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. 

Hyperparathyroidism 

Abnormally high levels of parathyroid hormone (PTH) cause hypercalcemia. This can result from either primary or secondary causes. Primary hyperparathyroidism is caused usually by a parathyroid adenoma, which is associated with autonomous PTH secretion. Secondary  hyperparathyroidism, on the other hand, can occur in the setting of chronic renal failure. In either situation, the presence of excessive amounts of this hormone leads to significant skeletal changes related to a persistently exuberant osteoclast activity that is associated with increased bone resorption and calcium mobilization. The entire skeleton is affected. PTH is directly responsible for the bone changes seen in primary hyperparathyroidism, but in secondary hyperparathyroidism additional influences also contribute. In chronic renal failure there is inadequate 1,25- (OH)2-D synthesis that ultimately affects gastrointestinal calcium absorption. The hyperphosphatemia of renal
failure also suppresses renal α1-hydroxylase, which further impair vitamin D synthesis; all these eventuate in hypocalcemia, which stimulates excessive secretion of PTH by the parathyroid glands, & hence elevation in PTH serum levels. 

Gross features
• There is increased osteoclastic activity, with bone resorption. Cortical and trabecular bone are lost and replaced by loose connective tissue. 
• Bone resorption is especially pronounced in the subperiosteal regions and produces characteristic radiographic changes, best seen along the radial aspect of the middle phalanges of the second and third fingers.

Microscopical features

• There is increased numbers of osteoclasts and accompanying erosion of bone surfaces.
• The marrow space contains increased amounts of loose fibrovascular tissue.
• Hemosiderin deposits are present, reflecting episodes of hemorrhage resulting from microfractures of the weakened bone.
• In some instances, collections of osteoclasts, reactive giant cells, and hemorrhagic debris form a distinct mass, termed "brown tumor of hyperparathyroidism". Cystic change is common in such lesions (hence the name osteitis fibrosa cystica). Patients with hyperparathyroidism have reduced bone mass, and hence are increasingly susceptible to fractures and bone deformities.

Hepatitis

Hepatitis viruses—this group of viruses causes hepatitis, a disease affecting the liver.
1. General characteristics of hepatitis.
a. The general presentation of hepatitis is the same regardless of the infecting virus; however, the time and severity of symptoms may differ.
b. Symptoms of hepatitis include fever, anorexia, malaise, nausea, jaundice, and brown-colored urine.
c. Complications of a hepatitis infection include cirrhosis, liver failure, and hepatorenal failure.

Posterior Pituitary Syndromes 

The posterior pituitary, or neurohypophysis, is composed of modified glial cells (termed pituicytes) and axonal processes extending from nerve cell bodies in the hypothalamus. The hypothalamic neurons produce two peptides: antidiuretic hormone (ADH) and oxytocin that are stored in axon terminals in the neurohypophysis.

The clinically important posterior pituitary syndromes involve ADH production and include  
1. Diabetes insipidus and 
2. Inappropriate secretion of high levels of ADH.  

- ADH is released into the general circulation in response to increased plasma oncotic pressure & left atrial distention. 
- It acts on the renal collecting tubules to increase the resorption of free water. 
- ADH deficiency causes  diabetes insipidus, a condition characterized by polyuria. If the cause is related to ADH Diabetes insipidus from - - ADH deficiency is designated as central, to differentiate it from nephrogenic diabetes insipidus due to renal tubular unresponsiveness to circulating ADH. 
- The clinical manifestations of both diseases are similar and include the excretion of large volumes of dilute urine with low specific gravity. Serum sodium and osmolality are increased as a result of excessive renal loss of free water, resulting in thirst and polydipsia. 

- ADH excess causes resorption of excessive amounts of free water, with resultant hyponatremia. 
- The most common causes of the syndrome include the secretion of ectopic ADH by malignant neoplasms (particularly small-cell carcinomas of the lung), and local injury to the hypothalamus and/or neurohypophysis. 

- The clinical manifestations are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction.

Acanthosis nigricans is a pigmented skin lesion commonly present in the axilla which is a phenotypic marker for an insulin-receptor abnormality as well as a marker for adenocarcinoma, most commonly of gastric origin.

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.