Tumor 2 Pathology and Histology A model of

Tumor 2 Pathology and Histology

A model of neoplastic transformation (Scientific Truth? ) Mutation in gene A Normal Cell Mutation in gene B, C, etc. Increased proliferation Increasing chromosomal aneuploidy Benign neoplasia However, this is NOT cancer Carcinoma

Hepatocellular Carcinoma

THIS IS CANCER Renal Cell Carcinoma

Metastatic Carcinoma to Liver

Cancer is NOT one disease Deaths Incidence

Germ cell layers Cancers are also classified according to what germ cell layer they originate.

Terminology • Neoplasia – “new growth” • Tumor – swelling caused by inflammation, now tumor = neoplasm • Cancer – Latin cancer = crab, malignant tumors • Oncology – Greek oncos = tumor

Terminology Neoplasias are classified into two basic types: • Benign – mass of proliferating cells not subject to normal physicological controls which can increase in size but not invade surrounding tissue or spread to other parts of the body • Malignant – mass of proliferating cells not subject to normal physiological control with capacity to extend (invade) adjacent normal tissues and to spread (metastasize) to distant organ sites CANCER refers to virtually all malignant neoplasias

Mesenchymal – connective tissue & endothelial related Benign • • • Fibroma Lipoma Chondroma Osteoma Hemangioma Meningioma Malignant • • • Fibrosarcoma Liposarcoma Chondrosarcoma Osteogenic sarcoma Angiosarcoma Invasive meningioma • Synovial sarcoma • Mesothelioma

Epithelial origin Benign Malignant • Squamous cell carcinoma • Adenoma • Renal tubular adenoma • Liver cell adenoma • Hydatidiform mole • • Basal cell carcinoma Adenocarcinoma Renal cell carcinoma Hepatocellular carcinoma • Choriocarcinoma • Seminoma • Embryonal carcinoma

Macroscopic Criteria for Classification of: Benign Malignant • Structure typical of tissue of origin • Encapsulated • Slow growth • No metastasis • Atypical structure • Locally invasive, infiltrating • Rapid & erratic growth • Metastasis

Fibroadenoma Ductal carcinoma

Microscopic Criteria for Classification of: Benign Malignant • • Well differentiated Uniform N: C = 1: 4 or 1: 6 Rare normal mitotic figures • Normal orientation • Abundant stroma • Generally less well differentiated to undifferentiated (anaplastic) • Pleomorphic • N: C = 1: 1 • Hyperchromatic • More mitoses, abnormal & bizarre • Loss of polarity • Tumor giant cells

Abnormal mitoses Pleomorphic, hyperchromatic, multinucleated, giant, “bizarre”

Abnormal mitosis - Here are three abnormal mitoses. Mitoses by themselves are not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.

Spread of Tumors • Direct invasion – infiltration & destruction of surrounding tissue • Metastasis – noncontiguous spread to other organ/body locations – Lymphatics – carcinomas, lymphatic drainage – Veins & arteries – sarcomas, renal cell carcinoma, hepatocellular carcinoma – Implantation – “open field”, ovarian carcinomas, appendix = pseudomyxoma peritonei

Staging of Malignant Neoplasms Stage Definition Tis/T 0 In situ, non-invasive (confined to epithelium) T 1 Small, minimally invasive within primary organ site T 2 Larger, more invasive within the primary organ site T 3 Larger and/or invasive beyond margins of primary organ site T 4 Very large and/or very invasive, spread to adjacent organs N 0 No lymph node involvement N 1 Regional lymph node involvement N 2 Extensive regional lymph node involvement N 3 More distant lymph node involvement M 0 No distant metastases M 1 Distant metastases present In the diagram above utilizing a lung carcinoma as an example, the principles of staging are illustrated:

Grading of Malignant Neoplasms Grade Definition I Well differentiated II Moderately differentiated III Poorly differentiated IV Nearly anaplastic

Neoplasia • Uncontrolled new growth by cells that are no longer under complete physiologic control • Irreversible • May be benign or malignant

Lipoma - Of course, neoplasms can be benign as well as malignant, though it is not always easy to tell how a neoplasm will act. Here is a benign lipoma on the serosal surface of the small intestine. It has the characteristics of a benign neoplasm: it is well circumscribed, slow growing, non-invasive, and closely resembles the tissue of origin (fat).

Lipoma - At low power magnification, a lipoma of the stomach is seen to be well demarcated from the mucosa at the lower center -right. This neoplasm is so well-differentiated that, except for its appearance as a localized mass, it is impossible to tell from normal adipose tissue.

Lipoma - Here is the lipoma at high magnification. This is a good example of how a benign neoplasm mimics the tissue of origin. These neoplastic adipocytes are indistinguishable from normal adipocytes.

Liposarcoma - This large mass lesion is a liposarcoma. Common sites are the retroperitoneum and thigh, and they occur in middle aged to older adults. This one is yellowish, like adipose tissue, and is well-differentiated. Though indolent, it continues growing to reach a large size, and following excision, it has a tendency to recur.

Liposarcoma - This liposarcoma has enough differentiation to determine the cell of origin (adipocyte), but there is still significant pleomorphism of these neoplastic cells (lipoblasts).

Liposarcoma - At high magnification, large bizarre lipoblasts are seen in this liposarcoma. Sarcomas are best treated surgically, because most respond poorly to chemotherapy or radiation.

The first step toward epithelial neoplasia is cellular transformation Traditionally, two forms of cellular transformation have been recognized that are potentially reversible, but may be steps toward a neoplasm. These are: • Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away. • Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated. However, Hyperplasia: an increase in the number of phenotypically normal cells, may also reflect an early stage of transformation.

Metaplasia - The chronic irritation from cigarette smoke has led to an exchanging of one type of epithelium (the normal respiratory epithelium at the right) for another (the more resilient squamous epithelium at the left). Thus, there is metaplasia of normal respiratory laryngeal epithelium to squamous epithelium in response to chronic irritation of smoking.

Dysplasia • “disordered growth” • • • Loss in uniformity of the individual cells Loss of architectural orientation Pleomorphism Hyperchromatic Increased mitoses (normal) Carcinoma in situ • Dysplastic changes involve entire thickness of epithelium • If left untreated, will progress to invasive cancer

Dysplasia - This is the next step toward neoplasia. Here, there is normal cervical squamous epithelium at the left, but dysplastic squamous epithelium at the right. Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium. Dysplasia is still reversible.

Dysplasia - When the entire epithelium is dysplastic and no normal epithelial cells are present, then the process has gone beyond dysplasia and is now neoplasia. If the basement membrane is still intact, as shown here, then the process is called "carcinoma in situ" because the carcinoma is still confined to the epithelium. Neoplastic epithelium is termed carcinoma.

Carcinoma in situ

Cervical Cancer – neoplastic epithelium has created a gross mass (tumor) and invaded underlying tissue.

Cervical Cancer – This is the microscopic appearance of neoplasia, or uncontrolled new growth. Here, the neoplasm is infiltrating into the underlying cervical stroma.

Squamous Cancer - This is a squamous cell carcinoma. Note the disorderly growth of the squamous epithelial cells in these large nests with pink keratin in the centers. Neoplasms may retain characteristics of their cell of origin. Benign neoplasms mimic the cell of origin very well, but malignant neoplasms less so.

Adenomatous polyps - Multiple adenomatous polyps (tubulovillous adenomas) of the cecum are seen here in a case of familial adenomatous polyposis, a genetic syndrome in which an abnormal genetic mutation leads to development of multiple neoplasms in the colon.

Differentiation - The concept of differentiation is demonstrated by this small adenomatous polyp (tubular adenoma) of the colon. Note the difference in staining quality between the epithelial cells of the adenoma at the top and the normal glandular epithelium of the colonic mucosa below.

Adenocarcinoma - micro - The infiltrating glands of this colonic adenocarcinoma demonstrate less differentiation than the adenomatous polyp, although they still resemble glands. In general, less differentiation of a neoplasm means a greater likelihood of malignant behavior. This is the basis for grading. The higher the grade, the more aggressive the malignant neoplasm. Benign neoplasms are not graded.

Prostate Gland - This is the gross appearance of nodular prostatic hyperplasia (benign prostatic hyperplasia, or BPH). The normal prostate is 3 to 4 cm in cross section, by comparison Prostate Gland - The normal appearance of prostate is shown at high magnification. Note the small pink laminated concretion (these are corpora amylacea) in the gland lumen to the left of center. Note the infoldings of the columnar epithelium.

Prostatic Adenocarcinoma - The gross appearance of adenocarcinoma of the prostate is shown here in cross section. The entire prostate is involved. The yellowish nodules represent larger foci of carcinoma. Prostatic Adenocarcinoma - At low magnification, a needle biopsy of prostate is seen. The biopsy is filled with back-toback glands with nuclei demonstrating hyperchromatism and pleomorphism. This is adenocarcinoma of prostate.

Tumor Invasion Lung Cancer Malignant neoplasms are also characterized by their tendency to invade surrounding tissues. Here, the tan tissue of a lung cancer is seen to be spreading along the bronchi into the surrounding lung. The dark round areas are lymph nodes also involved by the neoplasm.

Lung Cancer - This is a squamous cell carcinoma of the lung. It is a bulky mass that extends into surrounding lung parenchyma.

Breast Cancer - This infiltrating ductal carcinoma of the breast is definitely infiltrating the surrounding breast. The central white area is very hard and gritty, because the neoplasm is producing a desmoplastic reaction with lots of collagen. This is often called a "scirrhous" appearance. There is also focal dystrophic calcification leading to the gritty areas.

Breast Cancer - At high magnification, the infiltrating ductal carcinoma of breast has pleomorphic cells infiltrating through the stroma. Note the abundant pink collagen bands from desmoplasia, making the tumor feel firmer than normal breast tissue on palpation.

Perineural Invasion - Branches of peripheral nerve are invaded by nests of malignant cells. This is termed perineural invasion. This is often the reason why pain associated with cancers is unrelenting.

Metastases • A primary neoplasm is more likely to appear within an organ as a solitary mass. • The presence of metastases are the best indication that a neoplasm is malignant. The original clone of cells that developed into a neoplasm may not have had the ability to metastasize, but continued proliferation of the neoplastic cells and acquisition of more genetic mutations within the neoplastic cells can give them the ability to metastasize.

Peritoneal Metastases - Neoplasms can spread by seeding within body cavities such as the pleural cavity or peritoneal cavity. This pattern of spread is more typical for carcinomas than other neoplasms. Note the multitude of small tan tumor nodules seen over the peritoneal surface of the mesentery shown here.

Metastatic Carcinoma within Vessel - Both lymphatic and hematogenous spread of malignant neoplasms is possible to distant sites. Here, a breast carcinoma has spread to a lymphatic within the lung.

Metastatic Breast Cancer to Lung Pleura - Here is microscopic evidence of the spread of a carcinoma via body cavities. A focus of metastatic breast carcinoma is present along the pleura overlying the lung.

Sarcoma - This large fleshy mass arose in the retroperitoneum and is an example of a sarcoma. Sarcomas arise within mesenchymal tissues. This one happened to be a "malignant fibrous histiocytoma" which is a wastebasket term for sarcomas that do not resemble mesenchymal cells such as striated muscle (rhabdomyosarcoma), smooth muscle (leiomyosarcoma), fat (liposarcoma), blood vessels (angiosarcoma), bone (osteosarcoma), or cartilage (chondrosarcoma). Sarcomas tend to be big and bad. Examples of Non Epithelial Cancers

Sarcoma - Sarcomas tend to have a spindle cell pattern. Note that some of these neoplastic cells are much larger than others, and thus very pleomorphic.

Osteosarcoma - Here is an osteosarcoma of bone. The large, bulky mass arises in the cortex of the bone and extends outward. Osteosarcoma - The osteosarcoma is composed of spindle cells. The pink osteoid formation seen here is consistent with differentiation that suggests osteosarcoma

Summary • There is increasing emphasis from funding agencies for investigators performing cancer research to demonstrate a ‘Translational’ component between their studies and the clinical condition. • In order to make a VALID linkage between the investigator’s model system and the cancer being studied by the basic science investigator, an understanding of the histogenesis and histopathologic classification of the cancer they are studying is essential.