General Pathology VPM 152

Enrique Aburto http://people.upei.ca/eaburto Winter 2015

Lecture 6 Carcinogenic agents (cont’d); Local &

Systemic effects of Neoplasms

Disorders of Cell Growth & Neoplasia

Lymphoma

Spinal cord compression

Radiation Carcinogenesis

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

• many skin tumors 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 damaged cells are either repaired (NER pathway) or undergo apoptosis.

• excessive sun exposure overwhelms the NER pathway (inability to repair DNA)

• 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 non-pigmented locations with sparse hair coat.

Squamous cell carcinomas, eyelid / conjunctiva, bovines. These masses are usually ulcerated.

SCC’s typically metastasize quite late and can become very large if left untreated.

Images from Noah’s arkive

Chronic Inflammation

• ROS by inflammatory cells and cell regeneration at sites of chronic

inflammation may result in genomic damage.

• proliferating fibroblasts secrete growth factors that contribute to neoplastic

transformation of the resident cells.

Intraocular sarcomas following traumatic rupture of the lens capsule in cats can develop months or years

after trauma. 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.

• sarcomas at sites of subcutaneous injection; 1 in 103 – 1 in 104; 4 months to 13-15

years after vaccination; FeLV & Rabies vaccines

Feline postvaccinal sarcomas

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

• a persistent inflammatory reaction → continued proliferation of resident mesenchymal

cells → neoplastic transformation.

Feline postvaccinal 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 22% of cases in other studies).

Courtesy Ohio State University

Spirocercosis, dog. Submucosal nodules can transform to become malignant tumors e.g fibrosarcoma (arrow heads). A section of the parasite is shown by the arrows

Pathologic Basis of Veterinary Disease (2006), 4thed.

Spirocerca lupi typically causes nodular granulomatous inflammation in the submucosa at the distal third of the esophagus (e) which eventually may evolve into fibrosarcomas (F) in domestic and wild canids.

F

F

e

stomach

e

Effects of Neoplasms in the host

Local Effects: 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.

Compression of the spinal cord (SC) by a

subdural lymphoma (L), bovine. Noah’s

arkive.

L

SC

Intestinal lymphoma (top) and intestinal adenocarcinoma

(bottom). There is obstruction due to luminal obliteration or

stenosis (arrows). The intestinal segment 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

Local effects: Rupture or Infarction of Tumor

Hemangiosarcomas are frequently often found on the right atrium / auricle (right). They are prone to rupture with subsequent hemopericardium and cardiac tamponade (left).

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 autonomously secrete excess glucocorticoids without regard to decreased ACTH levels.

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

From Noah’s arkive

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

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.

Hormonal effects

Adrenal-associated endocrinopathy in domestic ferrets. The syndrome is the result of proliferative lesions of the adrenal cortex (hyperplasia, adenoma or carcinoma) which secretes excess amounts of estrogens (hyperestrogenism). Affected animals exhibit a range of cutaneous, behavioral, and reproductive changes. Spayed females may show an enlarged vulva. Note the symmetrical alopecia (hair loss) of this ferret (see above). The picture below shows a massive adrenal cortical carcinoma in a ferret.

Cachexia

• 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; its degree may not correlate with the size

of the tumor.

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

Other Cytokines

• other cytokines, IL-1 & IF-γ act synergistically with TNF.

• proteolysis inducing factor (PIF) can directly catabolize fat & muscle.

Cachexia

Cancer Cells as Metabolic Parasites

• revert to anaerobic metabolism (converting glucose to lactate), a wasteful form of

energy production (2 vs 34 ATP)

• utilize 5-10 times as much glucose as normal tissues (negative energy balance)

Tumor Necrosis Factor (TNF)

• TNF-α produced by macrophages or tumor cells, a mediator of wasting in

malignancies and chronic infectious diseases.

• TNF-α induces a net catabolic state (↑ catabolism of muscle & fat).

Anemia

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

• decreased production of rbc’s by the bone marrow (from ↓ 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,

German Shepherd. Note multiple

dark-red nodules in the omentum.

The dog developed chronic

hemoperitoneum and anemia.

Paraneoplastic Syndromes

• “manifestations 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 be the main presenting sign in animals.

Paraneoplastic Endocrine Syndromes

• systemic effects that mimic an endocrinopathy.

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

normally produced by the organ / tissue of origin.

Paraneoplastic Syndromes

• can be more life-threatening than the neoplasm itself;

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.

T

• production of PTHrP by tumor cells → Pseudohyperparathyroidism.

• PTHrP similar to PTH, same receptor on target cells; product of a different gene.

• PTHrP is the major Ca2+-regulating hormone in fetuses.

i) Humoral Hypercalcemia of Malignancy (HHM)

Paraneoplastic Syndromes

• most commonly seen in:

adenocarcinoma of apocrine glands of the anal sac (dogs)

lymphoma (dogs & cats)

squamous cell carcinoma (cats)

gastric carcinoma (horses)

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.

Paraneoplastic Syndromes

Some Other Paraneoplastic Syndromes

i) Cutaneous paraneoplastic syndromes

• a variety of paraneoplastic dermatosis with obscure pathogenesis (dogs & cats)

• other hormone-like factors produced by tumors: 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

ii) Other paraneoplastic endocrine syndromes

Paraneoplastic Syndromes

Nodular dermatofibrosis and cystic renal

adenocarcinomas, dog. Note the presence of multiple

cutaneous nodules composed of collagen (N). These growths

have been described in German shepherds and other breeds

associated with renal tumors which are often multiple, bilateral

and cystic (cystadenocarcinomas, C). Uterine leiomyomas

(often pedunculated) are also seen in females.

N

N

C

C

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

Some other Paraneoplastic Syndromes

Best wishes in your final exam