Episode 92:  Learn the difference between carcinoma, sarcoma, mesenchymal tumors, oncogenesis, and the protooncogenes.

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NEOPLASIA

I. Nomenclature: Benign vs. malignant

A. Difference between benign and malignant cancer:

Main difference – Benign usually does not metastasize, malignant has the capacity to metastasize. Exception: B9 tumor that metastasize: invasive mole (metastasize to lungs, but goes away).

B. Overview of Neoplasia

a) MC skin cancer INVADES but does not metastasize? basal cell carcinoma.

b) MC B9 tumor in woman is MC located in which organ? Uterus – it’s a leiomyoma; tumor of smooth muscle!

c) Fibroids – smooth muscle; become very hard

d) MC B9 tumor in male (yellow) = lipoma

e) B9 tumor of glands = adenomas (ie adrenal adenoma – thin adrenal cortex b/c it is functional; it could be making cortisol, therefore suppressing ACTH, and the zone fasiculata and reticularis would undergo ATROPHY…leads to Cushing’s. If tumor secreting mineralocorticoids – it is Conn’s syndrome, causing atrophy of the zone glomerulosa (GFR – salty sweet sex)

f) Tubular adenoma = MC precursor lesion for colon cancer (looks like strawberry on a stick)

C. Carcinoma vs. sarcoma

1. Carcinoma

Malignancy of epithelial tissue (3 epithelial tissues – squamous, glandular, and transitional)

a) Squamous carcinoma – how to recognize? Little swirls of increased redness (bright red) called squamous pearls;

b) Glandular carcinoma – Round glands, with something in the middle = adenocarcinoma

c) Transitional cell carcinoma – from bladder, ureter, renal pelvis (from genital urinary tract) – all with transitional epithelium. Therefore, 3 carcinomas = squamous, adenocarcinoma, and transitional cell carcinomas.

d) Example: Malignant melanoma – first step in management? Excision (b9 version = nevus), both are derived from melanocytes. This is the most rapidly increasing cancer in the USA, not MC. They are S-100 Ag “+” tumors – aput tumors

e) Aput Tumors: S-100 Ag “+” tumors – aput tumors; aput is precursor uptake decarboxylation, meaning that they are of neurosecretory or neural crest origin. Therefore, on EM, have neurosecretory granules. S-100 Ag is used to stain things of aput origin or neural crest origin (most, not all, will take up that Ag).

Examples of aput tumors: melanoma; small cell carcinoma of the lung; bronchial carcinoid; carcinoid tumor at the tip of the appendix; neuroblastoma (secretory tumor), ie 2 y/o with tumors all over skin, and on biopsy, it is S-100 “+”, tumor was from adrenal medulla, metastasize to skin.

2. Sarcomas

Sarcomas are malignancy of MESENCHYMAL tissue (not epithelial).

  • Sarcoma of smooth muscle = leioymyosarcoma;
  • Striated muscle = rhabdomyosarcoma;
  • Fat = liposarcoma; (these are malignancies of mesenchymal tissue, while carcinoma’s are of epithelial tissue).

Examples:

a) Bone, see metaphysis, see Codman’s triangle, and sunburst appearance on x-ray b/c this tumor actually makes bone. Dx = osteogenic sarcoma (bone making sarcoma).

b) Biopsy from girl having necrotic mass coming out of her vagina, Vimentin and keratin “-“, and desmin “+”, dx? Embryonal rhabdomyosarcoma (see striation of muscle). This is the MC sarcoma of children (vagina in little girls and penis in little boys).

c) Movable mass at angle of jaw = mixed tumor (in parotid); ‘mixed’ b/c two histologically have two different types of tissue but derived from SAME cell layer (not a teratoma, which is from three cell layers),. MC overall salivary gland tumor (usually b9) = mixed tumor.

d) Teratoma = tooth, hair, derived from all three cell layers (ectoderm, mesoderm, and endoderm) Aka germ cell tumors – b/c they are totipotential, and stay midline. Ex. anterior mediastinum, or pineal gland; therefore, teratomas are germ cell, midline tumors.

e) Cystic teratoma of the ovaries: 16 y/o girl with sudden onset of RLQ pain (don’t confuse with appendicitis, Crohn’s dz, ectopic pregnancy, follicular cyst). On x-ray, see calcifications of the pelvic area! – Cystic teratoma (the calcifications can be bone or teeth). Usually develop in midline – germ cell tumor.

II. Nomenclature: Leukemia and lymphoma

MC on the boards: Auer rod from myeloblast, and hypersegmented neutrophil from B12 and folate deficiency.

A. Leukemia

Malignancy of stem cells in the BM, and they can metastasize (like all cancer ) and to lymph nodes, leading to generalized lymphadenopathy and hepatosplenomegaly. Derived from stem cells in the marrow and metastasize.

B. Malignant lymphoma

Arise from LYMPH nodes, and can metastasize anywhere, include BM. The MC site in body for lymphoma NOT developing in lymph node: stomach Most extranodal (outside lymph node) primary lymphomas occur in the stomach; H. pylori can produce these. 2nd MCC location (lymphoid organ in the GI tract) = Payer’s patches (located in the terminal ileum). MC lymphoma = follicular B cell lymphoma. This is an example of knocking off apoptosis gene -14:18 translocation of a heavy chain; when you get the translocation, B cells will make bcl-2, which inactivates apoptotic gene in the B cell, therefore, the apoptotic gene is immortal, leads to cancer.

III. Nomenclature of Trophoblastic Tumors

A. Hydatidiform mole

Presents with cluster of grapes. It manifests in the first trimester with signs of preeclampsia (HP, proteinuria, edema in the first trimester). On ultrasound, will see uterus too large for its gestational age, with a snowstorm appearance = classic complete mole; and can progress to choriocarcinoma.

B. Choriocarcinoma mole

A benign tumor of the chorionic villus; chorionic villi are lined with trophoblastic cells, including synctiotrophoblast on the outside (has contact with the blood, from which O2 is extracted); under the synctiotrophoblast is the cytotrophoblast, then have warten’s jelly in the chorionic villus, then have vessel that becomes the umbilical vein, which has the most O2 in the vessels of the fetus. So, hydatidiform mole is a B9 tumor of the WHOLE chorionic villus, and it looks like grapes b/c it’s dilated up. Choriocarcinoma is a malignancy of the lining of the chorionic villus: the synctiotrophoblast and the cytotrophoblast (not the actual chorionic villus). Which makes hormones? The syncytiotrophoblast synthesizes B-HCG and human placental lactogen (growth hormone of pregnancy – it gives aa’s and glucose from mom to baby). So, when gestationally derived, and even when they metastasize to the lungs, they respond well to chemotherapy (methotrexate, chlabucil). Therefore, these are highly malignant tumors, but go away with chemotherapy.

IV. What does the suffix “oma” mean?

Everything that end in –oma is not necessarily b9 – ie melanoma (malignant tumor of melanocytes), lymphoma (malignant tumor of lymph nodes) Also, all that ends in –oma is not necessarily a neoplasm – ie hemartoma = overgrowth of tissue that is normally present in that area. Example: A bronchial hemartoma seen lung which is b9 cartilage and a solitary coin lesion is seen in lung (also wonder if it’s a granuloma). The polyp in Peutz Jeghers syndrome is a hemartoma (not even a neoplasm), that’s why there is no increase in risk of poly cancer. Hyperplastic polyp (MC polyp in GI) is a hemartoma, it’s a B9 tissue in place it is not suppose to be (ie pancreatic tissue in the stomach) – this is called a choristoma, or heterotopic ret.

Meckel’s Diverticulum: MC complication of Meckel’s Diverticulum = bleeding from a gastric mucosa that is ulcerated, or pancreatic tissue that is ulcerated. Should gastric mucosa be in the meckel’s diverticulum? No, b/c it is in the small bowel (about 2 ft from the ileocecal valve). Hemartomas are nonneoplastic, and therefore do not have cancer producing potential.

V. Malignant Cells

Increased mitotic rate does not mean cancer. What makes mitosis malignant is having an atypical mitotic spindle (they are aneuploid and have more than the normal 46 c’somes). Key thing that determines if it is malignant is its ability to metastasize. Malignant cells usually have a longer cell cycle than the cells they derived from. How many doubling times does it take to get a tumor that can be detected clinically? 30 doubling times means that the tumor goes through the cell cycle 30 times, and a tumor of one sonometer in size is produced; 109 in mass. Malignant cells are immortal – they don’t like each other and lack adhesion; if they were stuck to each other, they would have problems infiltrating tissue. Malignant cells have simple biochemical systems, typically anaerobic metabolism, and have many enzymes such as proteases (used to break through tissue), collagenases (used to break through BM). This is what makes a malignant cell malignant.

VI. Mechanisms of Metastasis: lymphatic, hematogenous, seeding

A. Lymphatic metastasizes:

How do carcinomas usually metastasize? Lymph nodes – they drain to their regional lymph nodes; ie breast cancer goes to axillary nodes or internal mammary nodes. For colon cancer, go to nodes around them (the local lymph nodes); same with carcinoma of the esophagus. What part of the lymph node do metastases go to? Subcapsular sinus. If they can get through the lymph node, they go to the efferent lymphatics which drains into the thoracic duct, and then into the subclavian, and then they become hematogenous. Therefore, carcinoma can become hematogenous, this means that they 1st went through the lymph nodes; now, they can spread to other organs (ie bone, liver, etc). This is better than sarcoma b/c can feel the lymph nodes by clinical exam and pick up before it spreads.

B. Hematogenous metastasizes:

On the other hand, sarcomas do not like to go to lymph nodes. They go right through BV’s and are characterized by hematogenous spread, and that’s why lungs and bones are common sites of sarcomas. They don’t like to go to lymph nodes. Therefore, they are a little worse b/c they immediately go hematogenous, and do not give a clue that they are spreading. Example: have angiosarcoma of the breast; would you do a radical dissection of the axilla? No, b/c angiosarcoma does not go to the lymph nodes, therefore, do a simple mastectomy. If it is breast carcinoma, take breast and lumpectomy and local axillary lymph nodes and complete the dissection.

Exceptions:

  • Follicular carcinoma of the thyroid (thinks it’s a sarcoma) – skips lymph nodes and goes straight to BV’s, and takes the hematogenous route.
  • Renal adenocarcinoma – goes to renal veins (also determines prognosis)
  • Hepatocellular carcinoma – like to attack the vessels

In general, carcinomas 1st like to go to lymph nodes, and the have the potential to become hematogenous. Sarcomas go hematogenous, making them dangerous.

C. Seeding:

Classical Example: cancers that are in cavities and have a potential of seeding, like little malignant implants. Most ovarian cancers are surface derived cancers, therefore derived from lining around the ovary, and they seed like little implants. Therefore, easy to throw out these implants and for it to metastasize to the omentum, and into the pouch of Douglas. The pouch of Douglas is posterior to the uterus and anterior to the rectum and is felt by digital rectal exam. The pouch of Douglas is to a woman, as the prostate gland is to the man. If you do a rectal on a man, and push forward, you will feel the prostate. If you do a rectal on a woman and push forward, this is the pouch of Douglas. This is an imp area b/c it’s the most dependent area of a woman’s pelvis and many things go here – clotted blood in a rupture ectopic pregnancy, where endometrial implants go in endometriosis, and where seeding goes in ovarian cancers (pouch of Douglas). So, seeding of ovarian cancer to the omentum and can actually invade. Can also seed in the pleural cavity, for example: peripherally located lung cancer that can seed into the pleural cavity. GBM (MC primary malignancy of the brain in adults) can seed into the spinal fluid and implant into the entire spinal cord, as can a medulloblastoma in a child. So, the 3 mechanisms for metastasis are lymphatic, hematogenous, and seeding.

VII. Most Common (MC) cancers

The first question is to ask: “Is the metastasis more common than primary cancer?” In most cases, metastasis is the MC cancer in an organ (not a primary cancer). Exception: renal adenocarcinoma (which is more common than metastasis to it).

Lung: MC cancer is metastasis from the breast cancer. Therefore, MC cancer in the lung is breast cancer. Therefore, women are more likely to get lung cancer.

Bone: MC cancer in bone is metastasis (not multiple myeloma or osteogenic sarcoma). MC cancer that metastasis to bone is breast cancer b/c the batsom system; it is a venous complex going from base of the  skull down to the sacrum, and has no valves in it. The little tributaries communicate with the vena cava and also go right into the vertebral bodies. Then they collect around the spinal cord and go up. For  example: a lady has a little plug of tumor in the intercostal vein, and bends down to pick up something off the ground, which causes the cancer to be dislodged from the vein to the vena cava to the batson plexus  in the vertebral bodies, and 3 months later she is complaining of lower back pain. All of a sudden, she is stage four cancer. MC bone metastasis TO the vertebral column. 2nd MC is the head of the femur (in a  woman, this is due to breast cancer – ie breast cancer in head of femur, when they thought it was degenerative arthritis).

MC organ metastasis to = lymph nodes (carcinomas are more common than sarcomas, and carcinomas like to go to lymph nodes, meaning it is the MC metastasis to)

Liver: MC cancer of liver = metastasis from lung into liver (not colon – colon is 2nd b/c portal vein drainage).

Testicular Cancer: Where would testicular cancer metastasize first? Paraortic lymph nodes; NOT the inguinal lymph nodes b/c it derived from the abdomen, and then descended. Example: seminoma (malignant) will metastasize to paraortic nodes b/c that is where it came from.

Left supraclavicular node, aka Virchow’s node. The MC primary metastasize to Virchow’s nodes = stomach cancer! There is a mass in the left supraclavicular nodes along with wt loss and epigastric distress.

Bone: Best test looking for bone mets? Radionucleide scan. Example: everywhere that is black in a woman is mets from breast cancer. MC bone metastasis to = vertebral column! Mets that are lytic (break bone down) and mets that are blastic (mets go into bone and induce osteoblastic response).

A. Lytic Metastasis: For lytic mets, they can lead to pathologic fractures and hypercalcemia.

Multiple myeloma with punched out lesions b/c all malignant plasma cells have IL-1 in them (aka osteoclast activating factor)

B. Blastic metastasis:

For blastic mets, alkaline phosphatase will be elevated. Example: this is a male with prostate cancer (prostate cancer is blastic!); it is making bone and will release alkaline phosphatase

MC location for mets = lumbar vertebrae. Example: 80 y/o man with lower lumbar pain with pt tenderness; what is first step in management? Digital rectal exam would be the first thing to do b/c this would be stage four dz, and the prostate is palpable; so, this is the easiest and cheapest test (not PSA, or radionucleide bone scan to make sure its not mets).

  • Lytic mets – have lucency (absence of bone) – ie vertebrae collapse
  • Blastic mets – have entity on x ray

If you see any specimen with multiple lesions in it, it is METS (primary cancers are confined to one area of the organ).

  • MC cancer brain = mets
  • MC cancer killer in men and women = lung cancer
  • MC primary site for cancer in brain = lung
  • MC cancer in lung = mets from breast
  • MC mets to adrenal = lung – therefore they always do a CT of the hilar lymph nodes, and adrenal glands in the staging of all lung cancers.
  • Bone = blastic, therefore the most likely cause is prostate cancer.

VIII. Stains and EM used to help diagnose disease:

Stains: desmin – good stain for muscle – ie used for rhabdomyosarcoma. Stain for keratin (most carcinomas have keratin in it, therefore stain for that). Stains help ID diff types of tumors, such as Vimentin- mesenchymal cells.

EM: Used when nothing else helps:

  • Auput tumor – see neurosecretory granules.
  • Histiocyte tumor (ie histiocytosis X) – see birbeck granules, with CD 1
  • Muscle – see actin and myosin filaments
  • Vascular malignancy – Wibble palad bodies (have vWF in them); they are of endothelial origin

IX. Oncogenesis:

A. Big picture of oncogenesis

1) Initiation (mutation – ie within the cell cycle)

2) Promotion (where multiple copies of the mutation are made)

3) Progression (sub-specializing) diff types of cancer cells have diff func – malignant cells with one purpose – to kill you. Diff cells with diff func: some stay where they are; some invade (and are given special things for it to be able to invade); some have special receptors to home in to specific organs; some resist chemo, some spread, some make enzymes to penetrate tissues.

2 sets of genes involved with cancer:

1) Involved in growth process (cell cycle related)

2) Genes that suppress things (suppressor genes)

B. Things that are involved in trying to get a cell to divide:

GF’s (epidermal derived GF); protooncogenes – normal genes, which haven’t been activated, and have normal function. When they have been activated, they become oncogenes, which are bad and become cancerous. Certain protooncogenes code for growth factors – ie sis, whose func is to make GF’s. All GF’s have to hook into a receptor; therefore certain protooncogenes whose main job is to make receptors – ie erb-2 = breast cancer, which codes for a receptor and ret = seen in MEN syndrome (MEN I and IIa and IIb). We have to send a message to the nucleus, so have another set of genes, whose job is to send the message; some located in the cell membrane. Example: ras protooncogene sends a GTP (a phosphorylated protein message), therefore it’s a cell membrane located messenger system.

Another example: abl protooncogene which lives in the cytosol, very close to the nuclear membrane and also is involved in messages. Who is the messenger sent to? The message is sent to a group of  protooncogenes in the nucleus. Once that message is sent to them, there is stimulation of nuclear transcription of that message; in other words, the cell divides and makes whatever it is supposed to make.

Classic protooncogenes there are – myc protooncogenes = n-myc and c-myc (n-myc is for neuroblastoma, and c-myc is for Burkitts lymphoma).


So, the protooncogenes involved make GF’s, growth factor receptors; send messages (which are often phosphorylated proteins). Example – ie insulin hooks into receptor on adipose and activated tyrosine kinase (located right on the receptor), which makes a phosphorylated product, goes to the nucleus (to divide), and also goes to GA and attaches to GLUT-4, which is made from golgi apparatus, goes to the cell membrane and there’s the receptor for glucose.

Therefore the messages go to nuclear transcribers in the nucleus and these are myc oncogenes.

The suppressor genes are controlling the cell cycle. The 2 most imp are Rb suppressor gene and p53 suppressor gene. Normally, they control the cell cycle and do not let cell cycle progress to S phase. If unregulated, cells go to S phase and become ‘initiated’.

How do we initiate a cell? Mutations–mechanisms: usually a point mutation ie substitutes aa for e/o. The p53 suppressor gene and the ras oncogenes is a pt mut’n. All suppressor genes are due to pt mut’n. Other mutations include:

  • Amplification – make multiple copies (erb-2 is an amplification system) and
  • Translocation (putting in another place and can’t go back) classic: CML translocation of abl (non receptor tyrosine kinase activity from c’some 9 to 22. On c’some 22, it fuses on a cluster region of the fusion gene, and b/c of the tyrosine kinase activity, it sends a message and stem cells keep dividing; aka Philly c’some.

Another example: Cancer assoc with Epstein Barr virus – translocation of myc nuclear transcriber gene from c’some 8 and puts it on c’some 14; it doesn’t like it there, so it leads to Burkitts lymphoma. Receptor for Epstein barr virus on all B cells – CD 21; when it hooks on to receptor, it causes B cells to become plasma cells and make Ab (therefore, this virus is an amazing stimulating of Ab synthesis, as is the CMV virus.) The more a cell divides, the worse it is if something happens to it; ie EBV virus , 8,14 translocation of myc oncogenes from 8 to 14 and all of a sudden you are making multiple copies, and leads to lymphoma (greater chance that you do something, the greater chance that you will screw up).

Follicular B cell lymphoma – translocation of 14:18; inactivation of suppressor gene.

Translocation 15:17 = acute progranulocytic leukemia; Rx – Vit A (retinoic acid) b/c it matures the blasts, therefore the malignant cell becomes B9.


C. Suppressor genes

Suppressor genes suppress, therefore if knocked off, whatever they were suppressing keeps on going. Key suppressor genes: p53, Rb gene, adenomatos polyposis coli (familial polyposis), neurofibromatosis, wilm’s tumor gene, brca1 and 2 (both involved in DNA repair, and one is on c’some 13 while the other is on c’some 17); brca1 can be breast cancer, ovarian cancer, or others; brca2 is TOTALLY related to breast cancer. Only 15% of breast cancers have genetic assoc with these genes, therefore, most cases are sporadic.

X. Common things that predispose mutations:

Protooncogenes are activated, while suppressor genes are inactivated 3 main ways this occurs: chemicals, viruses, radiation.

A. Chemicals:

Which of the three is most common in initiating a cell producing a mutation? Chemicals – smoking = MCC death in USA due to polycyclic hydrocarbons. By itself, smoking is MC than virally induced or radiation induced cancers. Smoking causes lung cancer, squamous cancer of the mouth, larynx, lung, pancreas, bladder, and if it’s not the #1 cause, it’s often #2, such leukemias, cervical ca, and colon.

  • MCC papillary tumor of the bladder = transitional cancer (smoking)
  • What if you worked in a dye industry? Aniline
  • What if you had Wegener’s granulomatosis, put on a drug and got hematuria, did cytology and saw cells, what drug is pt on? Cyclophosphamide (hemorrhagic cystitis); prevent with mesna, and can cause transitional cell carcinoma (therefore acts as a carcinogen!)
  • Lung cancer – MCC = polycyclic hydrocarbons from smoke; most often assoc with smoking is small cell and squamous.

B. Viruses:

Virus assoc cancer: a virus with nonpruritic raised red lesions. Dx? Kaposi’s sarcoma (due to HHV 8) Burkitts; due to Epstein barr varies which also causes nasopharyngeal carcinoma, esp. in Chinese liver – Hepatocellular carcinoma due to hepatitis B from Asia; also due to a mold – aflatoxin B; combo of hep B, cirrhosis, plus aflatoxin makes is common in Asia; can also be caused by hep C HIV is assoc with primary CNS lymphoma. They will ask: the rapidly increasing incidence of primary CNS lymphoma can be directly attributed to what? HIV

HPV causes squamous cancer of cervix, vagina, and vulva, and anus of homosexuals due to unprotected intercourse; due to HPV 16, 18, 31. This virus causes anal squamous cell carcinoma in homosexuals. The virus works by making two proteins, E6 which knocks off p53, while E7 knocks of Rb.

C. Radiation

MC cancer assoc with radiation = leukemia

MC leukemia assoc with radiation = CML (9, 22 translocation of abl)

Papillary carcinoma of thyroid is also commonly seen as a result of radiation.

  • Example: pt had radiation in head and neck, and has nontender nodular masses in cervical region = metastatic papillary carcinoma of the thyroid related to ionizing radiation.
  • Example: osteogenic sarcoma
  • Example: which medical profession is most subject to leukemia? Radiologist, leukemias are commonly caused by radiation and it’s the radiologist that are commonly involved with this.
  • Example: if you have Jacob Crutzfelt dz, what dr are you? Neuro-Pathologist (bc work with brains and prions)
  • Example: basal cell carcinoma (pic), multifocal; this is non ionizing radiation (ionizing radiation is the bad stuff). This is UV B light (b is bad); UV A light is for fluorescing superficial dermatophytes (wood’s light) or green’s patches in tuberous sclerosis (therefore used by dermatologists), aka black light. UV B light is what you protect yourself from to prevent getting skin cancers (basal cell = MC, then squamous cell, then melanoma). UV D = thymidine dimmers.
  • Example: lesion in sun exposed areas that is scraped off and grows back – aka solar (actinc) keratosis; it predisposes to squamous dysplasia. Arsenic is a metal that is associated with  skin cancer. Bangladesh has bad water supply which contains arsenic, therefore they have a high number of squamous skin cancers, and with time it can lead to cancer of the lung, and angiosarcoma of the liver.
  • Example: kid with white eye reflex – retinoblastoma – c’some 13. This dz is sporadic and familial. It takes the sporadic dz 2 separate mut’n to become retinoblastoma (knock off on each c’some 13). If it is familial, which is Autosomal dominant it takes just one mut’n, b/c you are born with one already inactivated, therefore only need one more mutation on the other chromosome in order to develop retinoblastoma. White eye reflex is not MC due to retinoblastoma – the MCC is congenital cataract (which can be due to CMV, rubella, or any congenital infections). Which drug predisposes to cataracts? Corticosteroids; therefore a person with Cushing’s dz may develop cataracts.

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