Maram Abdaljaleel MD Dermatopathologist and Neuropathologist University of

Maram Abdaljaleel, MD Dermatopathologist and Neuropathologist University of Jordan, School of Medicine

� The most common non-skin malignancy of women � 2 nd most common cause of cancer deaths in women, following carcinoma of the lung. � the worldwide incidence and mortality is increasing at an alarming rate. � Due to social changes delayed childbearing, fewer pregnancies, and reduced breastfeeding and with lack of access to optimal health care.

CA: A Cancer Journal for Clinicians Volume 62, Issue 1, pages 10 -29, 4 JAN 2012 DOI: 10. 3322/caac. 20138 http: //onlinelibrary. wiley. com/doi/10. 3322/caac. 20138/full#fig 1

� hormone receptors are: �estrogen receptor (ER) �progesterone receptor (PR) �human epidermal growth factor receptor 2 (HER 2, or ERBB 2), � Can be classified according to expression of hormone receptors into three major groups: • ER positive (HER 2 negative; 50%– 65% of cancers) • HER 2 positive (ER positive or negative; 10%– 20% of cancers) • Triple negative (ER, PR, and HER 2 negative; 10%– 20% of cancers)

� The three groups show striking differences in patient characteristics, pathologic features, treatment response, metastatic patterns, time to relapse, and outcome � Within each group are additional histologic subtypes, some of which also have clinical importance.

� Age: � incidence increases rapidly after age 30 � 75% of women with breast cancer are >50 yrs & only 5% are <40 yrs. � Gender � The incidence in men is only 1% of that in women. � Family History of Breast Cancer. � multiple affected first-degree relatives with early-onset breast cancer. Mostly related to various combinations of low penetrance, “weak” cancer genes In 5% to 10% it’s related to a highly penetrant germline mutations in tumor suppressor genes the lifetime risk of breast cancer >90%.

� Geographic �higher Factors. in the Americas and Europe than in Asia and Africa �migrants from low incidence to high-incidence areas tend to acquire the rates of their new home countries due to change in diet, reproductive patterns, breastfeeding practices and adoption of Western habits. � Race/Ethnicity. �highest rate in women of European descent because of higher incidence of ER-positive cancers. �Hispanic and African American develop cancer at a younger age and develop aggressive tumors.

� Reproductive History. �Early age of menarche, nulliparity, absence of breastfeeding, and older age at first pregnancy are all associated with increased risk due to increased the exposure to estrogenic stimulation. � Ionizing �Chest � Other Radiation Risk Factors. �Postmenopausal obesity �postmenopausal hormone replacement �mammographic density �alcohol consumption

� Factors that contribute directly to the development of breast cancer can be grouped into: � genetic: BRCA 1 and BRCA 2 HER 2 amplification: Cancers that overexpress HER 2 are highly proliferative. In the past they had a poor prognosis; however, the availability of therapeutic agents targeting HER 2 has improved the prognosis. Less common: TP 53 and PTEN The pathways in which familial breast cancer genes function also are often disturbed in sporadic cancers �Hormonal: Estrogen related �environmental

� Location: �upper outer quadrant (50%) �central portion(20%). �Lower outer quadrant 10% �Upper inner quadrant 10% �Lower inner quadrant 10% � 4% have bilateral primary tumors or sequential lesions in the same breast.

A. Noninvasive: (confined by a basement membrane and do not invade into stroma or lymphovascular channels), include: 1. Ductal carcinoma in situ 2. Lobular carcinoma in situ B. Invasive (infiltrating): 1. Invasive ductal carcinoma (includes all carcinomas that are not of a special type) 70% to 80% 2. Invasive lobular carcinoma 10% to 15% 3. Carcinoma with medullary features 5% 4. Mucinous carcinoma (colloid carcinoma) 5% 5. Tubular carcinoma 5% 6. Other types

� two morphologic types: � ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). � LCIS usually expands involved lobules, whereas DCIS distorts lobules into ductlike spaces � By definition, both “respect” the BM and do not invade into stroma or LV channels.

� Frequently associated with Calcifications detected by mammography � The prognosis : excellent (97% long-term survival after simple mastectomy) � Current treatment strategies: surgery and irradiation, tamoxifen � Significance: adjacent invasive CA; become invasive if untreated (1/3 of cases)

�Also called Carcinomas "not otherwise specified" � 70% to 80% �Precancerous lesion: usually DCIS �Clinical presentation: a mammographic density; a hard, palpable irregular mass. Advanced cancers may cause retraction of the nipple, or fixation to the chest wall. �Receptor profile: ½ to 2/3 express ER ; 20% HER 2 positive & 15% are negative for both

� 10 -15% of all breast carcinomas. �Precancerous lesion. 2/3 associated with LCIS. �multicentric and bilateral (10% to 20%). �Clinical presentation. Most present as palpable masses or mammographic densities �cells invade stroma individually and often are aligned in “single-file” �Almost all of these carcinomas express hormone receptors, but HER 2

� 5% �Triple negative �Microscopically: large anaplastic cells with pushing, well-circumscribed borders. With a pronounced lymphocytic infiltrate. �Precancerous lesions. usually absent �increased frequency in women with BRCA 1 mutations, . �Receptor profile. lack hormone receptors and do not overexpress HER 2/NEU.

�a rare subtype. � Microscopic picture. The tumor cells produce abundant quantities of extracellular mucin that dissects into the surrounding stroma. Grossly the tumors are usually soft and gelatinous. � ER-positive/HER 2 - negative cancer

� 10% of invasive carcinomas smaller than 1 cm found with mammographic screening. �Clinical presentation. irregular mammographic densities. �Microscopically, well-formed tubules with low-grade nuclei. �Lymph node metastases are rare, and prognosis is excellent. �ER-positive/HER 2 - negative cancer

�Fixation: adherent to the pectoral muscles or deep fascia of the chest wall �retraction or dimpling of the skin or nipple: adherence to the overlying skin � peau d'orange (orange peel): Involvement of the lymphatic pathways cause localized lymphedema, the skin becomes thickened around exaggerated hair follicles

�through lymphatic and hematogenous channels. �Favored mets are the bone, lungs, skeleton, liver, and adrenals and (less commonly) the brain, spleen, and pituitary. �Metastases may appear many years after apparent therapeutic control of the primary lesion �SCREENING : �mammographic screening �Magnetic resonance imaging MRI

1 - size. 2 - Lymph node involvement and the number of lymph nodes involved by metastases. 3 - Distant metastases. 4 - grade 5 - histologic type of carcinoma 6 - The presence or absence of estrogen or progesterone receptors. 7 - The proliferative rate of the cancer. 8 - Aneuploidy. worse prognosis. 9 - Overexpression of HER 2 � the importance of evaluating HER 2 s to predict response to a monoclonal antibody ("Herceptin") against the gene product.