus - Burkitt’s lymphoma, nasopharyngeal Ca.

4. Hepatitis B and C virus - liver Ca.

5. HIV - non-Hodgkin’s lymphoma, Kaposi’s sarcoma, squamous cell Ca.

Other Microorganisms

1. H. pylori - gastric Ca.

2. Schistosoma - urinary bladder Ca (squamous cell type).

Radiation

1. Acute and chronic myelocytic leukemia.

2. Papillary Ca thyroid in those exposed during infancy and childhood to head and neck irradiation.

CLINICAL FEATURES OF NEOPLASIA

Cancer Cachexia

-It is the combination of asthenia (emaciation) and anorexia

-seen in patients with advanced cancer.

-Mediators: Cachectin or tumor necrosis factor (TNF) and IL-1 liberated by activated macrophages.

Paraneoplastic Syndromes:

Paraneoplastic syndromes are seen in 10-15 percent of patients with cancer. They may represent the earliest manifestation of an occult neoplasm.

Endocrinal syndromes:

• Hypercalcemia – seen in squamous cell carcinoma of lung, breast Ca, renal cell Ca, bladder Ca.

Cause – PTH-related protein, TGFa, vitamin D.

• Cushing’s syndrome – seen in small cell Ca of lung, pancreatic Ca. Cause – ACTH.

• SIADH – seen in small cell Ca of lung, head and neck tumors. Cause – AVP and ANP.

• Carcinoid syndrome – seen in bronchial carcinoid (most common), pancreatic Ca, gastric Ca. Cause – serotonin, bradykinin, histamine.

• Polycythemia – seen in renal cell Ca, cerebellar hemangioblastoma, hepatocellular Ca. Cause – erythropoietin.

• Acromegaly – seen in carcinoid tumors, small cell of lung.

Hematological syndromes:

• Superficial thrombophlebitis or peripheral vascular thrombosis – seen in pancreatic Ca (Trousseau’s sign), GI tract Ca, breast Ca, lung Ca.

• Non-bacterial thrombotic endocarditis.

Neurological syndromes:

Central nervous system –

• Progressive multifocal encephalopathy – seen in small cell Ca of lung.

• Subacute cortical cerebellar degeneration – seen in small cell Ca of lung.

• Opsoclonus-myoclonus – seen in bronchial Ca.

Peripheral nerves –

• G-B syndrome – seen in Hodgkin’s lymphoma.

• Chronic demyelinating polyneuropathy.

Neuromuscular junction –

• Lambert-Eaton syndrome – seen in small cell Ca of lung.

• Myasthenia gravis – seen in thymoma.

Bone and soft tissue:

• Hypertrophic osteoarthropathy – seen in non-small cell Ca of lung.

• Clubbing – seen in non-small cell Ca of lung.

Metabolic:

• Hyperglycemia – seen in fibrosarcoma, liposarcoma and other sarcomas, hepatocellular Ca.

Note: Paraneoplastic syndromes associated with thymoma:

1. Hypogammaglobulinemia

2. Pure red cell aplasia

3. Myasthenia gravis

4. Grave’s disease

5. Pernicious anemia

6. Polymyositis.

GRADING AND STAGING

Grading

Grading is done on the basis of:

1. Grading of anaplasia (cell differentiation) and

2. Rate of growth.

Broder’s grading of squamous cell carcinoma:

Grade I: Well-differentiated (< 25% anaplastic cells).

Grade II : Moderately differentiated (25-50% anaplastic cells).

Grade III: Moderately differentiated (50-75% anaplastic cells).

Grade IV: Poorly differentiated (>75% anaplastic cells).

Staging

Staging is done on the basis of:

1. Primary tumor (size) - T

2. Lymph node involvement - N

3. Metastasis - M

Staging is based on clinical and radiological examination - clinicoradiological.

DIAGNOSIS OF TUMORS

Tumor Markers

Use of tumor markers:

1. Tumor markers are useful to assess the response to treatment.

2. For detection of recurrence after excision, e.g. CEA after colonic resection.

Exfoliative Cytology

It is useful for detection of Ca cervix, endometrium, lung, urinary bladder, prostrate, stomach.

Fine Needle Aspiration Cytology

FNAC is useful for detection of ca breast, thyroid, lymph nodes and salivary glands. FNA needle size is 22-26G.

Immunohistology:

Immunohistology is used for detection of –

1. Intermediate filaments –

– Cytokeratin - carcinoma (undifferentiated).

– Vimentin – sarcomas.

– Desmin – sarcomas (myogenic tumors).

2. Prostrate specific antigen.

3. Estrogen receptors and Her2/neu.

Flow Cytometry

Flow cytometry is used for –

1. Classification of leukemia and lymphomas on the basis

of CDs.

2. Assessment of DNA content (ploidy) of tumor cells.

CANCER THERAPY

Surgery

Uses of surgery:

1. Diagnosis - biopsy.

2. Staging - e.g. exploratory laparotomy for staging of Hodgkin’s lymphoma.

3. Treatment.

Aims of therapeutic surgery:

i. Resection of metastatic disease with the intent to cure.

ii. For palliation of advanced disease.

iii. To achieve cytoreduction when complete excision in not possible, e.g. in Wilms’ tumor.

iv. Reconstruction after definitive surgery, e.g. breast reconstruction.

v. Prevention - e.g. colectomy in patients with familial polyposis coli.

Radiotherapy

Physical characteristics:

• Ionizing radiation:

a. Electromagnetic (photons)-

They have the highest penetrating potential.

1. X-ray: Produced by electron-level transition within the atom.

2. Gamma rays: Produced by radioactive decay, typically from cobalt-60, cesium-137 and radium-226.

b. Particles-

1. Electron - electron beam therapy is used for skin cancers.

2. Proton.

3. Neutron.

4. Alpha particle - produced by helium atom.

• Unit of radiation:

Gray (Gy) - 1 Gy is the absorption of 1 joule of energy per kg of tissue.

1 Gy = 100 rad.

Biological characteristics:

• Mechanism of action:

Photons act by dislodging orbital electrons of the tissues through which they pass.

I

This collision produces a fast electron (Compton effect)

I

This ionizes molecules along its path producing secondary electrons and free hydroxyl (OH) radicals

I

Local cellular damage, especially of DNA

• DNA is the primary target for radiation-induced cell death. The damage caused to DNA is double-strand

break.

• Cells are most sensitive to radiation at G2 - M interface (mostly G2).

• Sensitivity to radiation:

– Most radiosensitive tissue is bone marrow (othersintestinal mucosa and skin).

– Least radiosensitive tissue is the nervous tissue.

– Most radiosensitive blood cells are lymphocytes.

Therapy:

• Types:

a. External beam therapy or teletherapy - radiation

delivered from a source outside the body.

b. Brachytherapyi.

Interstitial brachytherapy -

Source: Most commonly used metal is iridium- 192.

Use: Commonly used in the treatment for Ca cervix.

ii. Intracavitary brachytherapy – Source – 32P

Use: early ovarian cancer.

• Isotopes used in brachytherapy:

1. Cesmium-137

2. Gold-198

3. Cobalt-60 - half-life 5.26 years.

4. lridium-192

5. Radium-226 - half-life 1640 years (longest halflife).

• Use: Radiotherapy is used as a sole modality of treatment in highly radio-sensitive tumors like -

1. Limited stage Hodgkin’s lymphoma.

2. Some non-Hodgkin’s lymphomas.

3. Seminoma testis.

4. Head and neck cancer.

5. Ewing’s sarcoma.

6. Medulloblastoma.

• Complications:

a. Stochastic effects - not related to dose, e.g. leukemia (secondary), solid tumors.

b. Non-stochastic effects - dose related, e.g. cataracts, sterility.

c. Acute radiation sickness - at doses above 100 rem.

They include -

Hematopoietic syndrome - bone marrow suppression.

GI syndrome - nausea, vomiting.

CNS, CVS syndromes.

d. Long-term effects -

Skin - erythema (most common).

CVS - asymptomatic pericardial effusion (most common).

• Toxic doses:

Minimum lethal dose is about 200 rem. Some selected doses for organ damage –

– Kidney - 2500 rad.

– Liver - 4000 rad.

– Ovary - 2300 rad.

• Radiosensitizing agents:

1. 5-fluorouracil

2. Hydroxyurea

3. BUDR

4. Cisplatin

5. Actinomycin D

6. O2

7. Metronidazole.

• Radioprotecting agent

Amifostil.

Chemotherapy

Chemotherapeutic agents:

I. Alkylating agents:

1. Busulfan

2. Cyclophosphamide, Ifosfamide

3. Chlorambucil

4. Cisplatin

5. Melphalan

6. Nitrogen mustard, nitrosoureas

7. Thiotepa

II. Antimetabolites:

a. Pyrimidine analogues

1. Cytarabine

2. 5-Fluorouracil (5FU)

3. Gemcitabine

b. Purine analogues

1. Cladirabine

2. Fludarabine

3. Pentostatin

4. 6-mercaptopurine

5. Azathioprine

c. Folate antagonist: Methotrexate

d. Others: Hydroxyurea

III. Topoisomerase inhibitors:

a. Anthracyclines

1. Daunorubicin

2. Doxorubicin

b. Epipodophyllotoxins: Etoposide

IV. Plant alkaloids:

a. Taxanes: Paclitaxel

b. Vincas

1. Vinblastine

2. Vincristine

V. Antibiotics:

1. Bleomycin

2. Mitomycin C

VI. Miscellaneous:

1. Dacarbazine

2. L-asparaginase

3. Procarbazine.

Alkylating Agents

Mechanism of action:

They produce carbonium ion ® binds to guanine residues in DNA ® cross linking/abnormal base pairing/scission of DNA strand.

Side effects:

1. Azoospermia and male infertility.

2. Secondary leukemia.

3. Myelosuppression - most common.

CHEMOTHERAPEUTIC AGENTS:

ANTIMETABOLITES:

Vinca Alkaloids

Mechanism of action: They inhibit mitosis by binding to

tubulin; cause metaphase arrest.

Drugs:

• Vincristine –

Indication – ALL, side effects – peripheral neuropathy, alopecia.

• Vinblastine –

Indication – bladder Ca.

• Taxanes –

Indication – bladder Ca.

Topoisomerase Inhibitors

Mechanism of action: Topoisomerase II inhibitor.

Side effects: Cardiomyopathy, bone marrow suppression.

Drugs:

• Daunorubicin –

Indication – induction of remission in AML.

Side effects – cardiomyopathy.

• Doxorubicin (adriamycin) –

Indication – solid tumors like thyroid Ca, leiomyosarcoma.

Side effects – cardiomyopathy, retinal pigmentation.

Note: Mitroxantrone is a new doxorubicin analogue with less cardiotoxicity.

Antibiotics

Drugs:

• Bleomycin – Side effects – pulmonary fibrosis, nonischemic heart pain.

• Mitomycin C – Side effects – renal failure with microangiopathic anemia (HUS).

• Actinomycin D – Indication – Wilms’ tumor, rhabdomyosarcoma, methotrexate resistant

choriocarcinoma.

Others

Drugs:

• L-asparaginase – Side effects – liver damage, pancreatitis, CNS damage.

• Cisplatin – Side effects – emesis (most potent emetic), acute tubular necrosis – most common toxicity (most nephrotoxic chemotherapeutic agent), deafness, peripheral neuropathy, least bone marrow suppression.

Response of tumors to chemotherapy:

a. Curable by chemotherapy -

1. Acute leukemia - ALL and AML.

2. Lymphomas - Hodgkin’s and few non-Hodgkin’s lymphomas.

3. Carcinomas -

i. Testicular Ca

ii. Gestational trophoblastic Ca (choriocarcinoma)

iii. Wilms’ tumor

iv. Neuroblastoma

4. Sarcomas -

i. Ewing’s sarcoma

ii. Rhabdomyosarcoma

iii. Osteosarcoma

b. Chemotherapy has significant activity in

1. Chronic leukemias

2. Hairy cell leukemia

3. Carcinomas -

i. Small cell Ca of lung

ii. Breast, bladder and anal canal Ca

c. Minor activity -

1. Cervical Ca

2. Melanoma

Combination Therapy

Surgery + chemotherapy:

Neoadjuvant chemotherapy:

• It refers to the administration of chemotherapy before definite surgery.

• Used in Ca breast, lung, esophagus and osteosarcoma.

Surgery followed by chemotherapy:

• Used in Wilms’ tumor.

Chemoradiation: It is the treatment of choice for squamous cell carcinoma of anal canal.

Hormone Therapy

Hormone responsive tumors are –

1. Breast Ca –

i. Estrogen – diethylstilbestrol, estradiol.

ii. Antiestrogens – tamoxifen.

iii. Progestins – medroxyprogesterone acetate, megestrol acetate.

iv. Aromatase inhibitor – aminoglutethimide (medical castration).

2. Endometrial carcinoma - progestins.

3. Prostatic carcinoma -

i. Antiandrogens - Flutamide.

ii. GnRH agonist - Leuprolide

4. Carcinoid tumors (metastatic) –

Somatostatin analogue - Octreotide.

Biological Therapy

Interferons: Interferon a is used in the treatment of CML, hairy cell leukemia, AIDS associated Kaposi’s sarcoma, high risk melanoma. Interleukins: IL-2 is used in metastatic renal cell Ca and

melanoma.

Supportive Care

Pain relief:

WHO ladder - rational titration of oral analgesics.

i. Mild-to-moderate pain - oral NSAIDs.

ii. Pain persists and increases - opioid like codeine or

hydrocodeine is added to above therapy.

iii. Moderate to severe pain - oral morphine.

Nausea:

Acute emesis - within 24 hours of treatment.

i. Mild-to-moderate emetogenic agents-prochlorperazine and dexamethasone.

ii. Highly emetic agents - ondansetron, ganisetron.

Delayed emesis – 1 to 7 days after treatment.

– Oral dexamethasone + metoclopramide.

Infection:

Infection is the most common cause of death in cancer patients.

• Sweet’s syndrome:

Also called febrile neutrophilic dermatitis.

Treatment is by high dose steroids.

• Typhilitis (necrotizing colitis):

Almost always seen in neutropenic patients after chemotherapy.

Treatment - broad spectrum antibiotic.

• Infectons in granulocytopenic patients:

1. Staphylococcus epidermidis

2. Staphylococcus aureus

3. Streptococcus viridans

4. E. coli

5. Klebsiella

6. Pseudomonas

7. Candida albicans

Depression:

• Most common psychiatric manifestation in cancer patients is depression.

• Treatment - Fluoxetine.

SCREENING FOR CANCER:

TUMOR RELATED EMERGENCIES:

Tumor Lysis Syndrome

Characterized by:

• Hyperuricemia, hyperkalemia, hyperphosphatemia, lactic acidosis and hypocalcemia.

• It is caused by mass destruction of a large number of neoplastic cells especially during treatment of Burkitt’s lymphoma, ALL etc.

• It often leads to acute renal failure.

Superior Vena Cava Syndrome

Cause:

1. Lung cancer - small cell Ca and squamous cell Ca

- most common cause.

2. Lymphoma.

3. Metastatic tumors to mediastinum, e.g. testicular and breast Ca.

Others

Structural:

1. Spinal cord compression

2. Pericardial effusion and tamponade

3. Intestinal or urinary obstruction

4. Increased ICT.

Metabolic:

1. Hypoglycemia

2. Hypercalcemia

3. SIADH

4. Lactic acidosis

5. Adrenal insufficiency.

SKIN TUMORS:

VASCULAR MALFORMATIONS

Hemangioma

• It is the most common congenital malformation (hamartoma).

• Most commonly seen in skin and subcutaneous tissues, but may occur elsewhere in the body (liver, lung, brain, etc.).

Capillary Hemangioma

Strawberry hemangioma: Child is normal at birth. A red mark is noticed at 1-3 months after birth. It increases in size from 3 months up to 1 year. After 1 year, it starts to regress and complete involution occurs within 9 years.

Systemic associations:

i. Kasabach-Merritt syndrome - disseminated intravascular coagulation, thrombocytopenia.

ii. Maffuci’s syndrome – dyschondroplasia.

Treatment: Masterly inactivity.

Port Wine Stain (Naevus flammens)

Present since birth and persists for life.

Site: most common on face and scalp.

Systemic associations: Sturge-Weber syndrome.

Treatment: Pulsed tunable dye laser (argon).

Cavernous Hemangioma

• Present since birth with no tendency for spontaneous involution.

• Consists of multiple venous channels.

Site: face, cheek, ears, lips, tongue (others -liver, kidney and brain).

Glomus Tumor

Benign tumors that differentiate towards modified smooth

muscle cells called glomus cells.

Origin: It arises from arterial portion of the glomus body (Sucquet-Hoyer canal) which is an arteriovenous shunt in the dermis that contributes to temperature regulation.

Site: Most commonly the subungual areas of fingers and toes.

Treatment: Surgical excision.

NAEVI

A naevus is a hamartoma of melanocytes.

Pathology

In normal skin melanocytes appear as clear cells in the basal layer of the epidermis. They may increase in number to form benign pigmented naevi (moles) which include:

i. Lentigo - within basal layer of epidermis.

ii. Junctional - localized aggregation projecting into the dermis. They are most likely to turn malignant.

iii. Dermal - entirely within the dermis.

iv. Compound - features of both junctional and dermal naevi present.

Types

1. Congenital naevi: They are darkly pigmented with hairy or papillary appearance. They may turn malignant even during childhood.

2. Naevi appearing in childhood and adolescence: They are very common, usually junctional or compound type and may turn malignant.

3. Blue naevi: They are dermal naevi, most commonly on face dorsum of hands and feet and over the sacrum (Mongolian spot). Malignant change is rare.

4. Dysplastic naevi: They occur sporadically or in a familial form (autosomal dominant). They occur in both sunexposed and non-exposed areas of skin. Familial form has high risk of turning malignant (maximum risk).

PREMALIGNANT LESIONS

1. Actinic keratoses (also called senile or solar keratoses):

They are scaly lesions over the sun-exposed skin. They predispose to squamous cell carcinoma.

2. Bowen’s disease: It is an intraepidermal squamous cell carcinoma that is potentially malignant.

Risk factors - exposure to sun, arsenic poisoning.

Erythroplasia of Querat is a Bowen’s disease of the glans penis seen in uncircumcised males.

3. Radiodermatitis.

4. Chronic scars - develop into Marjolin’s ulcer.

5. Sebaceous epidermal naevus.

6. Porokeratosis.

MALIGNANT LESIONS

Basal Cell Carcinoma (BCC)

BCC is the most common malignant skin tumor.

Source: It arises from the basal layer of epidermis.

Risk factors:

1. Exposure to ultraviolet rays.

2. Fair complexion.

3. Immunosuppression.

4. Ionising radiation.

5. Xeroderma pigmentosa.

6. Naevoid BCC syndrome.

7. Exposure to arsenic.

Site: More than 85 percent of these tumors occur in the

head and neck region. Most common site is the face, on the cheeks. It is also called ‘tear cancer’.

Nature: BCC grows slowly, but become locally invasive and penetrates deeper tissues - hence called ‘rodent ulcer’. It rarely metastasizes.

Histology:

• It arises from pluripotent epithelial cells of the epidermis and hair follicles.

• Basaloid cells form islands in which peripheral cells are arranged in a palisaded fashion.

Clinical feature: It presents as pearly papules with superficial dilated vessels and ulcerates later. Some tumor contains melanin pigments.

Types:

i. Noduloulcerative (most common).

ii. Superficial (mimics eczema).

iii. Pigmented (may be mistaken for melanoma).

iv. Morpheaform (plaquelike lesion with telangiectasiawith keratosis is most aggressive).

v. Keratotic (basosquamous carcinoma).

Diagnosis: Incisional biopsy.

Treatment:

1. Surgical excision is the treatment of choice.

2. Electrodessication and curettage - most commonly used method.

3. Radiotherapy - BCC is very radiosensitive.

4. Moh’s micrographic surgery (chemosurgery) - for morpheaform (fibrosing) BCC.

Squamous Cell Carcinoma (SCC)

SCC is less common than BCC but is more likely to metastasize.

Risk factors:

• SCC arises in areas with some premalignant lesions listed above.

• Risk factors are same as BCC.

• Others - burn scars, venous ulcers, Bazin’s uIcer, Marjolin’s ulcer, lupus vulgaris, osteomyelitis sinus,

albinism, lichen planus, persistent heat injury (‘Khangri’ cancer).

Histology:

• SCC arises from the malphigian or squamous cell layer of the skin.

• Characteristically, malignant cells have whorled arrangement forming ‘keratin pearls’ or horn cells.

Clinical appearance: SCC presents as an ulcerative lesion with induration and raised, everted edge.

Metastasis: Through lymphatics to regional lymph nodes which become enlarged.

Treatment: Surgical excision, radiotherapy, Moh’s

micrographic surgery.

Variants:

Marjolin’s ulcer: It is a well-differentiated SCC occurring in chronic scars (most commonly burns) or ulcers (most commonly chronic venous ulcer).

Features:

• It grows slowly as the scar is relatively avascular.

• It is painless as there are no nerves left in the scars.

• No lymph node involvement as the lymphatics are destroyed in a chronic scar.

Treatment:

• Wide excision.

• Radiotherapy should not be used.

Verrucous Carcinoma

• It is a well-differentiated SCC.

Features:

• Large, soft, wart like (papillomatous).

• Invades locally but rarely metastasizes.

• Commonly occurs on the palm and sole - carcinoma ciniculatum.

Treatment: Wide excision.

Keratoacanthoma (Molluscum sebaceum) It arises as a rapid proliferation of squamous epidermal cells over 6-8 weeks after which it regresses spontaneously.

Malignant Melanoma

It is a malignant neoplasm arising from melanocytes in the epidermis of skin (epidermal cells).

Other sites: Oral and anogenital mucosal surfaces, the esophagus, the meninges, the eyes.

Predisposing factors:

1. Exposure to sun rays.

2. Fair complexion, blonde hair, blue eyes.

3. Family history of melanoma.

4. Dysplastic naevus syndrome.

5. Giant congenital naevi.

6. Genetics - albinism, xeroderma pigmentation.

Site:

Most common sites –

• In females - lower legs.

• In males - front or back of the trunk.

• In Bantus - the sole of the foot.

Genetics:

• Mutations of CKDN2A (p16) gene are found in 50 percent of melanoma patients.

• Mutational loss of PTEN gene is also common.

• Immunohistological marker for melanoma: S-100, HMB-45.

Incidence: Incidence has increased over decades. There is no overall sex predilection.

Histology: Radial growth phase - atypical proliferation of intraepidermal melanocytes which precedes the

development of dermal invasion (vertical growth phase) in all except nodular melanoma.

Types:

1. Superficial spreading: Most common; it occurs in any part of the body.

2. Lentigo maligna: Least common and least malignant, lentigo maligna (Hutchinson’s melanotic freckle) is

precursor lesion, most common in elderly and in sunexposed areas (especially face).

3. Acral lentiginous: Most common form in darkly pigmented people; occurs on palms and soles, mucosal surfaces, in nail beds and mucocutaneous junctions; similar to lentigo maligna melanoma but with more aggressive biologic behavior, poor prognosis.

4. Nodular: most malignant having invasive growth from onset.

5. Amelanotic: worst prognosis.

Metastasis:

• Via lymphatics to the regional lymph nodes; in-transit nodules or satellite nodules may be present.

• Through blood to liver (most common distant site), lungs, brain (most commonly from melanoma of choroids).

Staging:

It depends on the depth of invasion.

• Breslow’s classification –

i. Up to papillary dermis – 0.75 mm.

ii. In reticular dermis – 0.75-1.5 mm.

iii. Up to subcutaneous layer – 1.5 mm.

• Clark’s layers –

i. Restricted to epidermis and appendages.

ii. Invading papillary dermis without filling it.

iii. Filling papillary dermis and impinging on reticular dermis.

iv. Invading reticular dermis.

v. Invading subcutaneous tissue.

Diagnosis: Any suspicious lesion should be biopsied. The recommended technique is full-thickness excisional biopsy.

Treatment: Complete surgical excision with a margin of minimum 1 cm to maximum 2 cm.

Course and prognosis:

• Regression may occur in some thin melanomas.

• The most important prognostic factor is depth of invasion or the stage of the disease.

• Women have better prognosis than men

HEAD AND NECK TUMORS

ORAL AND OROPHARYNGEAL CANCER

Oral and oropharyngeal cancers are the most common type of cancer in India. Most commonly they are squamous cell carcinoma

Premalignant Lesions:

• Definite risk of malignancy –

1. Leucoplakia – most common lesion.

2. Erythroplakia – maximum risk.

3. Chronic hyperplastic candidiasis.

• Increased incidence of malignancy –

1. Oral submucosal fibrosis.

2. Syphilitic glossitis – painless ulcer.

3. Sideropenic dysphagia.

• Oral cancer is casual or causal –

1. Oral lichen planus.

2. Discoid lupus erythematosis.

3. Dyskeratosis congenital

Leucoplakia

• Leucoplakia is the most common premalignant lesion.

• It refers to a whitish, well-differentiated mucosal patch or plaque caused by epidermal thickening or

hyperkeratosis.

• It is most commonly associated with the cancer of floor of mouth.

Risk factors:

1. Smoking and tobacco chewing.

2. Alcohol intake.

3. Chronic friction.

Treatment: On stopping tobacco use 60 percent lesions resolve spontaneously.

• Surgical excision.

Erythroplakia

• It appears as red, velvety plaque.

• Histology: Parakeratosis with severe epithelial dysplasia.

• Chance of malignancy: 17 times higher than that of leucoplakia.

• Treatment: Surgical excision.

Chronic Hyperplastic Candidiasis

• Feature: Dense chalky plaques of keratin which are thicker and more opaque than leucoplakia.

• Site: Most common sites are the oral commissures

Oral Submucosal Fibrosis

It is a progressive fibrosis deep to the mucosa of oral cavity which causes trismus and ankyloglossia.

Etiology:

• Hypersensitivity to chilly, betel nut and tobacco.

• Vitamin deficiency.

Chance of malignancy: 30-33 percent.

Treatment:

• Intralesional steroid injection.

• Surgical - excision and grafting.

Carcinoma Cheek

Most commonly squamous cell Ca.

Site: Most commonly at the commissure or along the occlusal plain to the retromolar area, the majority being situated posteriorly.

Clinical feature: It may involve three nerves-

• Hypoglossal nerve causing deviation of tongue to the same side of lesion.

• Spinal accessory nerve causing defective shrugging of shoulder.

• Cervical sympathetic chain causing Horner’s syndrome.

• Eventually it causes fungation and bleeding from major vessels - carotid blow out.

Metastasis: Ca of buccal mucosa metastasizes to submandibular and upper deep cervical lymph nodes.

Treatment:

• For early growth - radiotherapy using 192 iridium wires (brachytherapy).

• In case of mandibular involvement - wide excision of the primary lesion plus hemimandibulectomy/ segmental resection of mandible/marginal mandibulectomy.

• In case of lymph node involvement - Same side - radical neck dissection. Opposite site - functional block

dissection.

Reconstruction by using –

• Muscle flap - pectoralis major, trapezius and latissimus dorsi

• Free tissue transfer based on microvascular techniques.

• Mandible reconstruction by cortical bone graft or rib, fibula or synthetic material.

Chemotherapy - Cis-platinum

Carcinoma of Tongue

Type:

• Microscopic - most commonly squamous cell Ca.

• Gross - ulcerative or ulceroproliferative.

Site: most commonly on the middle third of the lateral margins.

Clinical feature:

• The growth is exophytic with areas of ulceration.

• Pain which radiates to neck and ears.

• Difficulty in speech and swallowing.

Metastasis: To regional lymph nodes.

Treatment:

Principle:

< 1 cm – surgery as primary therapy

Tumour > 1 cm – radiotherapy is primary therapy, surgery for salvage

Surgery:

i. Wide excision for early growth < 1 cm, tumor at the tip of tongue (primary therapy).

ii. Hemiglossectomy in growth> 1 cm (for salvage).

In case of mandible and lymph node involvement surgery same as in Ca cheek.

Note: Wide excision or hemigolssectomy + hemimandibulectomy + radical neck dissection together is called Commando operation.

Radiotherapy:

• Primary therapy for larger (> 1 cm) tumors.

• For tumors located in the anterior 2/3rd of tongueinterstitial brachytherapy.

• For tumors located in the posterior 1/3rd of tongueteletherapy.

Reconstruction:

• < 1/3rd of resection - nothing.

• 1/3rd to 2/3rd resection - radial forearm flap.

• > 2/3rd resection - pectoralis major flap.

Carcinoma of Lip

This is the most common type of oral cancer worldwide.

Site: Most commonly the vermilion border of the lower lip.

Feature: The tumor tends to spread laterally. Lymph node involvement is a late feature.

Type: Squamous cell Ca.

Metastasis: First involves upper cervical lymph node (submandibular and submental).

Treatment: Both surgery and radiotherapy are highly effective.

For lesion < 2 cm – surgical excision is the primary therapy

Tumour For lesion > 2 cm – radiotherapy is the primary therapy

Reconstruction:

• Excision of lower lip up to 1/3rd can be sutured primarily without causing microstomia.

• Excision > 1/3rd of the lip requires reconstruction.

• A full thickness loss of middle 1/3rd of upper lip is best reconstructed by - Abbey flap and Estlander’s flap (basedon labial artery).

Prognosis: Best among oral cancers.

Note: Lymph node metastasis is least common in carcinoma of hard palate.

SALIVARY GLAND NEOPLASM

Classification

a. Epithelial:

1. Adenoma

Pleomorphic adenoma - most common salivary gland tumor.

Warthin’ s tumor (adenolymphoma) - second most common.

2. Carcinoma

Mucoepidermoid Ca - most common malignancy

Adenoid cystic Ca - most aggressive.

b. Non-epithelial:

1. In children – hemangioma, lymphangioma.

2. In adults – neurofibroma, neurilemmoma.

Incidence

• Most common sites for salivary neoplasm are the parotids and most of them are benign.

• Most common salivary gland tumor in children is mucoepidermoid Ca. Parotid Gland Tumors

Pleomorphic adenoma:

• Overall most common tumor.

• It is a mixed tumor arising from epithelium and mesenchyma.

• Benign in nature, but may turn to malignant.

• Sometimes it involves only the deep lobes - dumbbell tumor.

Warthin’s tumor:

• Occurs only in the parotid glands.

• More common in males, in 6-7th decade.

• More often bilateral (10%) or multicentric.

• It is due to trapping of jugular lymph sacs in parotid during developmental period.

• It produces ‘hot spot’ in 99mTc scan.

• It does not undergo malignant change.

• It can be enucleated without the danger of recurrence.

Mucoepidermoid Ca:

• It is the most common malignant tumor of salivary glands.

• It is very low grade histologically, slowly progressive and does not involve facial nerve.

• Radical treatment often not needed.

Adenoid cystic Ca:

• It is the most aggressive salivary gland tumor.

• Characterized by relentless perineural spread along the cranial nerves and into the brain.

• Distant metastasis may occur to lungs producing cannon ball shadow.

Diagnosis of parotid gland tumors:

• CT and MRI scan - best method.

• FNAC is also useful.

Management of parotid gland tumors:

• Surgery:

1. Superficial parotidectomy for all benign tumors in superficial lobe.

2. Total parotidectomy for all benign tumors in deep lobe and dumb bell tumor.

Complication of surgery:

Frey’s syndrome:

It is due to injury to auriculo-temporal nerve wherein postganglionic parasympathetic fibres from otic ganglion become united to sympathetic nerves from the superior cervical ganglion.

Clinical features - flushing, sweating, pain and hyperesthesia in the face whenever salivation is stimulated

(e.g. during mastication).

• Radiotherapy:

Indication - Deep lobe tumors, microscopically positive margin, malignant recurrence.

Submandibular Gland Tumors

• Benign - pleomorphic adenoma is most common.

Treatment - excision of both superficial and deep lobes of the gland.

• Malignant-

Treatment - wide excision with removal of adjacent muscles, soft tissues and mandible + postoperative radiotherapy.

Complications of submandibular gland surgery: Three cranial nerves are at risk during removal of the

submandibular glands namely -

1. The mandibular branch of the facial nerve.

2. The lingual nerve.

3. The hypoglossal nerve.

Minor Salivary Glands

• Most common site of minor salivary glands is the palate (40%).

• Most common tumor of minor salivary glands is adenoid cystic carcinoma (malignant).

TUMORS OF THE LARYNX

Non-neoplastic

Vocal Nodule (singer’s nodule)

This is a fibrous thickening of the vocal cord due to epithelial hyperplasia.

Site: Most common site is the junction of anterior 1/3rd and posterior 2/3rd of the vocal cord.

Cause: speech abuse.

Clinical feature:

• More common in females

• Increasing hoarseness is the main symptom.

Treatment:

• Speech therapy - preferred method, most lesions resolve spontaneously

• Surgery - removal of nodule by micro-laryngeal technique.

Vocal Cord Polyps

• Usually unilateral at the same site as of vocal nodule.

Treatment: Microdissection and speech therapy.

Reinke’s Edema (Bilateral Diffuse Polyposis)

• Bilateral multiple polyps along the length of the vocal cord.

Cause: Collection of edema fluid in the subepithelial space of Reinke.

Treatment: Vocal cord stripping.

Contact Ulcer:

• Ulceration and granuloma formation over the vocal processes of arytenoids.

Cause: Speech abuse.

Intubation Granuloma

• Bilateral involving posterior thirds of the true cords.

Cause: Faulty intubation (most common cause of laryngeal granuloma).

Treatment: Voice rest and endoscopic removal of the granuloma.

Leucoplakia or Keratosis

• Epithelial hyperplasia involving upper surface of one or both cords.

• It is a premalignant lesion.

Treatment

• Stripping of the vocal cords.

• Biopsy and radiotherapy in case of carcinoma in situ.

Laryngocele

• It is an air-filled cystic swelling due to dilatation of the ventricular saccule.

• It is seen in glass blowers, trumpet players and weight lifters.

• An external laryngocele presents as a reducible swelling in the neck which increases in size on coughing or performing Valsalva maneuver.

Neoplastic Tumors

Benign: Squamous Papilloma

Juvenile squamous papilloma:

• Multiple.

• Viral (HPV) in origin.

• Most commonly on the true and false cords and the epiglottis.

• Not premalignant.

• Treatment - CO2 laser is the treatment of choice; removal by direct laryngoscopy under GA.

• Chance of recurrence after removal.

Adult squamous papilloma:

• Single.

• More common in male.

• Site - anterior half of vocal cord or anterior commissure.

• Premalignant.

• Treatment - CO2 laser excision.

Malignant: Carcinoma of Larynx

Etiology:

1. Smoking and alcohol.

2. Leucoplakia or keratosis of larynx.

3. Adult papilloma.

4. Viral infection - herpes simplex virus.

5. Pachyderma larynx.

Epidemiology: More common in males between 40-70 years of age.

Histology: Most commonly squamous cell Ca.

Types with features:

Diagnosis:

• Direct laryngoscopy and biopsy - diagnostic.

• CT scan is very useful to detect lymph node involvement.

Management:

Radiotherapy:

• For early supraglottic and glottic tumors in stage I and II (mobile cord, no neck node).

Surgery:

• CIS is best treated by transoral endoscopic CO2 laser.

• Total laryngectomy is indicated in:

1. T3 lesions (with cord fixed).

2. All T4 lesions.

3. Invasion of thyroid or cricoid cartilage.

4. Bilateral arytenoid involvement.

5. Transglottic Ca.

• Neck dissection - is indicated in T3 and T4 lesions (stage III), in subgottic Ca.

Chemotherapy: Chemotherapy is indicated in advanced (stage IV) cases.

Speech therapy:

• Esophageal speech.

• Artificial larynx.

• Tracheoesophageal speech.

NEOPLASMS OF LUNG

BRONCHOGENIC CARCINOMA

Bronchogenic Ca is the leading cause of death worldwide.

Epidemiology

• Male: female = 2:1 (incidence is increasing among females).

• Age of onset - most commonly between 55-65 years.

Risk factors:

1. Cigarette smoking - both active and passive.

There is dose-response relationship between the lung cancer death rate and the total amount of smoking

(expressed in ‘cigarette pack-years’). Smoking is most commonly associated with squamous cell Ca and small cell Ca. It is least associated with adenocarcinoma.

Combination of smoking and asbestos exposure greatly increases the risk

2. Chronic exposure to asbestos.

3. Others - exposure to nickel, chromium, arsenic, coaltar.

Types

1. Small cell lung Ca (SCLC)/Oat cell Ca:

• SCLC is the most malignant type.

• Bloodstream metastasis occurs early, hence not amenable to surgery.

• Treatment is by chemotherapy with or without radiotherapy.

• It is the most radiosensitive of lung cancers.

• It has the worst prognosis.

2. Non-small cell Ca: They have slow course and amenable to surgery and/ or radiotherapy.

i. Squamous cell Ca (epidermoid Ca) -

It is the most common type in India. It has the best prognosis.

ii. Adenocarcinoma including bronchoalveolar Ca -

Adenocarcinoma is the most common lung cancer nowadays worldwide.

It is also the most common type in non-smokers, women and young patients (<45 years).

iii. Large cell Ca.

Pathology

• Squamous cell Ca and SCLC usually present as central masses with endobronchial growth.

• Adenocarcinoma and large cell Ca present as peripheral nodules or masses, frequently with pleural involvement.

• Cavitation - common in epidermoid and large cell Ca.

• Bronchoalveolar Ca arises from peripheral airways and is characterized