Disorders of Cell Growth & Neoplasia Lecture 6people.upei.ca/hanna/Neoplasia6/Neopl-L6WEB-10.pdf ·...
Transcript of Disorders of Cell Growth & Neoplasia Lecture 6people.upei.ca/hanna/Neoplasia6/Neopl-L6WEB-10.pdf ·...
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
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