General Pathology VPM 152. Disorders of Cell Growth & Neoplasia. Lecture 6 Carcinogenic agents (contd), Local and Systemic Effects of Neoplasms

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1 General Pathology VPM 152 Disorders of Cell Growth & Neoplasia Lecture 6 Carcinogenic agents (contd), Local and Systemic Effects of Neoplasms Enrique Aburto Apr 2010

2 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) carcinogenicity is due to mutations arising from pyrimidine dimer formation. 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. p53 and RAS are particularly prone to mutation by UV light.

3 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.

4 They typically metastasize quite late and can become very large if left untreated. Squamous cell carcinomas of the skin / conjunctiva are often ulcerated, bovines.

5 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. proliferating fibroblasts at the site of chronic inflammation can secrete growth factors that contribute to neoplastic transformation of some of the resident cells. this damage / proliferation may, over time, progress to neoplastic transformation. 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.

6 Feline Vaccine-site Sarcomas development of sarcomas in some cats at sites of subcutaneous injection (~5 per 10 4 ). 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).

7 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), 4 th ed., Mosby-Elsevier.

8 Local Effects (obstruction, ulceration and infection) benign or malignant tumors can cause local obstruction of tubular organs (intestinal or urinary tract). tumors on organ surfaces can have ulceration, bleeding, 2 o infections. d Squamous cell carcinoma, skin, ventral thorax/abdomen dog. The tumor is completely ulcerated 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).

9 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).

10 Systemic Effects of Neoplasms Hormonal effects Pathologic Basis of Veterinary Disease(2006), 4 th ed., Mosby-Elsevier. Robbins and Cotran Pathologic Basis of Disease (2010), 8 th ed., Elsevier, Inc. 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.

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

12 Cachexia designates a progressive weight loss due to decreased muscle mass and fat stores. 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. result of cytokines produced by tumor cells or host cells in response to the tumor.

13 Cachexia 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. 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. 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.

14 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.

15 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.

16 Paraneoplastic Syndromes Paraneoplastic Endocrine 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. i) Humoral Hypercalcemia of Malignancy (HHM) can be more immediately life-threatening than the neoplasm itself, since it may cause severe GI and CNS disturbances, cardiac arrhythmias and nephropathy. T 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), 4 th ed., Mosby-Elsevier.

17 Paraneoplastic Syndromes i) Humoral Hypercalcemia of Malignancy (HHM) 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. PTHrP has a normal paracrine function in adults and is the major Ca 2+ -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), 4 th ed., Mosby-Elsevier.

18 Paraneoplastic Syndromes Some Other Paraneoplastic Syndromes other hormone-like factors have been found to be produced by tumors, eg ACTH-like substance, TSH-like substance, insulin-like substance, erythropoietin. i) Cutaneous paraneoplastic syndromes a variety of paraneoplastic dermatosis, with obscure pathogenesis, esp. dogs & cats. Vet Dermatol 1997 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.

19 Paraneoplastic Syndromes Some Other Paraneoplastic Syndromes ii) Paraneoplastic neurologic syndromes iii) Coagulation abnormalities associated with thrombocytopenia iv) Myasthenia gravis in cats with thymoma Nodular dermatofibrosis and multiple cystic renal adenocarcinomas, dog. v) Hypoglycemia associated with intraabdominal leiomyomas / leiomyosarcomas vi) Persistent leukocytosis (often neutrophilia) associated with carcinomas

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21 DISTURBANCES OF GROWTH Agenesis / Aplasia Hypoplasia Dysplasia Hyperplasia Metaplasia Dysplasia Hamartoma Choristoma Cellular Aging

22 Terminology Benign Malignant Mixed Tumors Teratomas

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24 Carcinogenic Agents Oncogenic Viruses Oncogenic RNA viruses Oncogenic DNA viruses Chemical Carcinogenesis Radiation Carcinogenesis Chronic Inflammation

25 Systemic Effects of Neoplasms Local Effects and Compression of Adjacent Structures Rupture or Infarction of Tumor Hormonal effects Cachexia Anemia Paraneoplastic Syndromes

26 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 Best wishes in your final exam