General Pathology

VPM 152

Disorders of Cell Growth

& Neoplasia

Lecture 6Carcinogenic agents (contd), Local and Systemic

Effects of Neoplasms

Enrique Aburto Apr 2010

Radiation Carcinogenesis

• ionizing radiation, either weak (UV rays) or strong (medical) can induce neoplasia.

• many skin tumors in humans & animals are induced by UV light exposure.

• degree of risk associated with: type of UV rays (esp UV-B),

intensity of exposure (eg equator, high altitude)

amount of protective pigmentation (esp white regions)

• most cells with DNA damage are either repaired (NER pathway) or undergo apoptosis.

• postulated that excessive sun exposure overwhelms the capacity of the NER pathway.

• carcinogenicity is due to mutations arising from pyrimidine dimer formation.

• p53 and RAS are particularly prone to mutation by UV light.

The tumor most frequently associated with prolonged exposure to UV light in domestic animals is squamous cell

carcinoma. They typical occur in locations with lack of pigment and/or sparse hair coat.

Squamous cell carcinomas of

the skin / conjunctiva are often

ulcerated, bovines.

They typically metastasize

quite late and can become

very large if left untreated.

Chronic Inflammation

• generation of ROS by inflammatory cells and the continuous regeneration of cells to

replace ones lost at sites of chronic inflammation may result in genomic damage.

• this damage / proliferation may, over time, progress to neoplastic transformation.

• proliferating fibroblasts at the site of chronic inflammation can secrete growth factors

that contribute to neoplastic transformation of some of the resident cells.

Intraocular sarcomas can develop in the eyes of cats months or years after trauma to the eye with lens

rupture. Cross-section of normal globe (left). In the central photo, the white tumor tissue fills most of the

globe and a metallic fragment is indicated by the arrow (likely pellet or BB). In the photo to the right, the

globe is filled by the sarcomatous mass.

• development of sarcomas in some cats at sites of subcutaneous injection (~5 per 104).

Feline Vaccine-site Sarcomas

• a variety of sarcomas are seen, eg fibrosarcomas, chondrosarcomas, etc.

• a persistent inflammatory / immunologic reaction induces continued proliferation of

resident mesenchymal cells; may in some cases lead to neoplastic transformation.

Feline vaccine-site sarcomas typically show extensive local invasion with

frequent local recurrence. Metastasis, especially to local lymph nodes and lung,

has been reported (low in some studies, but up to 25% of cases in other studies).

Effects of Neoplasms in the host

Local Effects and Compression of Adjacent Structures

• expansile growth of benign pituitary / brain tumors can compress adjacent structures.

Adenoma, pituitary gland (sagittal section), dog. A large pituitary adenoma (A) has extended dorsally and

compresses the overlying brain. The optic chiasm (arrow) is also severely compressed. The adenohypophysis,

neurohypophysis, and hypothalamus have been destroyed by the neoplasm. Pathologic Basis of Veterinary Disease(2006), 4th ed., Mosby-Elsevier.

Intestinal lymphoma (top) and intestinal adenocarcinoma

(bottom), dogs. There is obstruction due to obliteration of the

lumen (arrows). The proximal portion proximal to the site of

obstruction is dilated (d).

Squamous cell carcinoma, skin, ventral

thorax/abdomen dog. The tumor is completely

ulcerated

d

• benign or malignant tumors can cause local

obstruction of tubular organs (intestinal or

urinary tract).

• tumors on organ surfaces can have

ulceration, bleeding, 2o infections.

Local Effects (obstruction, ulceration and

infection)

Rupture, bleeding or Infarction of Tumor

Hemangiosarcomas are frequently

often found on the right atrium / auricle

(bottom right). They are prone to rupture

with subsequent hemopericardium

(above).

Hormonal effects

Systemic Effects of Neoplasms

The two most common causes of hyperadrenocorticism (excess glucorticoids) in the dog are illustrated by the

two lesions above. A pituitary adenoma (right) autonomously secreting ACTH will cause bilateral diffuse adrenal

cortical hyperplasia and an accompanying excess in glucocorticoids. Alternatively, an adrenal cortical adenoma

(left) can, in some cases, autonomous secrete excess glucocorticoids without regard to decreased ACTH levels.

Pathologic Basis of Veterinary Disease(2006), 4th ed., Mosby-Elsevier.

Robbins and Cotran Pathologic Basis of Disease (2010),

8th ed., Elsevier, Inc.

Pathologic Basis of Veterinary Disease(2006), 4th ed., Mosby-Elsevier.

Hormonal effects

Sertoli cell tumor, testicle, dogs. This tumor is

usually benign but commonly associated with the

production of estrogens and a feminization syndrome

in dogs. Symmetrical alopecia and hyperpigmentation,

hyperestrogenism, skin, dog. Note the

symmetrical alopecia (hair loss) and

hyper­pigmentation over the caudal dorsal trunk

and caudolateral hind legs. In male dogs, the

symmetrical alopecia in conjunction with

enlargement of nipples, pendulous prepuce, and

attraction of other male dogs suggest the

possibility of hyperestrogenism.

Cachexia

• designates a progressive weight loss due to decreased muscle mass and fat stores.

• result of cytokines produced by tumor cells or host cells in response to the tumor.

can be the first clinical sign noticed and its degree does not necessarily correlate

with the total mass of the neoplastic tissue.

some types of human cancer are more prone than others to induce cachexia.

Other Cytokines

• other cytokines produced by macrophages, eg IL-1 & IF-γ act synergistically with TNF.

• other soluble factors from tumor cells (eg PIF) can directly catabolize fat & muscle.

Cachexia

Cancer Cells as Metabolic Parasites

• cancer cells tend to revert to anaerobic metabolism (converting glucose to lactate)

even in the presence of oxygen (2 vs 34 ATP).

• malignant cells tend to utilize anywhere from 5-10 times as much glucose as normal

tissues.

Tumor Necrosis Factor (TNF)

• TNF-α produced by macrophages or tumor cells themselves, is an important

mediator of wasting in malignancies and chronic infectious diseases.

• TNF-α induces a net catabolic state by increasing catabolism of specific tissues.

Anemia

• common manifestation of chronic disease (infections / malignancies).

• mainly due to decreased production of rbc’s by the bone marrow resulting from

decreased availability of iron.

• a mild decrease in the life-span of erythrocytes also occurs.

• chronic blood loss from hemorrhages within the tumor or adjacent tissues.

Disseminated (multicentric?)

hemangiosarcoma omentum, dog.

Note multiple dark-red nodules in the

omentum. The dog developed chronic

hemoperitoneum and anemia.

Paraneoplastic Syndromes

• definition = "symptom complexes in cancer-bearing patients that cannot readily be

explained, either by the local or distant spread of the tumor or by the elaboration of

hormones indigenous to the tissue from which the tumor arose"

• in ~15% of human patients with advanced malignant disease; can occasionally appear

as a manifestation of an occult, small neoplasm.

• not as prevalent in vet. med.; occasionally can be the main presenting sign.

Paraneoplastic Syndromes

• refers to systemic effects that in some way mimic an endocrinopathy.

• occur when tumors secrete hormones or hormone-like substances that are not

normally produced by the organ / tissue of origin.

Paraneoplastic Endocrine Syndromes

• can be more immediately life-threatening than

the neoplasm itself, since it may cause severe GI

and CNS disturbances, cardiac arrhythmias and

nephropathy.

i) Humoral Hypercalcemia of Malignancy (HHM)

Adenocarcinoma, apocrine glands of right

anal sac, anus, dog. The right perianal region

is distended by a small adenocarcinoma

(arrow), which has compressed the right side of

the anus. It also projects, as two nodules, on

the dorsolateral margin of the anus. T, Tail.

Pathologic Basis of Veterinary Disease(2006), 4th ed., Mosby-Elsevier.

T

• production of PTHrP by tumor cells is a major factor inducing HHM .

• PTHrP has some sequence homology with PTH, shares the same receptor on target

cells, but is immunologically distinct from PTH and is the product of a separate gene.

i) Humoral Hypercalcemia of Malignancy (HHM)

Paraneoplastic Syndromes

• PTHrP has a normal paracrine function in adults and is the major Ca2+-regulating

hormone in fetuses.

• In Vet. Med. most commonly seen in dogs with:

adenocarcinoma of apocrine glands of the anal sac.

lymphoma.

Adenocarcinoma, apocrine glands, anal sac,

dorsal plane, dog. A 1-cm-diameter nodule

(arrows) derived from apocrine glands of the wall

of the right anal sac protrudes into the lumen of the

anal sac. Anal sacs (A) are present on both sides

of the rectum (R).

Pathologic Basis of Veterinary Disease(2006), 4th ed., Mosby-Elsevier.

Paraneoplastic Syndromes

Some Other Paraneoplastic Syndromes

i) Cutaneous paraneoplastic syndromes

• a variety of paraneoplastic dermatosis, with obscure pathogenesis, esp. dogs & cats.

• other hormone-like factors have been found to be produced by tumors,

eg ACTH-like substance, TSH-like substance, insulin-like substance, erythropoietin.

Feline Paraneoplastic Alopecia – this syndrome is seen on rare occasions in cats with internal malignancies;

particularly pancreatic, biliary or intestinal adenocarcinomas. The bilaterally symmetric hair loss (alopecia) seen

above is from a cat with pancreatic adenocarcinoma.

Vet Dermatol 1997

Paraneoplastic Syndromes

Some Other Paraneoplastic Syndromes

ii) Paraneoplastic neurologic syndromes

iii) Coagulation abnormalities associated with thrombocytopenia

iv) Myasthenia gravis in cats with thymoma

v) Hypoglycemia associated with intraabdominal leiomyomas / leiomyosarcomas

vi) Persistent leukocytosis (often neutrophilia) associated with carcinomas

Nodular

dermatofibrosis and

multiple cystic renal

adenocarcinomas,

dog.

Hypoplasia

Agenesis / Aplasia

Dysplasia

Hyperplasia

Metaplasia

Dysplasia

Hamartoma

Choristoma

Cellular Aging

DISTURBANCES OF GROWTH

Terminology Benign

Malignant

Mixed Tumors

Teratomas

Oncogenic Viruses

Oncogenic RNA viruses

Oncogenic DNA viruses

Chemical Carcinogenesis

Chronic Inflammation

Carcinogenic Agents

Radiation Carcinogenesis

Systemic Effects of Neoplasms

Local Effects and Compression of Adjacent Structures

Rupture or Infarction of Tumor

Hormonal effects

Cachexia

Anemia

Paraneoplastic Syndromes

Best wishes in your final exam

LABORATORY PRACTICAL EXAM

Wednesday April 15, 2009

YOU NEED TO BRING: CLIP BOARD (TO WRITE ON), PEN / PENCIL

YOU NEED TO WEAR: LAB COAT & GLOVES

REMINDERS: Read the history carefully and answer the questions that

are asked!

There will be 25 stations with 80 minutes to complete the exam - so

organize your time accordingly (no more than 2 people at any one

station at a time).

With 30 students and 25 stations there will be times when there are 2

people at one station. The exam will be videotaped and there will be

numerous instructors milling about to prevent cheating.

SCHEDULE: Group A 9:30 to 10:50 - Aalders to Layton

Group B 11:00 to 12:20 - Leach to Wyer