Path block 4

Metastatic spread of cancer can occur via one of three pathways:

(1) direct spreading of body cavities or surfaces, (2) lymphatic spread, and (3) hematogenous spread - we will briefly review all three of these

Desmoplasia

-The figure shows an example of desmoplasia or a desmoplastic reaction • At high magnification, this infiltrating ductal carcinoma of breast has pleomorphic cells forming small nests and irregular glandlike structures • The carcinoma cells infiltrate through the collagenous stroma • Note the abundant pink collagen bands from desmoplasia, which makes the tumor feel firmer than normal surrounding breast tissue on palpation (thus, an example of clinicopathologic correlation)

Molecular basis of cancer

-epigenetics is the study of cellular and physiological trait variations that are not caused by changes in the DNA sequence • Epigenetic aberrations - also contribute to the malignant properties of cancer cells • Epigenetic modifications - included DNA methylation, modification of histones • Together: these two factors dictate which genes are expressed/which in turn determines the lineage commitment and differentiation state of both normal and neoplastic cells

Inflammatory breast cancer accounts for __ to __% of all breast cancers diagnosed in the US

1 to 5% Most inflammatory breast cancers are invasive ductal carcinomas: developed from cells that line the milk ducts of the breast and spread beyond the ducts

There are 4 classes of normal regulatory genes: These are the principle targets of genetic damage!!!

1. Growth promoting protooncogens 2. Growh inhibiting tumor suppressor genes 3. Genes that regulate programmed cell death (apoptosis) 4. Genes involved in DNA repair Sometimes, loss of a single allele of a tumor suppressor gene - reduces the level of activity of the protein enough/ loss of gene function d/t damage to a single allele - haploinsufficiency

All tumors (benign or malignant) have 2 basic components:

1. Proliferating neoplastic cells (parenchyma) 2. Supportive stroma (connective tissue and blood vessels) Some tumors have SCANT STROMA: soft, fleshy neoplasm or the parenchyma cells stimulate the formation of an abundant collagenous stroma called DESMOPLASIA

The presence of the histologic diagnosis of CIN3/carcinoma in situ is a good indicator of risk of the development of subsequent cancer • The time span between HPV infection and CIN3 has been calculated to be

7 - 15 years with most infections occurring in the later teens or early twenties and CIN3 diagnosis peaking around 25 - 30 years of age • The risk and timing of invasion below the basement membrane is impossible to predict • The median age of women with CIN3 is 27-30 years, while the median age of women with invasive cancer is much older, sometimes after a time span of ten years

Colon polyps

Adenoma - term applied to a benign epithelial neoplasm/derived from glands •You really cannot tell if these growths are benign or malignant - until you look at microscopic sections***

Nomenclature of benign tumors: Adenoma and papilloma

Adenoma: A benign epithelial neoplasm forms glandular patterns. Also refers to tumors derived from glands but not necessarily reproducing glandular patterns Papilloma: a benign epithelial neoplasm producing micro or macroscopically visible finger like warty projections from the epithelial surface

Lung metastasis

All caval blood flows to the lungs • Figure shows a microscopic view of lung metastasis • A colonic adenocarcinoma has formed a metastatic nodule

• Figure shows you, again, that the genetic predisposition to cancer can be divided into three (3) categories • Less than 10% of cancer patients - have inherited mutations that predispose to cancer/and the percentage is even lower (ca. 0.1%) for certain types of tumors • And genes that are causally associated with cancers (that have a strong hereditary component) - are generally also involved in the much more common sporadic forms of the same tumor

BRCA1, BRCA2: BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins • These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cell's genetic material • When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly • As a result, cells are more likely to develop additional genetic alterations that can lead to cancer

Dye in sentinal nodes

Blue dye filling sentinel lymph node(s) in the axilla: • A blue dye in lumpectomy site • B axillary lymph nodes: levels I • C axillary lymph nodes: levels II • D axillary lymph nodes: levels III • E large lymphatic channels • F small lymphatic channels • G sentinel lymph nodes 62

Cells with mutations in DNA repair genes are called MUTATOR PHENOTYPE With some exceptions:

Both alleles of DNA repair genes must be inactivated to induce the above kind of genomic instability DNA repair genes may also be thought of as TUMOR SUPPRESSOR GENES: ex: BRCA 1, 2

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer • Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers • In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall

Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts***** • A woman's lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2****

metastatic breast cancer to liver Tumor cells invading into liver tissue. Immunohistological study to confirm origin of tumor cells

Breast cancer - usually spreads to BONE, but can metastasize to other sites as well/as shown in the slide above • Re differential diagnosis - if liver enzymes suddenly increase and/or if there has been a past history of breast cancer/or if liver scans show a discrete mass → then a more complete workup is required • Here, immuno stains have been done - ER/PR, for example

Adenocarcinoma is the name of a broad category of cancers. Carcinoma with GLANDULAR growth pattern microscopically

Cancer that begins in cells that line internal organs and that have glandular (secretory properties), mucin production This type occurs in cells that line organs such as colon, lungs and breast

Carcinogenesis

Carcinogenesis - results from the accumulation of complementary mutations in a stepwise fashion over time • Early on - all of the cells in a tumor are genetically identical/being the progeny of a single founding transformed cell • During the process of at least 30 cell doublings ( attaining a mass of ca. 1 gram) - the initial clonality is gone and the tumor constituent cells are often extremely heterogeneous genetically***** • This can be determined - by a genetic comparison drawn from sequencing of DNA obtained from different tumor sites***** 55

Certain types of fatty acids or their metabolites may initiate or promote prostate carcinoma development

Certain types of fatty acids or their metabolites may initiate or promote prostate carcinoma development The evidence for this hypothesis is conflicting, but one study suggests that linoleic acid (omega-6 polyunsaturated fatty acid) may stimulate prostate cancer cells, while omega-3 fatty acids inhibit cell growth

Nonhereditory predisposing conditions Acquired conditions that predispose cancer can be divided into:

Chronic inflammation Precursor lesions Immunodeficiency states

Mutant alleles of protooncogens are considered Damage one protongogen = 1 oncogen = cancer (Dominant) only 1 tumor suppressor gene: it still will suppress cancer. You have to damage BOTH normal alleles of the suppressor to get cancer (recessive)

DOMINANT Because they transform cells despite the presence of a normal counterpart However, BOTH NORMAL alleles of the tumor suppressor genes MUST be damaged for transformation to occur These are referred to as RECESSIVE ONCOGENES

Occupational cancers appear to be the

DOMINANT risk factor for most cancers! These environmental carcinogens are everywhere in the ambient environment, workplace, food, and personal practices ex: ultraviolet radiation, meds (methotrexate), vinyl chloride (angiosarcoma of the liver) - at Uniroyal rubber plant in Akron, Ohio), asbestos, high fat diets, alcohol, etc.

Environmental factors cont.

Diet: prostate cancer association with high fat, red meat Breast cancer: animal fat Obesity: 14% of deaths in men, 20% in women Reproduction: lifelong cumulative exposure to estrogen if unopposed to progesterone: increases risk of cancers (breast and endometrium) Environmental carcinogens: workplace, in food, UV light

H. Pylori is a Gram-negative, microaerophilic bacterium found in the stomach, and may be present in other parts of the body, such as the eye Humans are essentially the only reservoir for Helicobacter pylori, which is estimated to colonize the stomach of about half the world's population Although the bacteria generally do not invade the mucosa, attachment to the epithelium leads to an inflammatory reaction with neutrophils, lymphocytes, plasma cells, and macrophages Over time, the persistent inflammation leads to changes in the gastric mucosa that may predispose to the development of

Dysplasia!! The known costs of H. pylori colonization include increased risk of peptic ulcer disease (PUD), gastric adenocarcinoma, and gastric lymphoma • In epidemiological studies, colonization with H. pylori has been demonstrated to be associated with an increased risk of non-cardia gastric adenocarcinoma, especially in individuals who have harbored the organism for 10 years or longer • It is also well established that elimination of H. pylori changes the natural history of PUD and gastric MALT-type lymphoma • Over the past 20 years, regimens that use acid-suppressing agents, combined with multiple antibiotics, and in particular clarithromycin have been highly successful for H. pylori eradication

Fibroadenoma of breast micro

Fibroadenoma = the most common benign breast lesion/usually occurs in young women • It is considered to arise in the lobule • Microscopic: shows a lesion with proliferation of both stromal and epithelial elements • Classically, two patterns have been described: (a) a pericanalicular pattern and (b) an intracanalicular pattern (you do not need to know these types for test purposes in this course) • On high power examination: the epithelial components are seen to be lined by the usual two cell types

fibroadenoma of breast

Fibroadenomas - are freely movable on examination/palpation and are not "fixed" within the surrounding breast tissue

Infultrating carcinoma vs. typical fibroadenoma

Figure on the left: shows the cut surface of a biopsy specimen/containing a typical infiltrating carcinoma/the irregular outline of the tumor and contraction from the surrounding tissue produce a slightly concave cut surface • Figure on the right: shows the cut surface of a biopsy specimen containing a typical fibroadenoma/the lesion has a smooth, rounded outline with a suggestion of a lobulated structure/and it protrudes from the surrounding breast tissue • Source: Sternberg's Diagnostic Surgical Pathology, 5th Edition, Chapter 9, "The Breast"

Removal of lymph nodes

Figure shows - One of the "blue/hot" lymph nodes being removed from the right axilla • In the breast, a network of lymphatic vessels drain fluid and cells to the bean shaped lymph nodes in the axilla (armpit) • The sentinel node is the very first lymph node(s) to receive drainage from a cancer containing area of the breast • Put another way, when breast cancer cells begin to escape from the primary tumor site in the breast they travel to the lymph nodes under the arm; the first lymph node they reach is the 'sentinel' lymph node**** • When breast cancer is diagnosed - women (and men) must often undergo axillary lymph node dissection (i.e., removal of underarm nodes) to check for the spread of cancer • This process is part of staging the cancer • Unfortunately, the removal of these lymph nodes can lead to lymphedema (chronic swelling) of the arm in a certain percentage-- about 10-20%--of cases 63

Barrat's esophagus

Figure shows the histological appearance of the GE junction in Barrett esophagus Note the transition between esophageal squamous mucosa (left) and barrett metaplasia with abundant metaplastic goblet cells (right)

Injection of blue dye

First step: Injection of blue dye in lumpectomy site: • A blue dye in lumpectomy site • B axillary lymph nodes: levels I • C axillary lymph nodes: levels II • D axillary lymph nodes: levels III • OR, if a radiotracer is also used: Before going to the operating room, the surgeon injects a small dose of a low-level radioactive tracer called technetium-99 into the breast in the region of the patient's tumor • Technetium-99 contains less radiation than a standard x-ray, CT scan or bone scan and is a relatively safe substance • A blue dye is also injected to help visually track the location of the sentinel node during surgery • The surgeon then uses a hand held counter to detect the radioactive tracer and locate the sentinel node

Genetic predisposition to cancer It is difficult to sort out the hereditary and nonhereditary contributions because these factors often interact

For many types both environmental factors and hereditary predispositions exist LESS than 10% of cancer patients have INHERITED mutations predisposing to cancer Genetic predisposition divided into 3 categories: 1. Autosomal dominant inherited cancer syndrome 2. Defective DNA repair syndromes 3. Familial cancers

Adenocarcinoma of the colon can be divided into 3 grades based on the overview of cell arrangement and degree of tubular (Acinar) arrangement:

Grade I: composed mainly of simple tubules Grade II: composed of tubules/ simple, complex or slightly irregular Grade III: predominance of the absence of glandular differentiation/ solid like pattern

Intracellular bridging

High power of squamous cell carcinoma showing the presence of intercellular bridges (arrow show one of the bridges) • Mitosis/a mitotic figure can also be seen in the figure • Fine "lines" between cells = intercellular bridging • On E.M. - they are identified as desmosomes (only epithelia should have these desmosomes)

Inflammatory breast cancer progresses rapidly, often in a matter of weeks or months. Inflammatory breast cancer is either stage

III or IV at diagnosis, depending on whether cancer cells have spread only to nearby lymph nodes or to other tissues as well

Carcinoma in situ

In dysplastic squamous epithelium - mitoses are not confined to the basal layers/but can appear at all levels/incluing the surface cells • When dysplastic changes are marked and involve the entire thickness of the epithelium (but do not extend beyond the basement membrane) - this is called CIS/carcinoma in situ (or CIN3) • Not all dysplasia - leads to cancer/even full thickness dysplasia may take years to become invasive - but who wants to wait and see??

Desmoplasia

In some cases - the parenchymal cells of the tumor stimulate the formation of an abundant collagenous stroma/desmoplasia •The nomenclature of tumors (and their biologic behavior) - based mainly on the parenchymal component

• Strategic removal of just one or a few key underarm nodes can accurately assess overall lymph node status in women who have relatively small breast cancers (smaller than 5 cm) and who have lymph nodes that don't feel abnormal before surgery • Studies have shown that after almost 5 years, women who had just the sentinel node removed were as likely to be alive and free of cancer as women who had more lymph nodes removed

In the operating room - the surgeon injects a radioactive liquid, a blue dye, or both into the area around the tumor • The doctor then watches to see where the dye travels and seems to concentrate • A special instrument is used to track the radioactive liquid/or, if a blue dye has been injected, then the node with the greatest amount of blue dye is the sentinel lymph node

Cancer can occur anywhere in the body

In women - breast cancer is most common • In men -it is prostate cancer • Lung cancer and colorectal cancer can affect both men and women in high numbers

Environmental factors

Infectious agents: account for 15%o f all cancers: HPV, cancers of cervix, head, neck and anus Smoking/tobacco: cigarette smoking: cancer of mouth pharynx, larynx, esophagus, pancreas, bladder, and ca. 90% of lung cancer deaths Alcohol consumption: increased risk of carcinoma of oropharynx, larynx, esophagus, alcoholic cirrhosis, hepatocellular carcinoma exposure to aromatic amines (e.g., dyes/dye industry) increases risk of bladder cancer

some cancers, such as leukemia, rarely form masses (i.e., solid tumors)

Instead, these cancer cells involve the blood and blood-forming organs/then circulate through other tissues where they grow

lymphovascular invasion example

It is sometimes difficult to tell if a tumor bolus is in a lymphatic channel or blood vessel/could do stains for endothelial cells (CD 31, Factor VIII-related antigen) - to see if, indeed, we are in a vessel/and not simply due to "tumor retraction" - which is an artifact

cervical intraepithelial neoplasia is a PRECANCER lesion characterized by abnormal cell proliferation of the parabasal cells induced by infection of high risk HPV

Koilocytes/koilocytic atypia/koilocytic change= (enlarged cells with perinuclear cytoplasmic clearing; pyknotic nuclei with irregular membranes) • Koilocytes are usually found in condyloma and CIN 1 lesions (and also in CIN 2 lesions) • CIN may be categorized into grades 1, 2 and 3 depending upon the proportion of the thickness of the epithelium showing mature and differentiated cells • Invasion of the basement membrane correlates with invasive cervical/squamous cell carcinoma from CIS****

fibroadenoma of breast

Left figure: the radiogram shows a characteristically well-circumscribed mass •Right figure: gross - see a rubbery, white, well-circumscribed mass/clearly demarcated from the surrounding yellow adipose tissue/the absence of adipose tissue accounts for the radiodensity of the lesion/lesion is freely movable when breast is examined and not fixed in its location (i.e., much more likely to be a benign neoplasm/growth)

Cervical dysplasia is classified as low-grade or high-grade, depending on the extent of the abnormal cell growth

Low-grade cervical dysplasia progresses very slowly and often gets better on its own • High-grade cervical dysplasia can lead to cervical cancer/Without treatment, 30 - 50% of cases of severe cervical dysplasia progress to invasive cancer/The risk of cancer is lower for mild dysplasia • Cervical dysplasia is associated with the human papillomavirus (HPV), a sexually transmitted virus • A vaccine is available to protect against HPV, and regular Pap tests can usually find cervical dysplasia and treat it in its early stage • Currently, 11% of U.S. women report that they do not have regular Pap tests

Malignant vs. benign: Cancerous tumors are

MALIGNANT. This means they can spread into or invade nearby tissues As these tumors grow, some cancer cells can break off and travel to distant places in the body through BLOOD or LYMPH and form new tumors. This is METASTISIS

Regarding metastisis

Metastatic adenocarcinoma (composted of malignant gland like structures) in a lymph node: it is common for carcinomas to metastasize to lymph nodes. The first nodes involved are those draining the site of the primary

Colon: invasive adenocarcinoma, micro

Microscopically, a moderately differentiated adenocarcinoma of colon is seen here • There is still a glandular configuration, but the glands are irregular and very crowded • Many of them have lumens containing bluish mucin

New topic: benign breast tumors: Re local invasion

Most benign tumors grow as cohesive expansile masses and remain localized at the site of origin They do not have the capacity to invade or metastasize to distant sites Often develop a fibrous capsule around them (Example: fibroadenoma of breast: discrete, movable mass)

Invasive carcinoma of the breast

NOS = "not otherwise specified"

Blue dye drainage pattern:

Next step: Blue dye draining away from lumpectomy site, within lymphatic channels, towards the axilla: • A blue dye in lumpectomy site • B axillary lymph nodes: levels I • C axillary lymph nodes: levels II • D axillary lymph nodes: levels III • E large lymphatic channels • F small lymphatic channels • G sentinel lymph nodes taking up dye

Normal cervix: gross

Note the ectocervix and endocervix, and vaginal cuff

Normal cervix

Notice the cells with glycogen - at the "top" of the section

Pathways of spread: seeding of body cavities and surfaces

Occurs when a malignant tumor penetrates into the surrounding space or field Most often involves peritoneal cavity other cavities may be involved as well (pleural, pericardial, subarachoid, joint spaces) Frequently seen in ovarian carcinoma

Oncogenes arise as a result of mutations that increase the expression level or activity of a proto-oncogene

Oncogenes - typically exhibit increased production of these proteins, thus leading to increased cell division, decreased cell differentiation, and inhibition of cell death; taken together, these phenotypes define cancer cells An oncogene is a gene that has the potential to cause cancer*****

Anaplastic carcinoma

One has to rely on immunostains and/or histological stains to try and identify the origin of the tumor cells

Cancer characteristic types: Squamous cell carcinoma

One producing recognizable squamous cells arising in any epithelium May arise in areas where there is stratified squamous epithelium This can be either the NATIVE cell type OR Metaplastic in nature (bronchus, endocervix, etc)

epidemiology of CIN Invasive squamous cell cervical cancers are preceded by a long phase of preinvasive disease, collectively referred to as cervical intraepithelial neoplasia (CIN) More severe grades of CIN (2 and 3) reveal a greater proportion of the thickness of the epithelium composed of undifferentiated cells.

Persistent infection with one or more of the oncogenic subtypes of human papillomaviruses (HPV) is a necessary cause for cervical neoplasia. • Most cervical abnormalities caused by HPV infection are unlikely to progress to high-grade CIN or cervical cancer. • Most low-grade CIN regress within relatively short periods or do not progress to high-grade lesions. • High-grade CIN carries a much higher probability of progressing to invasive cancer. • The precursor lesion arising from the columnar epithelium is referred to as adenocarcinoma in situ (AIS) • AIS may be associated with CIN in one-to two-thirds of cases.

Uterine Leiomyoma

Recall what normal myometrium looks like from your histology course

chronic inflammatory states that predispose somebody to cancer: not hereditary

Robbins states that the exact mechanism that links chronic inflammation and cancer development has not been established - it might be that the immune response to such inflammation becomes maladaptive, and thus promotes tumorigenesis • GERD/gastroesophageal reflux disease - is certainly associated with esophageal cancer/get metaplasia (goblet cell metaplasia) - which can lead to dysplasia - to severe dysplasia - to full thickness dysplasia - to invasive adenocarcinoma

Anaplastic Tumor

See tumor giant cells/some possessing only a single huge polymorphic nucleus •Others having two or more large, hyperchromatic nuclei (as we see here) •Both the cells and the nuclei - show pleomorphism (variation in size, shape and staining/the "three S's") - but the pleomorphic nuclei "catch your eye" first! •Slide shows the main feature of abnormal nuclear morphology/hyperchromatic (in cases like this, one sees an abnormal N:C ratio/may approach 1:1, instead of normal 1:4 or 1:6)

Infiltrating ductal carcinoma of the breast, gross

Some desmoplastic tumors (e.g., some cancers of the female breast) - are stony hard or scirrhous •this represents a case of invasive breast cancer

metastisis to LN vs normal LN

The bottom figure: shows the subcapsular sinus/with no metastatic tumor cells • Afferent lymphatics drain into this sinus, which communicates with intercollicular sinuses efferent lymphatics exit at the hilus

Cervical dysplasia

The figure shows an illustration of the various grades of squamous intraepithelial lesions and CIN (comparison of nomenclature) • Cervical dysplasia is the abnormal growth of precancerous cells on the surface of the cervix

Small lymphocytic lymphoma (SLL) and (CLL)

The majority of the tumor cells are small round lymphocytes. A pro lymphocyte is a larger cell with a centrally placed nucleolus (shown by arrow. ) Also known as chronic lymphocytic leukemia •The two disorders differ only in the degree of peripheral blood lymphocytosis •Diagnostic criterion for CLL = absolute lymphocyte count >4000 per mm3 •CLL = the most common leukemia of adults in the western world

Epidemiology of cancer

The most common tumors in men are: • Prostate • Lung • Colorectal cancers • The most common tumors in women are: 1st:lung 2nd: Breast • Colon and rectum • Lung cancer - now causes more deaths in women than breast cancer (p. 276, Robbins, 9th Ed.) • Death due to primary liver cancers - have almost doubled over the past 40 years (due to infection with hepatitis C virus/HCV) • African Americans - have had the largest decline in cancer mortality during the past decade

Carcinoma of cervix

This is an obvious malignant neoplasm

metastatic ovarian cancer

This seeding of body cavities - is especially characteristic of ovarian carcinoma/often spreads to the peritoneal surfaces • Metastases from epithelial ovarian carcinoma involving the omentum • Carcinomas arising in the ovaries - are very likely to show seeding into the peritoneal cavity

Adenosarcoma of the colon

Upper figure: This is normal colonic mucosa/Note the crypts that are lined by numerous goblet cells In the submucosa is a lymphoid nodule The gut-associated lymphoid tissue as a unit represents the largest lymphoid organ of the body. • Colon cancer/colonic adenocarcinoma • This tumor is considered differentiated - because gland formation can be seen - the main point is glands are still being formed!

Uterine leiomyoma, gross

Uterus has been bi-valved/via the cervical os/with a metal probe

invasive ductal carcinoma of breast

We have seen this slide previously before • Figure shows the tumor infiltrating the surrounding breast tissue • This tumor would feel "stony hard" on palpation

Poorly differentiated SCC: larynx

You also see lots of mitoses/mitotic figures (but you see abundant pink cytoplasm)

Carcinogenesis is a multi step process at both the phenotypic and genetic levels: •Results from the accumulation of multiple mutations

a malignant neoplasm has many phenotypic attributes called CANCER HALLMARKS: Excessive growth Local invasiveness The ability to form distant metastases The above features: acquired in a stepwise fashion is called TUMOR PROGRESSION

Cancer: a general term for a group of more than 100 diseases. It is an uncontrolled growth of

abnormal cells. All cancers start because abnormal cells grow out of control. Normal control mechanisms stop working Old cells do not die and cells grow out of control, forming new abnormal cells They form a mass called a tumor

DNA repair genes Mutations of DNA repair genes effects include:

affect cell proliferation or survival indirectly by influencing the ability of the organism to repair non lethal damage in other genes This includes: protooncogenes, tumor suppressor genes, and genes that regulate apoptosis A disability in the DNA repair genes can predispose to mutations in the genome: can lead to neoplastic transformation The mutation of DNA repair genes itself do not directly transform cells (either by changing/affecting proliferation or apoptosis)

Metaplasia = the reversible conversion of normal tissue cells into

another, less differentiated cell type in response to chronic stress or injury •With prolonged exposure to the inducing stimulus, cancerous transformation can occur •Or think of it this way: metaplasia =The conversion of one type of adult tissue and/or cells—most commonly epithelia—into another; e.g., squamous metaplasia, in which non-keratinized squamous epithelium replaces ciliated columnar cells in the bronchi of smokers

The term soft tissue is used to distinguish these kinds of sarcomas from bone sarcomas Sarcomas can arise in

any part of the body. Half of them develop in arms or legs The rest in the trunk, head and neck, internal organs, or retroperitoneum

Axillary LN with metastasis

axillary lymph node with metastatic breast carcinoma: the SUBSCAPULAR SINUS is distended with tumor cells/ nests of tumor cells have also invaded the sub capsular cortex

In breast cancer - since cancers most often arise in the upper outer quadrant - they generally spread first to the

axillary lymph nodes (the sentinel node)

Leukemia is lymphoid neoplasms presenting with widespread involvement of the

bone marrow. Usually accompanied by the presence of large numbers of tumor cells in the peripheral blood The line between "lymphocytic leukemias" and the "lymphomas" often blurs The terms leukemia and lymphoma merely describe the usual tissue distribution of the disease at the time of clinical presentation

Exception: Gliomas of the CNS and basal cell carcinomas of skin

both invasive but rarely metastasize

the sentinel node:

breast cancer sentinel node biopsy can spare women the increased morbidity of a complete axillary dissection The clinical assessment of nodal involvement is very inaccurate with both false positive and false negative findings

A tumor = is an abnormal lump or collection of cells/but not all tumors are

cancer (thus, cancer implies the ability to grow abnormally and to spread to other body sites/i.e., metastasize)

Cancers associated with infections agents: In tissue injury there is compensatory proliferation of cells to repair the damage. Also produce growth factors, cytokines, chemokines, other bioactive substances by activated immune cells. These substances promote

cell survival, tissue remodeling and angiogenesis •In some cases/chronic inflammation may increase pool of tissue stem cells - which become subject to the effect of mutagens (see. P. 279)/also ROS - produced which are directly genotoxic •Board question - concerning liver flukes and cancer/Clonorchis sinensis - liver fluke/eating raw freshwater fish/associated with cholangiocarcinoma

Most benign tumors are WELL DIFFERENTIATED (few mitotic figures of normal configuration) composed of

cells resembling the mature normal cells of the tissue of origin of the neoplasm

•Reactive stroma/desmoplasia/desmoplastic reaction - made up of

connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes •the Growth and evolution of a tumor is very dependent on the stroma (even though the neoplastic cells largely determine a tumor's behavior and pathologic consequences)

Nodal enlargement of lymph nodes in proximity to a cancer does not necessarily mean

dissemination of the primary lesion: Enlargement could be due to inflammation

Sarcoma features: A malignant tumor arising in mesenchymal tissue, usually called a sarcoma (sar=fleshy) Because they have little CT stroma they are

fleshy. They arise from multi potential mesenchymal cells and undergo differentiation along one or more lines ex: fibrosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma

Products of oncogenes - called oncoproteins/resemble the normal counterparts of proto-oncogenes (proto-oncoproteins) - but are often lacking

important internal regulatory elements/thus they do not depend on growth factors, or other external signals

Endoscopic view of tubular adenoma

in the sigmoid colon •Sometimes it is not easy to differentiate between a benign and a malignant lesion/These lesions are all benign •Tubular adenoma or adenomatous polyp - These are the most common type of polyp and are the ones referred to most often when a doctor speaks of colon or rectal polyps; about 70% of polyps removed are of this type •Adenomas carry a definite cancer risk that rises as the polyp grows larger •Adenomatous polyps usually cause no symptoms, but, if detected early, they can be removed during a colonoscopy before any cancer cells form •The good news is that polyps grow slowly and may take years to turn into cancer •Patients with a history of adenomatous polyps must be periodically reexamined

Evidence from many case-control studies has found an association between dietary fat and prostate cancer risk, though studies have not uniformly reached this conclusion • In a review of published studies of the relationship between dietary fat and prostate cancer risk, among descriptive studies, approximately half found an

increased risk with increased dietary fat and half found no association Dietary fat may increase serum androgen levels, thereby increasing prostate cancer risk This hypothesis is supported by observations from South Africa and the United States that changes in dietary fat intake change urinary and serum levels of androgens

Metastases: dermal lymphatics

inflammatory carcinoma with lymphovascular invasion. The skin overlying the breast has prominent lymphatic spaces filled with small metastases from breast carcinoma

Breast cancers of the inner quadrant - drain to nodes along the internal mammary arteries/thus, the

infraclavicular and supraclavicular L.N.'s might show evidence of metastasis

Pathways of spread: hematogenous spread As a rule, carcinomas preferentially metastasize to lymph nodes although intralymphatic tumor cells can pass directly into the blood vascular system through venolymphatic communications and vise versa

is typical of SARCOMAS but is also seen with carcinomas Arterial spread may occur, but arteries with their thicker walls are less readily penetrated than are veins With venous invasion, the blood borne cells follow the venous flow draining the site of the neoplasm The liver and lungs are the MOST FREQUENTLY involved secondarily in hemotogenous spread

Hence, if this is a left axillary lymph node, then the primary site of the cancer is likely in the

left breast

In general - the more aggressive and more rapidly growing tumors and larger tumors - are more likely to

metastasize/i.e., metastatic spread correlates with lack of differentiation, aggressiveness, local invasion, rapid growth and large size

About 30% of newly diagnosed solid tumors (excluding skin cancers other than melanomas) present with

metastic spread already

People can inherit abnormal DNA (i.e., passed on from their parents) However, most often DNA damage is caused by:

mistakes that happen while the normal cell is reproducing or via something in the environment • The cause of the DNA damage may be sometimes obvious (e.g., cigarette smoking or sun exposure) • However - it is rare to know exactly what caused any person's cancer

Molecular basis of cancer: A tumor is formed by the CLONAL EXPANSION of a single precursor cell that has incurred genetic damage: tumors are MONOCLONAL Clonality of tumors:

monoclonal tumor cells are defined as a group of cells produced from a single ancestral tumor cell by repeated cellular replication Said to form a single "clone" population •Nonlethal genetic damage - lies at the heart of carcinogenesis •Such genetic damage - can be acquired by the action of environmental agents/chemicals, radiation, viruses, or inherited in the germ line

Villous adenomas = Villous adenomas are associated more often with larger adenomas and

more severe degrees of dysplasia/These adenomas occur more frequently in the rectum and rectosigmoid, although they may occur anywhere in the colon/ They generally are sessile structures that appear as velvety or cauliflower like projections

Transport through lymphatics is the

most common pathway for initial dissemination of CARCINOMAS Sarcomas - may also use this route/although we think of them spreading via hematogenous routes

inflammatory carcinoma: peau D orange, involving part of the areola Re the figure shown: Inflammatory breast cancer symptoms - include

pain or bruise in the breast, skin changes in the breast area, sudden swelling of the breast or itching of the breast • Inflammatory breast cancer (IBC) is a rare and very aggressive disease in which cancer cells BLOCK LYMPH VESSELS in the skin of the breast This type of breast cancer is called "inflammatory" because the breast often looks swollen and red, or "inflamed

Clonal/monoclonal population - neoplastic cells - constitute the

parenchyma of a tumor (either benign or malignant)

Lymphoma is cancer arising from Lymphocytes. Lymphoid neoplasms encompass a diverse group of entities. In many instances the phenotype of neoplastic cell closely resembles that of a

particular stage of normal lymphocyte differentiation Lymphoma is a term used to describe proliferations arising as a DISCRETE MASS

Features of squamous cells:

presence of KERATIN PEARLS (stain orange on H&E INTERCELLULAR BRIDGES Seen as Desmosomes or "tight junctions" on EM microscopy EM confirms presence of desmosomes and tonofilaments

Well differentiated SCC

presence of keratinization within the cells which give the cells abundant pink cytoplasm, (this may be absent in poorly differentiated type) • Intraepithelial keratin in the shape of a whorl is termed squamous eddy or pearl (outside cell)

All portal area drainage flows to the liver All Caval blood flows to the lungs Certain cancers have

propensity for INVASION OF VEINS Renal cell carcinoma: invades branches of the renal vein Hepatocellular carcinoma: often penetrates portal and hepatic radicles to grow within them into the main venous channels

Fibrosarcoma: tumor composed of malignant spindle cells arranged in a HERRINGBONE PATTERN

rare lesions • can occur any where in the body • most commonly in the retroperitoneum, the thigh, the knee, and the distal extremities • Typically, unencapsulated, soft, fish-flesh masses • often having areas of hemorrhage and necrosis • Aggressive tumors! • Recurring in more than 50% of cases • Metastasize in more than 25% of cases

Cells become cancer because of DNA damage. In a normal cell, when DNA is damaged the cell either repairs or dies. In cancer cells, the damaged DNA is not

repaired and the cell does not die. Consequence: the cell goes on making new cells that the body does not need. These new cells: all have the same damaged DNA as the first abnormal cells

Colonic carcinoma

shows colon carcinoma invading pericolic adipose tissue (shown in Robbins, p. 273) is discussed in the framework of "seeding of body cavities and surfaces"/once the tumor cells have reached the pericolic fat - they are likely to further into the peritoneal cavity

Unlike malignant tumors - benign tumors do not

spread into, or invade, nearby tissues • Benign tumors - can sometimes be quite large, however • When removed, benign tumors - usually do not grow back/whereas malignant tumors sometimes do • Benign tumors cannot grow into (invade) other tissues but they can cause problems when they press on other tissues (like the brain which can be life threatening) • Remember: Because benign tumors cannot invade - they also cannot spread to other parts of the body (metastasize)

Lymphovascular invasion/LVI - term used to encompass either lymphatic or hematogenous spread of tumor/The presence or absence of the invasion of cancer cells into blood vessels and/or the lymphatic system Symptoms of inflammatory breast cancer include:

swelling (edema) and redness (erythema) that affect a third or more of the breast • The skin of the breast may also appear pink, reddish purple, or bruised In addition, the skin may have ridges or appear pitted, like the skin of an orange (called peau d'orange)/These symptoms are caused by the buildup of fluid (lymph) in the skin of the breast/This fluid buildup occurs because cancer cells have blocked lymph vessels in the skin, preventing the normal flow of lymph through the tissue may contain a solid tumor that can be felt during a physical exam, but, more often, a tumor cannot be felt Other symptoms of inflammatory breast cancer include a rapid increase in breast size; sensations of heaviness, burning, or tenderness in the breast; or a nipple that is inverted Swollen lymph nodes may also be present UNDER THE ARM, near the COLLARBONE, or in both places*****

Differentiation is

the extent to which parenchymal cells resemble corresponding normal parenchymal cells morphologically and functionally Lack of differentiation is: anaplasia = a hallmark of malignancy Malignant tumors: wide range of parenchymal differentiation

Sentinel lymph node dissection is an alternative to traditional axillary lymph node dissection. The surgeon looks for the first lymph node that filters fluid draining away from the area of breast cancer. If cancer cells are breaking away from tumor and traveling away via lymph, the SENTINAL LYMPH NODE is more likely than others to contain cancer. The sentinal node is defined as:

the first node in a regional lymphatic basin that receives lymph flow from the primary tumor (Robbins, p. 273) • The idea behind sentinel node dissection is this: Instead of removing 10 or more lymph nodes and analyzing all of them to look for cancer, remove only the one node that is most likely to have it • If this node is clean, chances are the other nodes have not been affected In reality, some surgeons usually removes a cluster of two or three nodes — the sentinel node and those closest to it

Tumor suppressor gene: A gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase

the probability of a tumor. In that way, a tumor suppressor is similar to an oncogene Loss of tumor suppressor gene results in loss of cell cycle control (example: retinoblastoma susceptibility gene RB) However, cancer is more often a multistep process during which cells acquire a series of mutations that collectively lead to decreased tumor suppressor gene function and increased proto-oncogene function • The net result is a heterogeneous tumor cell population that grows uncontrollably, divides without restraint, and fails to respond to signals that would normally cause cell death

Neoplasia = the formation or presence of a new, abnormal growth of tissue (but

this does not state that every neoplastic growth is malignant!) NOTE: in most cases - the cancer forms a tumor/over time, the tumors can replace normal tissue (and thus, replace normal cellular function/this involves the pathophysiology of neoplasia), crowd it, or push it aside

Villous adenomas (larger and more severe degrees of dysplasia) are the most likely

to become cancerous, and tubular adenomas are the least likely •Think of the analogy of "Jack in the Beanstalk" - if you have to climb down the beanstalk -- this takes "time" vs. if you are sitting on the ground (e.g., a sessile adenoma) - you can spread faster

Metastases

tumor implants, not continuous with primary tumor defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor

Poorly differentiated/ undifferentiated tumors have primitive appearing,

unspecialized cells (anaplasia) let's look at some more examples of various tumors showing features of differentiation and pleomorphism

Large studies in England and Germany showed that vegetarians were about 40% less likely to develop cancer compared to meat eaters

• Harvard studies showed that daily meat eaters have approximately three times the colon cancer risk, compared to those who rarely eat meat • Countries with a higher intake of fat, especially fat from animal products, such as meat and dairy products, have a higher incidence of breast cancer • The consumption of high-fat foods such as meat, dairy products, fried foods, and even vegetable oils causes a woman's body to make more estrogens, which encourage cancer cell growth in the breast and other organs that are sensitive to female sex hormones

Liver metastasis

• Liver and lungs most frequently involved in hematogenous spread • All portal drainage flows to the liver

Uterine Leiomyoma, micro

• The microscopic appearance of this leiomyoma (a neoplasm arising from smooth muscle) indicates that the cells do not vary greatly in size and shape and closely resemble normal smooth muscle cells • Rather rounded ends/just like the cigars shown in the figure in the upper right hand corner

micrometastasis and occult metastasis in lymph node

•At UVM: IHC/immunohistochemical stains are not utilized for clinical interpretation of lymph nodes/unless suspicious cells are identified on H&E sections

Colonic polyp: benign glandular tumor Adenoma/adenomatous polyp aka tubular adenoma Projects into the colonic lumen and is attached to the mucosa by a distinct stalk

•Figure shows a tubular adenoma •Polyp - when a neoplasm, benign or malignant → produces a macroscopically visible projection above a mucosal surface •One sees a tinctorial difference (in intensity of staining) between the cells of the polyp and the surrounding (more normal-appearing) colonic mucosal cells

Nomenclature of tumors

•In general/benign tumors - so designated by the attachment of the suffix "oma" (exceptions are lymphoma, sarcoma, melanoma) •Malignant tumors - from mesenchymal tissue - called sarcomas •Malignant tumors of epithelial origin - called carcinomas (from any of the three germ layers) •The three "oma's" that are malignant: lymphoma, sarcoma, hepatoma (hepatocellular carcinoma)

Adenomatous polyp of the colon (micro)

•The polyps that become cancerous are called adenomatous polyps or adenomas. •Adenomatous polyps are, by definition, neoplastic/Although benign, they are the direct precursors of adenocarcinomas and follow a predictable cancerous temporal course unless interrupted by treatment/They can be either pedunculated or sessile • Adenomas account for approximately 75% of all colon polyps •There are several subtypes of adenoma that differ primarily in the way the cells of the polyp are assembled when they are examined under the microscope/Thus, there are tubular, villous, or tubulo-villous adenomas.

Grade III colorectal cancer

•Where are the glands? •Highly anaplastic undifferentiated cells (from any tissue) - lose their resemblance to the normal cells (from which they have arisen)****