LARGE INTESTINE (COLON) 

Congenital anomalies 

1. Hirschsprung's disease produces a markedly distended colon, usually proximal to the rectum. Caused by a section of aganglionic colon, which failed to develop normally due to the absence of ganglion cells).
This results in bowel obstruction and distention of the bowel proximal to the affected area.

2. Imperforate anus is due to a failure of perforation of the membrane that separates the endodermal hindgut from the ectodermal anal dimple. 

Benign conditions

1. Diverticular disease refers to multiple outpouchings of the colon.
Incidence. Diverticular disease is present in 30%-50%  adult autopsies in the United States. There is a higher dence with increasing age. 
Pathogenesis. Herniation of mucosa and submucoq through weak areas of the gut wall where arterial vasa recta perforate the muscularis is a characteristic pathological finding of the disease. 

Clinical features

- Diverticulosis is often asymptomatic, but may present with pain and/or rectal bleeding.
- In contrast, diverticulitis presents with pain and fever.  It is distinguished from diverticulosis by the presence of inflammation, which may or may not cause symptom. 

When symptomatic, the patlent experiences colicky left lower abdominal pain, change in bowel habits, and melena, so-called " left-sided appendicitis." 

Pathology 
Grossly, diverticula are seen most frequently in the sigmoid colon. 

Inflammatory diseases 

1. Crohn's disease, or regional enteritis, causes a segmental, recurrent, granulomatous inflammatory disease of the bowel. It most commonly involves the terminal ileum and colon but may involve any part of the gastrointestinal tract. There is a familial disposition. 
Etiology.

There is probably a similar etiology for both Crohn's disease and ulcerative colitis, which together are called inflammatory bowel disease. The following possible etiologies have been considered: infectious; immunologic (both antibody-mediated and cell-mediated); deficiencies of suppressor cells; and nutritional, hormonal, vascular, and traumatic factors. 

Clinical features.

Crohn's disease usually begins in early adulthood and is common in Ashkenazic Jews. Patients present with colicky pain, diarrhea, weight loss, malaise, malabsorption, low-grade fever, and melena. There is typically a remitting and relapsing course. If the involved bowel is resected, lesions frequently develop in previously uninvolved regions of the bowel. 

Pathology. Crohn's disease has a very characteristic pathology. 
Grossly, there are segmental areas (skip lesions) of involvement, most commonly in the terminal ileum. 

3. Ulcerative colitis is a chronic relapsing disease characterized by ulcerations, predominantly of the rectum and left colon, but which may affect the entire colon and occasionally the terminal ileum.

Incidence is higher in Caucasians than in Blacks, and is also more frequent in women than in men. The typical age of onset ranges from 12-35 years of age. There is a definite familial predisposition. 

Etiology. Etiologic theories are similar to those for Crohn's disease. Some inflammatory bowel disease has microscopic  features of both ulcerative colitis and Crohn's disease. 

Clinical course is characterized by relapsing bloody mucus diarrhea, which may lead to dehydration and electrolyte  imbalances, lower abdominal pain, and cramps. There is an  increased incidence of carcinoma of the colon, up to 50% after 25 years with the disease. 

Pathology 

Grossly, the disease almost always involves the rectum. It may extend proximally to involve part of the colon or its entirety. There are superficial mucosal ulcers, shortening of the bowel, narrowing of the lumen, pseudopolyps, and backwash ileitis. 

In contrast to Crohn's disease, the inflammation is usually confined to the mucosa and submucosa. 

Pseudomembranous colitis is an inflammatory process characterized by a pseudomembranous exudate coating the colonic mucosa 

Pathogenesis. The syndrome is associated with antibiotic  use (especially clindamycin), allowing proliferation of Clostridium difficile, which produces an exotoxin.

Clinical features include diarrhea that is often bloody, fever, and leukocytosis.
Diagnosis is made by identification of C. difficile and toxin  in stool.
Treatment includes stopping the original antibiotic and starting oral vancomycin or metronidazole. This disease is often a terminal complication in immunosuppressed patients. 

Vascular lesions 
Hemorrhoids are variceal dilatations of the anal and perianal venous plexus. They are caused by elevated intra-abdominal venous pressure, often from constipation and pregnancy and are occasionally due to portal hypertension, where they are associated with esophageal varices. Hemorrhoids may under thrombosis, inflammation, and recanalization. External hemorrhoids are due to dilatation of the inferior hemorrhoidal
plexus, while internal hemorrhoids are due to dilatation of the superior hemorrhoidal plexus. 

Polyps are mucosal protrusions. 

1. Hyperplastic polyps comprise 90% of all polyps. They are no neoplastic and occur mostly in the rectosigmoid colon. 
Grossly, they form smooth, discrete, round elevations.

2. Adenomatous polyps are true neoplasms. There is a higher incidence of cancer in larger polyps and in those containing a greater proportion of villous growth.

a. Tubular adenomas (pedunculated polyps) make up 75% of adenomatous polyps. They may be sporadic or familial 

For sporadic polyps, the ratlo of men to women is 2:1. The average age of onset is 60. 
Grossly, most occur in the left colon. Cancerous transformation (i.e., invasion of the lamina propria or the stalk) occurs in approximately 4% of patients.

b. Villous adenomas are the largest, least common polyps, and are usually sessile. About one-third are cancerous. Most are within view of the colonoscope. 
(1) Grossly, they form "cauliflower-like" sessile growth 1-10 cm in diameter, which are broad-based and have no stalks. 

3. Familial polyposis is due to deletion of a gene located on chromosome 5q. 

Familial multiple polyposis (adenomatous polyposis coli) shows autosomal dominant inheritance and the appearance of polyps during adolescence; polyps start in the rectosigmoid area and spread to cover the entire colon. The polyps are indistinguishable from sporadic adenomatous polyps. Virtually all patients develop cancers. When diagnosed, total colectomy is recommended. 

Gardner's syndrome refers to colonic polyps associated with other neoplasms (e.g., in skin, subcutaneous tissue, bone) and desmoid tumors. The risk of colon cancer is nearly 100%. 

Peutz-Jeghers syndrome presents with polyps on the entire gastrointestinal tract (especially the small intestine) associ-
ated with melanin pigmentation of the buccal mucosa, lips, palms, and soles. The polyps are hamartomas and are not premalignant. Peutz-Jeghers syndrome shows autosomal dominant inheritance. 

Turcot's syndrome is characterized by colonic polyps associated with brain tumors (i.e., gliomas, medulloblastomas). 

Malignant tumors 

Adenocarcinoma is the histologic type of 98% of all colonic cancers. Both environmental and genetic factors have been
identified.

Incidence is very high in urban, Western societies. It is the  third most common tumor in both women and men. The peak incidence
is in the seventh decade of life. 

Pathogenesis is associated with villous adenomas, ulcerative colitis, Crohn's disease, familial polyposis, and Gardner's syndrome. lncidence is possibly related to high meat intake, low-fiber diet, and deficient vitamin intake. A number of chromosomal abnormalities hme been associated with the development of colon cancer. 

Clinical features include rectal bleeding, change in bow habits, weakness, malaise, and weight loss in high-stage disease. The tumor spread by direct metastasis to nodes, liver, lung, and bones. carcinoembryonic antigen (CEA) is a tumor marker that helps to monitor tumor recurrence after surgery or tumor progression in  some patients.

Pathology 
(1) Grossly, 75% of tumors occur in the rectum and sigmoid colon.
(2) Microscopically, these tumors are typical mucin-producing adenocarcinomas. 
2. Squamous cell carcinoma forms in the anal region. It is often associated with papilloma viruses and its incidence is rising in homosexual males with AIDS. 

Other lung diseases

1.Sarcoidosis

1. Sarcoidosis

a. More common in African-Americans.

b. Associated with the presence of noncaseating granulomas.

Sarcoidosis is an immune system disorder characterised by non-necrotising granulomas (small inflammatory nodules). Virtually any organ can be affected, however, granulomas most often appear in the lungs or the lymph nodes.

Signs and symptoms

• Sarcoidosis is a systemic disease that can affect any organ. Common symptoms are vague, such as fatigue unchanged by sleep, lack of energy, aches and pains, dry eyes, blurry vision, shortness of breath, a dry hacking cough or skin lesions. The cutaneous symptoms are protean, and range from rashes and noduli (small bumps) to erythema nodosum or lupus pernio
• Renal, liver, heart or brain involvement may cause further symptoms and altered functioning. Manifestations in the eye include uveitis and retinal inflammation
• Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis.
• Hypercalcemia (high calcium levels) and its symptoms may be the result of excessive vitamin D production
• Sarcoidosis most often manifests as a restrictive disease of the lungs, causing a decrease in lung volume and decreased compliance (the ability to stretch). The vital capacity (full breath in, to full breath out) is decreased, and most of this air can be blown out in the first second. This means the FEV1/FVC ratio is increased from the normal of about 80%, to 90%.

Treatment

Corticosteroids, most commonly prednisone

2. Cystic fibrosis

a. Transmission: caused by a genetic mutation (nucleotide deletion) on chromosome 7, resulting in abnormal chloride channels.

b. The most common hereditary disease in Caucasians.

c. Genetic transmission: autosomal recessive.

d. Affects all exocrine glands. Organs affected include lungs, pancreas, salivary glands, and intestines. Thick secretions or mucous plugs are

seen to obstruct the pulmonary airways and intestinal tracts.

e. Is ultimately fatal.

f. Diagnostic test: sweat test—sweat contains increased amounts of chloride.

3. Atelectasis

a. Characterized by collapse of the alveoli.

b. May be caused by a deficiency of surfactant and/or hypoventilation of alveoli.

Osteoporosis
 
is characterized by increased porosity of the skeleton resulting from reduced bone mass. The disorder may be localized to a certain bone (s), as in disuse osteoporosis of a limb, or generalized involving the entire skeleton. Generalized osteoporosis may be primary, or secondary

Primary generalized osteoporosis
• Postmenopausal
• Senile
Secondary generalized osteoporosis

A. Endocrine disorders
• Hyperparathyroidism
• Hypo or hyperthyroidism
• Others

B. Neoplasia
• Multiple myeloma
• Carcinomatosis 

C. Gastrointestinal disorders
• Malnutrition & malabsorption
• Vit D & C deficiency
• Hepatic insufficiency 

D. Drugs
• Corticosteroids
• Anticoagulants
• Chemotherapy
• Alcohol 

E. Miscellaneous
• osteogenesis imperfecta
• immobilization
• pulmonary disease 

Senile and postmenopausal osteoporosis are the most common forms. In the fourth decade in both sexes, bone resorption begins to overrun bone deposition. Such losses generally occur in areas containing abundant cancelloues bone such as the vertebrae & femoral neck. The postmenopausal state accelerates the rate of loss; that is why females are more susceptible to osteoporosis and its complications. 

Gross features
• Because of bone loss, the bony trabeculae are thinner and more widely separated than usual. This leads to obvious porosity of otherwise spongy cancellous bones

Microscopic features
• There is thinning of the trabeculae and widening of Haversian canals.
• The mineral content of the thinned bone is normal, and thus there is no alteration in the ratio of minerals to protein matrix

Etiology & Pathogenesis

• Osteoporosis involves an imbalance of bone formation, bone resorption, & regulation of osteoclast activation. It occurs when the balance tilts in favor of resorption.
• Osteoclasts (as macrophages) bear receptors (called RANK receptors) that when stimulated activate the nuclear factor (NFκB) transcriptional pathway. RANK ligand synthesized by bone stromal cells and osteoblasts activates RANK. RANK activation converts macrophages into bone-crunching osteoclasts and is therefore a major stimulus for bone resorption.
• Osteoprotegerin (OPG) is a receptor secreted by osteoblasts and stromal cells, which can bind RANK ligand and by doing so makes the ligand unavailable to activate RANK, thus limiting osteoclast bone-resorbing activity.
• Dysregulation of RANK, RANK ligand, and OPG interactions seems to be a major contributor in the pathogenesis of osteoporosis. Such dysregulation can occur for a variety of reasons, including aging and estrogen deficiency.
• Influence of age: with increasing age, osteoblasts synthetic activity of bone matrix progressively diminished in the face of fully active osteoclasts.
• The hypoestrogenic effects: the decline in estrogen levels associated with menopause correlates with an annual decline of as much as 2% of cortical bone and 9% of cancellous bone. The hypoestrogenic effects are attributable in part to augmented cytokine production (especially interleukin-1 and TNF). These translate into increased RANK-RANK ligand activity and diminished OPG.
• Physical activity: reduced physical activity increases bone loss. This effect is obvious in an immobilized limb, but also occurs diffusely with decreased physical activity in older individuals.
• Genetic factors: these influence vitamin D receptors efficiency, calcium uptake, or PTH synthesis and responses.
• Calcium nutritional insufficiency: the majority of adolescent girls (but not boys) have insufficient dietary intake of calcium. As a result, they do not achieve the maximal peak bone mass, and are therefore likely to develop clinically significant osteoporosis at an earlier age.
• Secondary causes of osteoporosis: these include prolonged glucocorticoid therapy (increases bone resorption and reduce bone synthesis.)
The clinical outcome of osteoporosis depends on which bones are involved. Thoracic and lumbar vertebral fractures are extremely common, and produce loss of height and various deformities, including kyphoscoliosis that can compromise respiratory function. Pulmonary embolism and pneumonia are common complications of fractures of the femoral neck, pelvis, or spine. 

PRIMARY LYMPHEDEMA  
can occur as:
1- A congenital defect, resulting from lymphatic agenesis or hypoplasia.  

2- Secondary or obstructive lymphedema  
- blockage of a previously normal lymphatic; e.g. Malignant tumors 
- Surgical procedures that remove lymph nodes 
- Postirradiation  
- Fibrosis 
- Filariasis 
- Postinflammatory thrombosis and scarring 

Diagnostic techniques used in pathology

The pathologist uses the following techniques to the diagnose diseases:

a. Histopathology

b. Cytopathology

c. Hematopathology

d. Immunohistochemistry

e. Microbiological examination

f. Biochemical examination

g. Cytogenetics

h. Molecular techniques

i. Autopsy

Histopathological techniques

Histopathological examination studies tissues under the microscope. During this study, the pathologist looks for abnormal structures in the tissue. Tissues for histopathological examination are obtained by biopsy. Biopsy is a tissue sample from a living person to identify the disease. Biopsy can be either incisional or excisional.

Once the tissue is removed from the patient, it has to be immediately fixed by putting it into adequate amount of 10% Formaldehyde (10% formalin) before sending it to the pathologist.

The purpose of fixation is:

1. to prevent autolysis and bacterial decomposition and putrefaction

2. to coagulate the tissue to prevent loss of easily diffusible substances

3. to fortify the tissue against the deleterious effects of the various stages in the preparation of sections and tissue processing.

 4. to leave the tissues in a condition which facilitates differential staining with dyes and other reagents.