DIPHTHERIA

An acute, contagious disease caused by Corynebacterium diphtheriae, characterized by the formation of a fibrinous pseudomembrane, usually on the respiratory mucosa, and by myocardial and neural tissue damage secondary to an exotoxin.

Cutaneous diphtheria (infection of the skin) can occur when any disruption of the integument is colonized by C. diphtheriae. Lacerations, abrasions, ulcers, burns, and other wounds are potential reservoirs of the organism. Skin carriage of C. diphtheriae is also a silent reservoir of infection.

Pathology

C. diphtheriae may produce exotoxins lethal to the adjacent host cells. Occasionally, the primary site is the skin or mucosa elsewhere. The exotoxin, carried by the blood, also damages cells in distant organs, creating pathologic lesions in the respiratory passages, oropharynx, myocardium, nervous system, and kidneys.

The myocardium may show fatty degeneration or fibrosis. Degenerative changes in cranial or peripheral nerves occur chiefly in the motor fibers

In severe cases, anterior horn cells and anterior and posterior nerve roots may show damage proportional to the duration of infection before antitoxin is given. The kidneys may show a reversible interstitial nephritis with extensive cellular infiltration.

The diphtheria bacillus first destroys a layer of superficial epithelium, usually in patches, and the resulting exudate coagulates to form a grayish pseudomembrane containing bacteria, fibrin, leukocytes, and necrotic epithelial cells. However, the areas of bacterial multiplication and toxin absorption are wider and deeper than indicated by the size of the membrane formed in the wake of the spreading infection.

Immunodeficiency

This may be :- 
- Congenital (Primary)
- Acquired (Secondary)

Features : Complete or near complete lack of T & B lymphoid tissue. Fatal early in life Even with marrow grafting, chances of graft versus host reaction is high.

T Cell Defects :

- Thymic dysplasia
- Digeorge’s syndrome
- Nazelof’s syndrome
- Ataxia teltngiectaisa
- Wiscott Aldrich’s syndrome

These  lessons show predominantly defective cell mediated immunity. But they may also show partial immunoglobulin defects cell mediated immunity. But they may also show partial immunoglobulin defects due to absence og T-B co-operation.

C. Humoral immunity defects.
Bruron type- aggammaglobulinaemia.
- Dysgammaglobulinaemias-variable immunodeficiency’s of one or more classes.

Acquired deficiency

A. Immuno suppression by :
- Irradiation.
- Corticoids.
- Anti metabolites.
- Anti lymphocyte serum.

B. Neaplasia  of lymphoid system :

- Hodgkin's and Non Hodgkin's lymphomas.
- Chronic lymphocytic leukaemia..
- Multime myeloma and other paraproteinaemias (normal immunoglobulins reduced in spite of hyperglobulinaemia).

c. excessive protein loss.
- Nephrotic Syndrome.
- Protein losing enteropathy.

Chemical Mediators In Inflammation

Can be classified as :

A. Neurogenic

Also called the Triple Response of Lewis. It involves neurogenic vasodilatation of arterioles due to antidromic axon reflex arc. The constituents of the response are:

1. arteriolar vasoconstriction followed by

2. arteriolar vasodilatation

3. swelling

B. Chemical

1. Amines: Histamine and 5 hydroxytryptamine. Released  from platelets and mast cells.

Actions: Immediate and short lived.

Dilatation of arterioles.

Increased capillary premeability.

Kinins: Bradykinin and kallidin These are present in inactive from and are  activated by kinin forming proteases

Actions:

Arteriolar dilatation.

Increased vascular permeability

Pain

Kinin forming proteases Plasmin and Kallikrein. Present as inactive precursors.

Cleavage products of complement C₃a und C₅a are called anaphylatoxins

Actions:

Histamine release from mast cells

Chemotaxis (also C₅₆₇ )

Enhance phagocytosis.

 Polymorph components

Cationic: proteins which cause

Increased permeability

Histamine release.

Chemotaxis of monocytes

Neutral proteases which:

Cleave C3 and C5 to active form

Convert Kininogen to Kinin

Increase permeability.

Acid proteases which liberate leucokinins

Slow reacting. substance of anaphylaxis: (SRS-A) is a lipid released from mast cell.

Action --Increases vascular permeability

Prostaglandins: E1 + E2 _.

Platelets are rich source

Action:

Platelets are a rich source.

Vasodilatation.

Increased permeability.

Pain.

VIII. Miscellaneous: like

Tissue lactic acid.

 Bacterial toxins.

ATROPHY
It is the acquired decrease in the size of an organ due to decrease in the size and/or number of its constituent cells.
Causes:
(1) Physiological

- Foetal involution.
    o    Branchial clefts.
    o    Ductus arterious.
- Involution of thymus and other lymphoid organs in childhood and adolescence.
- In adults:
    o    Post-partum uterus.
    o    Post-menopausal ovaries and uterus
    o    Post-lactational breast
    o    Thymus.
(2) Pathological:
- Generalised as in

    o    Ageing.
    o    Severe starvation and cachexia
- Localised :
    o    Disuse atropy of bone and muscle.
    o    Ischaemic atrophy as in arteriosclerotic kidney. .
    o    Pressure atrophy due  to tumours and of kidney in hydronephrosis.
    o    Lack of trophic stimulus to endocrines and gonads.
 

Hyperpituitarism 

Causes  
A. Pituitary; usually anterior lobe

1. Adenoma (the most common cause)
2. Hyperplasia  
3. Carcinoma  

B. Extra-pituitary causes 
1. Hormone producing extra-pituitary tumors (ectopic hormone production)
2. Certain hypothalamic disorders 

Pituitary adenomas are classified according to the hormone(s) produced by the neoplastic cells; these are detected by immunohistochemically-stained tissue sections. Pituitary adenomas can be functional (associated with hormone excess with their related clinical manifestations) or silent. 

Pathogenesis
Guanine nucleotide-binding protein (G-protein) mutations are the best characterized molecular abnormalities. Such mutations eventuate in a persistent increase in intracellular cAMP, which is a potent mitogenic stimulus promoting cellular proliferation and hormone synthesis and secretion. In the setting of MEN-1 syndrome there are mutations in the MEN-1 (menin) gene. 

Gross features

• Adenomas are usually soft & well-circumscribed   
• Larger lesions extend superiorly through the sellar diaphragm compressing the optic chiasm and adjacent structures .  
• Invasive adenomas refer to nonencapsulated tumors that infiltrate adjacent bone, dura, and even brain.

Microscopic features.  

• Adenomas are composed of monomorphic, polygonal cells displayed in sheets, cords, or papillae. Their nuclei may be uniform or pleomorphic but the mitotic activity is scanty. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic. 
• The connective tissue is scanty that is why many lesions are soft & even gelatinous in consistency.  

Prolactinomas are the most common type of hyperfunctioning pituitary adenoma.
Hyperprolactinemia causes amenorrhea, galactorrhea, loss of libido, and infertility. 

Growth Hormone-Producing Adenomas (somatotroph cell adenomas) are the second most common type of functional pituitary adenoma. Because the clinical manifestations of excessive growth hormone may be subtle, the tumor may be quite large by the time they come to clinical attention. If such tumors occur before closure of epiphyses (prepubertal children), excessive levels of growth hormone result in gigantism. If elevated levels persist, or present after closure of the epiphyses, individuals develop acromegaly. 

Corticotroph Cell Adenomas are mostly small (microadenomas) at the time of diagnosis. They may be clinically silent or cause hypercortisolism referred to as Cushing disease 

Other Anterior Pituitary Neoplasms 
• Gonadotroph adenomas (luteinizing hormone [LH]-producing and follicle-stimulating hormone [FSH]producing)
• Thyrotroph (thyroid-stimulating hormone [TSH]-producing) adenomas 
• Nonfunctioning pituitary adenomas (hormone-negative (null cell) adenomas) Nonfunctioning adenomas constitute approximately 25% of all pituitary tumors; they typically present through their mass effects. 

Bone-Forming Tumors

1. Osteoma is a benign lesion of bone that in many cases represent a developmental abnormaly or reactive growth rather than true neoplasms. They are most common in the head, including the paranasal sinuses. 
Microscopically, there is a mixture of woven and lamellar bone. They may cause local mechanical problems (e.g., obstruction of a sinus cavity) and cosmetic deformities. 

2. Osteoid Osteoma and Osteoblastoma 
are benign neoplasms with very similar histologic features. Both lesions typically arise during the 2nd & 3rd decades. They are well-circumscribed lesions, usually involving the cortex. The central area of the tumor, termed the nidus, is characteristically radiolucent. Osteoid osteomas arise most often in the proximal femur and tibia, and are by definition less than 2 cm, whereas osteoblastomas are larger. Localized pain is an almost universal complaint with osteoid osteomas, and is usually relieved by aspirin. Osteoblastomas arise most often in the vertebral column; they also cause pain, which is not responsive to aspirin. Malignant transformation is rare unless the lesion is treated with radiation. 

Gross features

• Both lesions are round-to-oval masses of hemorrhagic gritty tan tissue.
• A rim of sclerotic bone is present at the edge of both types of tumors. 

Microscopic features
• There are interlacing trabeculae of woven bone surrounded by osteoblasts.
• The intervening connective tissue is loose, vascular & contains variable numbers of giant cells.

3. Osteosarcoma

This is “a bone-producing malignant mesenchymal tumor.” Excluding myeloma and lymphoma, osteosarcoma is the most common primary malignant tumor of bone (20%). The peak age of incidence is 10-25 years with 75% of the affected patients are younger than age 20 years; there is a second peak that occurrs in the elderly, usually secondary to other conditions, e.g. Paget disease, bone infarcts, and prior irradiation. Most tumors arise in the metaphysis of the long bones of the extremities, with 60% occurring about the knee, 15% around the hip, & 10% at the shoulder. The most common type of osteosarcoma is primary, solitary, intramedullary, and poorly differentiated, producing a predominantly bony matrix.

Gross features

• The tumor is gritty, gray-white, often with foci of hemorrhage and cystic degeneration.
• It frequently destroys the surrounding cortex to extend into the soft tissue.
• There is extensive spread within the medullary canal, with replacement of the marrow. However, penetration
of the epiphyseal plate or the joint space is infrequent.

Microscopic features

• Tumor cells are pleomorphic with large hyperchromatic nuclei; bizarre tumor giant cells are common, as are mitoses.
• The direct production of mineralized or unmineralized bone (osteoid) by malignant cells is essential for diagnosis of osteosarcoma. The neoplastic bone is typically fine, lace-like but can also be deposited in broad sheets.
• Cartilage can be present in varying amounts. When malignant cartilage is abundant, the tumor is called a chondroblastic osteosarcoma.

Pathogenesis

• Several genetic mutations are closely associated with the development of osteosarcoma. In particular, RB gene mutations that occur in both sporadic tumors, and in individuals with hereditary retinoblastomas. In the latter there are germ-line mutations in the RB gene (inherited).
• Spontaneous osteosarcomas also frequently exhibit mutations in genes that regulate the cell cycle including p53, cyclins, etc.

Osteosarcomas typically present as painful enlarging masses.

Radiographs usually show a large, destructive, mixed lytic and blastic mass with infiltrating margins. The tumor frequently breaks the cortex and lifts the periosteum. The latter results in a reactive periosteal bone formation; a triangular shadow on x-ray between the cortex and raised periosteum (Codman triangle) is characteristic but not specific of osteosarcomas.
Osteosarcomas typically spread hematogenously; 10% to 20% of patients have demonstrable pulmonary metastases at the time of diagnosis.