In modern usage, a TUMOR/NEOPLASM (the words are exact synonyms) may be thought of as an attempt by the body under some

stimulus to make some new sort of organ. It develops in the wrong shape, in the wrong place, and it persists after the initiating stimulus is removed. Tumors are LIKE organs: All have parenchyma and stroma. Cells usually look similar to cells in the organ where the tumor arose. Cells will continue to perform some of the functions of the parent organ and express most of the same proteins. Tumors are DIFFERENT from organs: They don't contribute to the homeostasis of the body. They usually grow more rapidly than surrounding tissues. Some benign and all malignant tumors never cease to grow. When a benign tumor "ceases to grow", it simply means that the number of cells dying off equals the number of new cells. Since the genome of malignant tumors is by definition destabilized, more-and-more activelyproliferating clones of cells appear, so continued growth is inevitable. "Spontaneous regression" of a cancer (i.e., massive shrinkage or disappearance without adequate therapy to explain it) is much-discussed phenomenon that occasionally happens. More often than not, the cancer comes back after a few months. The phenomenon is fairly well known in CNS lymphomas and melanomas (areas of "partial regression" are often seen in the primary; it's a good prognostic indicator one metastasized melanoma in 400 will spontaneously regress Melanoma the basis (especially in the latter) is almost certainly an immune attack. If there are metastases, they may or may not also disappear. Spontaneous remissions of other cancers are less common. There are perhaps fifty reported hepatocellular carcinomas that "self-cured"; how many stayed cured is unknown Primary melanomas and primary testicular cancers are famous for occasionally vanishing, leaving their metastases behind. Non-small-cell lung cancer sometimes spontaneous regresses completely on its own, but of course comes back ( A few pediatric cancers, notably neuroblastoma, often self-cure. They all arise from cells that are programmed to die anyway as the child gets older. More about this later. Testicular carcinomas often present as metastases, with the primary no longer detectable except perhaps as a scar -- take it anyway as there's likely to be viable cancer). * You may hear more in the future about the "abscopal" / "distant bystander effect", in which local treatment (radiation or otherwise) results in regression of distant tumor masses "due to immunity". Controversial. See Cancer Treatment Reviews

 Benign tumors regress by mechanisms that are better-understood. Uterine leiomyomas, being estrogen-dependent, regress at menopause. Hemangiomas undergo thrombosis and self-destruct; especially in children, the "leave it alone" approach is often best Most tumors show some derangement of histologic architecture. Malignant tumors are locally invasive and have metastatic potential. We have already learned a few essential terms:

Anaplasia: Ugly cells. A marker for cancer or pre-cancer. Neoplasia: A new, useless organ produced by cells bearing mutations. Dysplasia: Ugly cells in an epithelium, without invasion. Near-synonyms are "carcinoma in situ", "intraepithelial neoplasia", "incipient neoplasia", "precancer", and (most popular today) "intraepithelial lesion". Now learn these terms: Malignant: A neoplasm that will invade the surround tissue. A synonym for "malignant neoplasm" is "cancer". Most types of cancer will also eventually spread to remote sites; hence the importance of timely detection and cure. Benign: (1) A neoplasm that will compress but not invade the surrounding tissue. (2) Loosely, any non-cancer, non-precancer diagnosis.

Characteristics of BENIGN ("good") tumors:

Cells resemble normal cells and tumor architecture resembles that of the parent organ ("well-differentiated"). Usually are spherical and compress the surrounding tissues (giving rise to the appearance of a "capsule"). Grow slowly and have few mitotic figures. Never metastasize. (If it metastasizes, it has turned malignant.) Benign tumors may cause problems: The tumor may secrete something in excess (typically a hormone). The tumor may compress surrounding structures. {00221} meningioma compressing brain {01855} craniopharyngioma

Characteristics of MALIGNANT ("bad") tumors

1)Malignant tumors generally grow more rapidly than benign tumors. malignant tumor grows as rapidly as an embryo, bone marrow or intestinal epithelium. the more abnormal a tumor appears under the microscope, the more rapidly it grows and the worse the patient's prognosis. 2)Cells differ morphologically and functionally from normal cells, and tumor architecture is less organized than that of parent tissue. 3)Tumor cells are locally invasive; the tumor grows into the surrounding tissue and destroys it. such tumors called karkinoma after karkinos, For some reason, cartilage, tendon, and elastic tissue almost never get invaded. {08845} cholangiocarcinoma invading around a nerve ("perineural invasion") 4)The tumor will eventually metastasize, spreading to another site remote from the original tumor (exceptions: basal cell carcinomas of skin, cancers of glial origin). MALIGNANT TUMOR and CANCER are synonyms.

Microscopic appearance of Malignant Tumors:

-Individual cell morphology and tumor architecture may be "well-differentiated" (good prognosis) to "poorly-differentiated" ("anaplastic", bad prognosis). The malignant-looking cell: 1)Increased nuclear DNA (obvious on H&E; the hard-core get flow cytometry), 2)increased nuclear/cytoplasmic ratio 3)Nuclear changes -hyperchromatic nucleus, coarsening of chromatin, wrinkled nuclear edges, macronucleoli, weird-shaped nucleoli. Multinucleation is a marker for cancer only if the nuclei within an individual cell are obviously different from one another. 4)Numerous and bizarre mitotic figures. Tripolar mitoses are only the most familiar of the many weird patterns you may see. (NOTE: Mitotic figures last longer in cancers than in healthy tissues, so this is not "proof that cancers grow very rapidly".) 5)Failure to mature along normal functional lines.,Cells of widely varying sizes., Loss of orientation of cells to one another. -There MAY also be microscopic visible INVASION (tumor cells growing into adjacent normal structures where they don't belong), and/or indirect evidence (hemorrhage and/or necrosis; either is important evidence that the tumor in question is malignant). {00221} meningioma compressing brain {01855} craniopharyngioma "Intraepithelial spread" is possible and may take the form of single cells ("Paget's disease" of the nipple from an underlying breast cancer, many melanomas) or of DYSPLASIA / CARCINOMA IN SITU, in which an epithelial surface is replaced by a layer of anaplastic cells that has not (yet) penetrated the basement membrane. Benign or malignant, each tumor has a "cell of origin" from its tissue. Tumor cells almost always mimic one cell type of some normal organ, usually the one in which the tumor arose. -Cells may continue to elaborate keratin, mucus, hormones, immune globulin, etc. And they may show cross-striations (skeletal muscle cells), microvilli (certain glandular cancers), melanosomes (melanocyte cancer).etc. The resemblance will be better or worse depending on whether the tumor is "well-differentiated" or "poorly differentiated." The main tools are electron microscopy and immunoperoxidase stains ("the brown revolution").

SQUAMOUS CELL CARCINOMAS These arise anywhere there is a stratified squamous epithelium, either healthy (skin, esophagus, mouth, many others) or metaplastic (endocervix, bronchi). Look for any (or even all) of the following:

1)keratin (will stain orange-red on H&E) 2)pearls (i.e., whorls that mimic little hairs) * For the truly hard-core: You'll meet non-malignant keratin pearls again as the Hassal's corpuscles of the thymus, the horn cysts of seborrheic keratoses, and the smelly "tonsilloliths" that many people hock up from their tonsils. 3)desmosomes ("intercellular bridges", "prickles") 4)tonofilaments (electron microscopy) 5)Single-cell apoptosis (cells think they're at the top of the epidermis)

The better these things show, the better-differentiated the tumor! (Benign squamous tumors are uninteresting connective tissue covered with almostnormal-looking stratified squamous epithelium.) ADENOCARCINOMAS These arise anywhere there are glands, even single-celled glands (i.e., goblet cells) Look for any (or even all) of the following: 1)lumens (intercellular, intracellular) 2)especially, glands-within-glands ("Swiss cheese")

3)"inside-out" glands, with the malignant cells growing around a fibrous stalk ("papillary growth" / tree-like / arborescent) ] 4) mucin (intercellular "lakes", intracellular; "mucicarmine" stain will identify these) 5)other secretory products, depending on the gland of origin (immunostain may be required) 6)cells forming cohesive nests, or at least sticking to one another 7)signet-ring cells (distended with a product, typically one that they would ordinarily have secreted), alone or in clusters 8)microvilli

Adenomas
Adenomas exhibit most of the same features (though not glands-within-glands or signet-ring cells), and look benign. (An adenoma may contain dysplasia without invasion; in that case, the adenoma is considered benign but premalignant.) See below.

SPINDLE-CELL SARCOMAS These arise anywhere where there is connective tissue. Look for cells with elongated nuclei running parallel, with at least a modest amount of cytoplasm. 16671 leiomyosarcoma (smooth muscle cells, slightly high N/C ratio) LEUKEMIAS AND LYMPHOMAS Look for cells that resemble blood precursors, not sticking tightly together. (These features distinguish these common cancers from carcinomas and sarcomas.) 23776 acute leukemia, basophils predominate

Immunostains worth learning now:

CEA: endodermal adenocarcinomas ("carcinoembryonic antigen") CLA: tumors of white cells ("common leukocyte antigen")

desmin: myosarcomas EMA: adenocarcinomas ("epithelial membrane antigen") Factor VIII: endothelium GFAP: glial tumors ("glial fibril acid protein") NSE: oat cell CA, isletomas, APUDomas ("neuron-specific enolase") keratin family: most epithelial neoplasms S-100: melanoma, schwannoma, brain, antigen-presenting dendritic macrophages, histiocytosis X, some myoepithelium vimentin: mesenchymomas, melanomas, kidney tubule Benign tumors may cause problems: The tumor may secrete something in excess (typically a hormone). The tumor may compress surrounding structures. {00221} meningioma compressing brain {01855} craniopharyngioma

Malignant carcinomas
A few benign tumors sometimes transform into malignant tumors. Once this happens, they are no longer benign (so, benign tumors never metastasize). In some syndromes, benign tumors may be multiple. The most common cancers in the U.S. (by occurrence): Males (in descending order): prostate ,lung , colon-rectu Females (in descending order): breast , lung , colon-rectum (69360)

The most commonly cancer KILLERS in the U.S.: Males (in descending order): lung ,prostate,colon-rectum Females (in descending order): lung), breast colon-rectum (24130)

NOTE: Worldwide (WHO 2009), the great cancer killers are lung ,stomach colorectal (,liver and breast Among men, in descending order: lung, stomach, liver, colorectal, esophagus, and prostate. Among women: Breast, lung, stomach,

colorectal, cervix. NOTE: Worldwide, cancer of the cervix is the great nonobstetrical killer of young women. NOTE: The other great killer in some of the poor nations is hepatocellular carcinoma, which is primarily a man's tumor (because of hepatitis B carrier status and iron overload). Thanks to the decline in deaths from atherosclerosis, cancer is now the leading cause of death in U.S. females, and is about tied with atherosclerosis for US males.

What do cancers look like?

You remember that benign tumors are usually round like a ball. (The same can be true of some very tame cancers.) The Gross appearances of cancers usually fits one of three patterns: EXOPHYTIC: tumor grows as a lump, often with a cauliflower-like surface ("fungating"; smoother tumors are "polypoid"). (Malignant tumors seldom appear "encapsulated.") ENDOPHYTIC: tumor grows as an ulcer (i.e., the part that was probably protruding from the surface sloughed).

INFILTRATING: tumor cells invade an organ diffusely without changing its shape. Any cancer is likely to exhibit HEMORRHAGE and/or NECROSIS, grossly and microscopically. These result from the cancer cells invading the tumor's own blood vessels. WHAT IS THE DIFFERENCE BETWEEN DYSPLASIA AND CARCINOMA IN SITU? First idea: "Carcinoma in situ is full-thickness dysplasia. Turn the epithelium upside-down. If it looks the same, it is carcinoma in situ. The cells have completely forgotten how to mature." This merely reminds us that going from the mildest dysplasia to the meanest carcinoma in situ is a continuum. It's "cancer" when, and only when, the first malignant cell manages to grow through the basement membrane -- and that means it's no longer "in situ". Second idea: "Dysplasia is reversible and carcinoma in situ is not." I have been hearing this since I entered medical school without anybody ever explaining why I should believe it. How are you going to tell? Today, some people are managing milder cervical dysplasias "conservatively", we know the likelihood of regression depends on the virus and what genes are still working but still no one is leaving the high-grade carcinoma-in-situ alone. However, nobody would "just watch" a high-grade intra-epithelial lesion "to see whether it goes away by itself". Third idea: "Who cares? Call them both INTRAEPITHELIAL ANAPLASIA. Mild, moderate, or severe." This made so much sense that Bethesda decided in the 1990's to call them "intraepithelial neoplasia" instead. Realizing the error, their current term is "intraepithelial lesion."

Metastatic spread:
There are four routes: (1) Seeding of serosal surfaces (or, in the case of CNS tumors, up and down the neuraxis in the CSF) (2) Mechanical transplantation (rare, typically iatrogenic; (3) Via lymphatics (traditional route for tumors of epithelial origin, i.e., carcinomas) Tumors spread first to regional lymph nodes, then (because of disruption of directions of lymph flow) to any lymph nodes or organs

(4) Via blood vessels (traditional route for tumors of mesenchymal origin, i.e., sarcomas, because the tumor cells are in direct contact with blood vessels from the beginning) Regardless of the route of metastatic spread, certain tumors have unexplained preference for certain metastatic sites. Why? Even today, there's no clear molecular explanation. The common sites for metastatic spread for many common cancers include lymph nodes, lung, liver, bone, and brain. Most cancers won't metastasize to the skeletal muscles, spleen or subcutaneous fat. Requirements for successful metastatic spread:

Basement membrane and endothelial penetration Attachment at metastatic site Stromal induction "Tumor angiogenesis factor" , Collagen production by local fibroblasts (if dense, tumor is called "desmoplastic") Metastatic nodules are called "metastases" or (vulgarly) "mets".

Malignant tumors: Grade and Stage:

The grade and stage of a cancer are determined to offer a prognosis and to determine treatment. Both grade and stage are usually represented by Roman numerals, the best situation by I, the worst by III, IV, or V depending on the tumor type and determined by rules. Do not confuse grade and stage!

TUMOR GRADE: assigned by the pathologist to reflect the cancer's degree of differentiation. You won't be doing this yourself for your patients, but we will teach you some of the systems. Grade I: Well-differentiated, cells look like normal organ (benign = Grade 0) Grade II: Not so well-differentiated Grade III: Worse than that Grade IV: Even worse Grade V: Worst of all (most tumor types are graded I-III or I-IV)

 TUMOR STAGE: assigned by the clinician on the basis of all available information on the extent of tumor spread. Stage I might mean the tumor is smaller than 1 cm diameter, without metastases Stage II might mean the tumor is larger than 1 cm and/or is symptomatic and/or there are metastases to the regional lymph nodes Stage III might mean the tumor has infiltrated a nonresectable structure and/or there are distant metastases Rules for assigning stage are quite elaborate and different for each type of tumor.

Alternative system: TNM "T" for tumor: T1 might mean primary tumor is smaller than 1 cm in diameter T2 might mean primary tumor is larger than 1 cm in diameter T3 might mean primary tumor is invading something non-resectable "N" for regional lymph nodes: N0 would mean no tumor in regional lymph nodes N1 might mean tumor in a few nearby lymph nodes N2 might mean many nodes, or some nodes farther downstream, are involved "M" for metastases: M0 would mean no distant metastases M1 would imply distant metastases, etc. * So the TNM stage for a lung cancer that is invading or encasing the superior vena cava but has metastases only in two nearby lymph nodes might be T3 N1 M0. Memorizing tumor staging systems is not an appropriate pathology learning objective, and I will not test you on it.

Generally tumors of high GRADE present at high STAGE, while tumors of low GRADE present at low STAGE. Tumor Nomenclature

I. To assign a name to a tumor that you have examined, begin by writing the suffix -OMA. Most tumor names end in this way. (Unfortunately, the suffix simply means "swelling", and some non-neoplasms also use the suffix, i.e., GRANULOMA, HEMATOMA, XANTHOMA, traumatic NEUROMA, and "gossypiboma" for a sponge left in after surgery Am. J. For. Med. Path. 33: 54, 2012). II. If the tumor is MALIGNANT, write the root CARCIN- ("crab") if the tumor is of epithelial origin, or SARC- ("flesh") if the tumor is of mesenchymal origin, before OMA. If the tumor is BENIGN, do not write anything. III. Now choose one or more roots to describe the cell of origin. If the tumor originated in GLANDULAR epithelium, use the root ADENO-. (It probably makes little glands and/or mucin.) If the tumor originated in SQUAMOUS or UROTHELIUM (formerly called "transitional epithelium"), is BENIGN, and protrudes above the epithelial surface, use the root PAPILLO-. If it meets the first two criteria but does not protrude, the pathologist knows the name but you don't need to just now. If the tumor originated in NON-GLANDULAR EPITHELIUM and is MALIGNANT, name it for the cell of origin. Basal cell carcinoma (skin) Renal cell carcinoma (proximal tubule) Squamous cell carcinoma (squamous epithelium) Cholangiocarcinoma (bile ducts) If the tumor originated from a NON-EPITHELIAL cell, look for a root in the following list. (We do not consider endothelium and mesothelium to be epithelium for this purpose.)

FIBRO-: fibroblasts MYXO-: myxoid tissue (Wharton's jelly, etc.) CHONDRO-: cartilage OSTEO-: osteoblasts LIPO-: fat CHORDO-: notochord remnants LEIOMYO-: smooth muscle RHABDOMYO-: striated muscle

 SCHWANNO- / NEURILEMMO- : nerve sheath (perineurium) NEUROFIBRO-: nerve sheath (endoneurium) HEMANGIO-: blood vessels LYMPHANGIO-: lymphatics GLOMANGIO-: glomus SYNOVIO-: synovium MESOTHELIO-: mesothelium MENINGIO-: arachnoid granulation LYMPHO-: lymphocytes There are a few epithelial roots you will have to learn. For example:

CHORIO-: placenta PHEOCHROMOCYTO-: adrenal medulla and similar tissue

If the neoplastic cell types are MIXED, use a compound, for example, fibroadenoma. Some tumors arise in "totipotential cells" and contain a variety of different mature and/or immature