Patho sheet.breast #4 - Aseel 7attar

Pathology sheet #
Done by :aseel hattar

This sheet is about 2 topics :
1-polycythemia vera
2-breast


Polycythemia
The hallmark of vera is the excessive neoplastic proliferation & maturation of erythroid, granulocytic, and megakaryocytic elements, producing a panmyelosis. Although platelet and granulocyte numbers are increased, the most obvious clinical signs and symptoms are related to the absolute increase in red cell mass. This must be distinguished from relative polycythemia, which results from hemoconcentration. Unlike reactive forms of absolute polycythemia, PCV is associated with low levels of erythropoietin in the serum, which is a reflection of the hypersensitivity of the neoplastic clone to erythropoietin and other growth factors.
(polycythemia is due to high erythropiotin level.
Polycythemia vera is due to hypersensetivty to erythropiotrn so erythropiotin is low)

Recently it was observed that in nearly all cases, PCV cells carry a particular mutation in JAK2, a tyrosine kinase that acts in the signaling pathways downstream of the erythropoietin receptor and other growth factor receptors. This mutation, which results in a valine-to-phenylalanine substitution at residue 617, is sufficient to render cells expressing the erythropoietic receptor hypersensitive to erythropoietin, suggesting that it is probably an important part of the pathogenesis of PCV.
The major anatomic changes in PCV stem from the increase in blood volume and viscosity brought about by the polycythemia

As a result of the increased viscosity and vascular stasis, thromboses and infarctions are common, particularly in the heart, spleen, and kidneys. Hemorrhages occur in about a third of these individuals, probably as a result of excessive distention of blood vessels and abnormal platelet function.
Platelets produced from the neoplastic clone are often dysfunctional.
(all 3 clones are affected :red white plattlets).


As in CML (chronic mylogenous leukemia ) , the peripheral blood often shows increased basophil.
The bone marrow is hypercellular due to the hyperplasia of erythroid, myeloid, and megakaryocytic forms. In addition, some degree of marrow fibrosis is present in 10% of patients at the time of diagnosis. In a subset of patients, the disease progresses to myelofibrosis, where the marrow space is largely replaced by fibroblasts and collagen.
clinically PCV appears insidiously, usually in late middle age. Patients are plethoric and often somewhat cyanotic. Histamine release from the neoplastic basophils may contribute to pruritus, which can be intense. Excessive histamine release may also account for the peptic ulceration seen in these individuals. Other complaints are referable to the thrombotic and hemorrhagic tendencies and to hypertension. Headache, dizziness, gastrointestinal symptoms, hematemesis, and melena are common. Because of the high rate of cell turnover, symptomatic gout is seen in 5% to 10% of cases.


The diagnosis is usually made in the laboratory. Red cell counts range from 6 to 10 million per microliter, and the hematocrit often approaches 60%. The other myeloid lineages are also hyperproliferative.
About 30% of patients develop thrombotic complications, usually affecting the brain or heart. Hepatic vein thrombosis, giving rise to the Budd-Chiari syndrome , is an uncommon but grave complication.
life-threatening hemorrhages occur in 5% to 10% of patients. In those receiving no treatment, death occurs from vascular complications within months after diagnosis; however, if the red cell mass is maintained at near normal levels by phlebotomies, the median survival is around 10 years.

Phlebotomies:sa7eb dam to reduce red cells . and they don’t gave it to other person .
(in polycythima vera the problem is more with erythroid
In cml the problem is more with the mayloid ).

Essential thrombocythemia is a myloprolifrative disorder arising from multiprolifrative stem cells but the increase proliferating and production is confined to the megakaryocytic element. Where the cells of megakaryocytic series have diminished requirements for growth factors.
This function of plattlets derived from the neoplastic clone primerly contributes to the major clinical featuers of bleeding & thrombocytosis.
Marrow cellularty is usually mild th moderat , increase in megakaryocytic is ofter markedly increase in # & include abnormal large forms.
( thrombocytosis usually is more than 6 handred thaousend per micro leter.
It also have abnormally large plattlets ).
Neoplastic extramedullary hematopoisis can produce mild organomegaly in less than 50% of cases .

Uncommen essential thrombocytosis can evolved into?? manofibrosis?? Or transform to AML .
It usually occurs after age of 60 ,quantitative &qualitative abnormalities in plattltes under lines the major clinical manifestation of thrombosis & hemorhege.
Erythromylagia &burning of hands &feet caused by occlusion of small arteriols by plattltes is a charictaristic symptom .

Essential thrombocytosis has long asymptomatic period punctuated by thrombotic &hemorhageic crisis. & the middian survival is 12 to 15 years .
(the problem here is with the megakariocye)

Primary mylofibrosis

Primary marrow fibrosis with myloid metaplasia also asises from transformed multipotient stem cells ,but differs in the proggretion to mylofibrosis occure early in the course.
(all myloprolifrative disorders can turn to secondary mylofibrosis .
In primary mylofibrosis there is no antecedent myloprolifrative disorder .)




The pathologic feature system fromk extensive collagen deposition in the marrow by non-neoplastic fibroblat .
(the deposition of collagen is from benign fibroblast in bon marrow not from neoplastic cells )

Marrow obliteration result in extensive extramedullary hematopoisis in spleen liver & lymph nodes.
Fibrosis may be caused by inappropriate release of plattlet derive growth factor & transforming growth factor B from neoplastic megakariocyte.
(cytokines are produced by neoplastic megakariocyte .
Deposition of collagen is from fibro blast )
Early the marrow is hypercellular & contain large displastic megakariocyte with proggrition diffuse fibrosis displaces hematopiotic elements .
Late in the course the fibrotic marrow space can be largly converted to bone (ostioseclerosis) (thick bone )
Fibrotic obliteration of marrow spaces lead to excessive extramedullary hematopoisis in spleen (most ) ,liver , lymph nodes .

Nucleated erythriod progenitor cells & early granulocytes are released from the fibrotic marrow & site of extramedullry hematopoisis so called ( leukoerythroblastosis:immatured myliod cells ,nucleated RBCs in peripheral blood .)
Other finding in peripheral (????) include tear drop erythrocytes , increase basophils &abnormally large plattlets .

Moderat to sever normochromic animia is common , thrombocytopenia often sever appears with disease proggrition .

Primary mylofibrosis is uncommon in indevedula younger than 60. the disorder becomes in attention because of proggrisive animia or spleenic enlargement.

Prognosis is variable with the middian survival period of 1-5 years .
Threatinnig to life include intercurrent infections ,thrombotic episiodes ,bleeding &transformation to AML in 5-20% of patients.



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BREAST

Lesions of the female breast are much more common than lesions of the male breast, which is remarkably seldom affected. These lesions usually take the form of palpable, sometimes painful, nodules or masses. Fortunately, most are benign, but as is well known, breast cancer was the foremost cause of cancer deaths in women in the United States until 1986, when it was supplanted by carcinoma of the lung.
(nowadays the first killer cancer of the femal is lung cancer).

fibrocystic change, because it is the most common cause of breast "lumps" and because of the continuing controversy about the association of particular variants with breast carcinoma.

Fibrocyctic changing , This designation is applied to a miscellany of changes in the female breast that range from those that are innocuous to patterns associated with an increased risk of breast carcinoma. Some of these alterations (stromal fibrosis and microcysts or macrocysts) produce palpable "lumps." It is widely accepted that this range of changes is the consequence of an exaggeration and distortion of the cyclic breast changes that occur normally in the menstrual cycle. Estrogenic therapy and oral contraceptives do not seem to increase the incidence of these alterations; indeed, oral contraceptives may decrease the risk.
(they think that fibrocyctic change is very commen in females up to 80% and it can produce breast lumps that mimics breast cancer. And it's due to distortion of the normal cyclic changes due to estrogen so some people consider it a phisyologic prossess so they change it's name from fibrocyctic disease to fibrocyctic change)





Afemale with a breast lump , it could be : 30% no disease
30% no disease
(the most) 40% fibrocyctic changes
10%cancer
7% fibroadenoma
13% miscellaneous benign

The alterations are here subdivided into nonproliferative and proliferative patterns. The nonproliferative lesions include cysts and/or fibrosis without epithelial cell hyperplasia, known as simple fibrocystic change. The proliferative lesions include a range of innocuous to atypical duct or ductular epithelial cell hyperplasias and sclerosing adenosis. All tend to arise during reproductive period of life but may persist after menopause. The various changes, particularly the nonproliferative ones, are so common, being found at autopsy in 60% to 80% of women, that they almost constitute physiologic variants.

Nonproliferative Change.

Cysts and Fibrosis

Nonproliferative change is the most common type of alteration, characterized by an increase in fibrous stroma associated with dilation of ducts and formation of cysts of various sizes.
Grossly, a single large cyst may form within one breast, but the disorder is usually multifocal and often bilateral.
The cysts vary from smaller than 1 cm to 5 cm in diameter. Unopened, they are brown to blue (blue dome cysts) and are filled with serous, turbid fluid . The secretory products within the cysts may calcify to appear as microcalcifications in mammograms .Histologically, in smaller cysts, the epithelium is more cuboidal to columnar and is sometimes multilayered in focal areas. In larger cysts it may be flattened or even totally atrophic. Occasionally, mild epithelial proliferation leads to piled-up masses or small papillary excrescences. Frequently, cysts are lined by large polygonal cells that have an abundant granular, eosinophilic cytoplasm, with small, round, deeply chromatic nuclei, called apocrine metaplasia; this is virtually always benign.




Proliferative Change


Epithelial Hyperplasia
The terms epithelial hyperplasia and proliferative fibrocystic change encompass a range of proliferative lesions within the ductules, the terminal ducts, and sometimes

the lobules of the breast. Some of the epithelial hyperplasias are mild and orderly, and carry little risk of carcinoma, but at the other end of the spectrum are the more florid atypical hyperplasias that carry a significantly greater risk of cancer.
(y3ne in prolifretive lesions of fibrocyctic change there is increase risk of cancer).









Morphologically
The ducts, ductules, or lobules may be filled with orderly cuboidal cells, within which small gland patterns can be discerned (called fenestrations) (Fig. 19-26). Sometimes the proliferating epithelium projects in multiple small papillary excrescences into the ductal lumen (ductal papillomatosis).
In some instances the hyperplastic cells become monomorphic with complex architectural patterns. In short, they have changes approaching those of ductal carcinoma in situ . Such hyperplasia is called atypical.
Atypical lobular hyperplasia is the term used to describe hyperplasias that cytologically resemble lobular carcinoma in situ, but the cells do not fill or distend more than 50% of the acini within a lobule. Atypical lobular hyperplasia is associated with an increased risk of invasive carcinoma.
Epithelial hyperplasia per se does not often produce a clinically discrete breast mass. Occasionally, it produces microcalcifications on mammography,
florid papillomatosis may be associated with a serous or serosanguineous nipple discharge.
(the intra ductal papilloma is the most common cause of bloody nipple discharge)
.
Sclerosing Adenosis
This variant is less common than cysts and hyperplasia, but it is significant because its clinical and morphologic features may be deceptively similar to those of carcinoma. These lesions contain marked intralobular fibrosis and proliferation of small ductules and acini.
Grossly, the lesion has a hard, rubbery consistency, similar to that of breast cancer. Histologically, sclerosing adenosis is characterized by proliferation of lining epithelial cells and myoepithelial cells in small ducts and ductules, yielding masses of small gland patterns within a fibrous stroma . Aggregated glands or proliferating ductules may be virtually back to back, with single or multiple layers of cells in contact with one another (adenosis). Marked stromal fibrosis, which may compress and distort the proliferating epithelium, is always associated with the adenosis.
This overgrowth of fibrous tissue may completely compress the lumina of the acini and ducts, so that they appear as solid cords of cells. This pattern may then be difficult to distinguish histologically from an invasive scirrhous carcinoma.
This pattern may then be difficult to distinguish histologically from an invasive scirrhous carcinoma. The presence of double layers of epithelium and the identification of myoepithelial elements are helpful in suggesting a benign diagnosis.
(to distinguish between cancer & sclerosing adenosis is to do spiceal stain for myoepithelial cells : if it is +ve its sclerosig adenosis not cancer
Because cancer has 2 layers myoepithelial & epithelial .
Sclerosing adenoasis has just 1 layer myoepithelial .)

relation ship of fibrocyctic changes to breast carcinoma



Minimal or no increased risk of breast carcinoma: fibrosis, cystic changes (microscopic or macroscopic), apocrine metaplasia, mild hyperplasia, fibroadenoma.Slightly increased risk (1.5-2 times): moderate to florid hyperplasia (without atypia), ductal papillomatosis, sclerosing adenosis.Significantly increased risk (5 times): atypical hyperplasia, ductular or lobular (seen in 15% of biopsies).Proliferative lesions may be multifocal, and the risk of subsequent carcinoma extends to both breasts.A family history of breast cancer may increase the risk in all categories (e.g., to ∼10-fold with atypical hyperplasia).

INFLAMMATIONS


Inflammations of the breast are uncommon and during the acute stages usually cause pain and tenderness in the involved areas.
Acute mastitis develops when bacteria gain access to the breast tissue through the ducts; when there is inspissation of secretions; through fissures in the nipples, which usually develop during the early weeks of nursing; or from various forms of dermatitis involving the nipple.
Staphylococcal infections induce single or multiple abscesses accompanied by the typical clinical acute inflammatory changes.
Streptococcal infections generally spread throughout the entire breast, causing pain, marked swelling, and breast tenderness.
Mammary duct ectasia (periductal or plasma cell mastitis) is a nonbacterial chronic inflammation of the breast associated with inspissation of breast secretions in the main excretory ducts. Ductal dilation with ductal rupture leads to reactive changes in the surrounding breast substance. It is an uncommon condition, usually encountered in women in their 40s and 50s who have borne children.

Morphology
Usually the inflammatory changes are confined to an area drained by one or several of the major excretory ducts of the nipple. There is increased firmness of the tissue, and on cross-section dilated ropelike ducts are apparent from which thick, cheesy secretions can be extruded. Histologically, the ducts are filled by granular debris, sometimes containing leukocytes, principally lipid-laden macrophages. The lining epithelium is generally destroyed. The most distinguishing features are the prominence of a lymphocytic and plasma cell infiltration and occasional granulomas in the periductal stroma.
Mammary duct ectasia is of principal importance because it leads to induration of the breast substance and, more significantly, to retraction of the skin or nipple, mimicking the changes caused by some carcinomas.
Traumatic fat necrosis is an uncommon and innocuous lesion that is significant only because it produces a mass. Most, but not all, women with this condition report some antecedent trauma to the breast.
During the early stage of traumatic fat necrosis, the lesion is small, often tender, rarely more than 2 cm in diameter, and sharply localized. It consists of a central focus of necrotic fat cells surrounded by neutrophils and lipid-filled macrophages, which is later enclosed by fibrous tissue and mononuclear leukocytes. Eventually the focus is replaced by scar tissue, or the debris becomes encysted within the scar. Calcifications may develop in either the scar or cyst wall.