Pathology_Robbins

Pathology_Robbins. Endocrine disorders, such as thyroid disease, adrenal disease, or pituitary tumors. Ovarian lesions, such as a functioning ovarian tumor (granulosa cell tumors) or polycystic ovarian syndrome (see section on that follows). Generalized metabolic disturbances, such as obesity, malnutrition, or other chronic systemic disorders. Dysfunctional uterine bleeding also may result from an inadequate luteal phase, which is thought to stem from Table19.2CausesofAbnormalUterineBleedingbyAgeGroup ReproductiveageComplicationsofpregnancy(abortion,trophoblasticdisease,ectopicpregnancy)Proliferations(leiomyoma,adenomyosis,polyps,endometrialhyperplasia,carcinoma)AnovulatorycycleOvulatorydysfunctionalbleeding(e.g.,inadequatelutealphase) Proliferations(carcinoma,hyperplasia,polyps) PostmenopauseProliferations(carcinoma,hyperplasia,polyps)Endometrialatrophy http://ebooksmedicine.net insufficient production of progesterone by the corpus luteum.


Pathology_Robbins

Pathology_Robbins. PostmenopauseProliferations(carcinoma,hyperplasia,polyps)Endometrialatrophy http://ebooksmedicine.net insufficient production of progesterone by the corpus luteum. Adenomyosisreferstogrowthofendometriumintothemyometriumoftenwithuterineenlargement. Endometriosisreferstoendometrialglandsandstromalocatedoutsidetheuterusandmostofteninvolvesthepelvicorabdominalperitoneum.Rarely,distantsitessuchasthelymphnodesandthelungsalsoareinvolved. Theectopicendometriuminendometriosisundergoescyclicbleeding,andtheconditionisacommoncauseofdysmenorrheaandpelvicpain. The most common proliferative lesions of the uterine corpus are endometrial hyperplasia, endometrial carcinomas, endometrial polyps, and smooth muscle tumors. All tend to produce abnormal uterine bleeding as their earliest manifestation.


Pathology_Robbins

Pathology_Robbins. An excess of estrogen relative to progestin, if sufficiently prolonged or marked, can induce exaggerated endometrial proliferation (hyperplasia), which is an important precursor of endometrial carcinoma. A common cause of estrogen excess is obesity, as adipose tissue converts steroid precursors into estrogens. Other potential causes of estrogen excess include failure of ovulation (such as in perimenopause), prolonged administration of estrogenic steroids without counterbalancing progestin, and estrogen-producing ovarian lesions (such as polycystic ovary syndrome and granulosa-theca cell tumors of the ovary). Endometrial hyperplasia is placed in two categories based on the presence of cytologic atypia: hyperplasia without atypia and hyperplasia with atypia ( Fig. 19.11).


Pathology_Robbins

Pathology_Robbins. Endometrial hyperplasia is placed in two categories based on the presence of cytologic atypia: hyperplasia without atypia and hyperplasia with atypia ( Fig. 19.11). The importance of this classification is that the presence of cytologic atypia correlates with the development or concurrent finding of endometrial carcinoma. Hyperplasia without cellular atypia carries a low risk (between 1% and 3%) for progression to endometrial carcinoma, whereas hyperplasia with atypia, also called endometrial intraepithelial neoplasia (EIN), is associated with a much higher risk (20%–50%). When hyperplasia with atypia is discovered, it must be carefully evaluated for the presence of cancer and usually warrants a hysterectomy in patients no longer desiring fertility. In younger patients, treatment with high-dose progestins may be used in an attempt to preserve the uterus.


Pathology_Robbins

Pathology_Robbins. Unopposed estrogen is also a risk factor for the most common type of endometrial carcinoma (see later), and inactivation of the PTEN tumor suppressor gene has been identified at a substantial frequency in hyperplasia with atypia (approximately 50%) and endometrioid carcinoma (>70%). Along with clinicopathologic and epidemiologic studies, these findings indicate that hyperplasia with atypia is a precursor lesion for endometrioid endometrial carcinoma. Fig.19.11Endometrialhyperplasia.(A)Anovulatoryor“disordered”endo-metriumcontainingdilatedglands.(B)Hyperplasiawithoutatypia,character-izedbynestsofcloselypackedglands.(C)Hyperplasiawithatypia,seenasglandularcrowdingandcellularatypia. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In the United States and many other Western countries, endometrial carcinoma is the most frequent cancer occurring in the female genital tract. It generally appears between the ages of 55 and 65 years and is uncommon before age 40. Endometrial carcinoma can be broadly divided into two histologically and pathogenically distinct categories: endometrioid and serous carcinoma. There are other less common types of endometrial carcinoma, such as clear cell carcinoma and mixed Mullerian tumor (carcinosarcoma), but these will not be discussed further.


Pathology_Robbins

Pathology_Robbins. Endometrioid cancers arise in association with estrogen excess in the setting of endometrial hyperplasia in perimenopausal women, whereas serous cancers arise in the setting of endometrial atrophy in older postmenopausal women. The endometrioid type accounts for 80% of cases of endometrial carcinomas. These tumors are designated as endometrioid because of their histologic similarity to normal endometrial glands. Risk factors for this type of carcinoma include (1) obesity, (2) diabetes, (3) hypertension, (4) infertility, and (5) exposure to unopposed estrogen. Many of these risk factors result in increased estrogenic stimulation of the endometrium and are associated with endometrial hyperplasia. In fact, it is well recognized that prolonged estrogen replacement therapy and estrogen-secreting ovarian tumors increase the risk of the endometrioid type of endometrial carcinoma. Mutations in mismatch repair genes and the tumor suppressor gene PTEN are early events in the stepwise


Pathology_Robbins

Pathology_Robbins. ovarian tumors increase the risk of the endometrioid type of endometrial carcinoma. Mutations in mismatch repair genes and the tumor suppressor gene PTEN are early events in the stepwise development of endometrioid carcinoma. Women with germline mutations in PTEN (Cowden Syndrome) and germline alterations in DNA mismatch repair genes (Lynch Syndrome) are at high risk for this cancer. TP53 mutations occur but are relatively uncommon and are late events in the genesis of this tumor type.


Pathology_Robbins

Pathology_Robbins. The serous type of endometrial carcinoma is less common but also far more aggressive. It accounts, for roughly 15% of tumors and is not associated with unopposed estrogen or endometrial hyperplasia. Nearly all cases of serous carcinoma have mutations in the TP53 tumor suppressor gene, whereas mutations in DNA mismatch repair genes and in PTEN are rare. Serous tumors are preceded by a lesion called serous endometrial intraepithelial carcinoma (SEIC) in which TP53 mutations are often detected, suggesting an early role for such mutations in the development of this form of endometrial carcinoma. Fig.19.12A–B ).Theyincludearangeofhistologictypes,includingthoseshowingmucinous,tubal(ciliated),andsquamousdifferentiation.Endometrioidcarcinomasofteninfiltratethemyometriumandcanentervascularspaces(lymphovascularinvasion).Theymayalsometastasizetoregionallymphnodes.Endometrioidcarcinomasaregraded1to3,basedonthedegreeofdifferentiation.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.19.12C–D ),afindingthatcorrelateswiththepresenceofTP53 mutations(mutantp53accumulatesandhenceismoreeasilydetectedbystaining). Endometrial carcinomas usually manifest with irregular or postmenopausal bleeding. With progression, the uterus enlarges and may become affixed to surrounding structures as the cancer infiltrates surrounding tissues. Endometrioid carcinoma usually is slow to metastasize, but if left untreated, eventually disseminates to regional nodes and more distant sites. With therapy, the 5-year survival rate for early-stage endometrioid carcinoma is 90%, but survival drops precipitously in higher-stage tumors. The prognosis with serous carcinomas is strongly dependent on operative staging but because of its aggressive behavior it often presents as high-stage disease with a poor prognosis. Endometrialhyperplasiaresultsfromunopposedendogenousorexogenousestrogen.


Pathology_Robbins

Pathology_Robbins. Stageisthemajordeterminantofsurvivalinbothtypes.Seroustumorstendtomanifestmorefrequentlywithextrauterineextensionandthereforehaveaworseprognosisthanendometrioidcarcinomas. These polyps are usually sessile and range from 0.5 to 3 cm in diameter. Larger polyps may project from the http://ebooksmedicine.net Fig.19.12Endometrialcarcinoma.(A)Endometrioidtype,grade1,infiltratingmyometriumandgrowinginaglandularpattern.(B)Endometrioidtype,grade3,hasapredominantlysolidgrowthpattern.(C)Serouscarcinomaoftheendometrium,withpapillaformationandmarkedcytologicatypia.(D)Immunohis-tochemicalstainingshowsaccumulationofp53,afindingassociatedwithTP53 mutation.


Pathology_Robbins

Pathology_Robbins. endometrial mucosa into the uterine cavity. They are composed of endometrium resembling the basalis, frequently with small muscular arteries. Some glands are normal architecturally, but more often they are cystically dilated. The stromal cells are monoclonal, often with a rearrangement of chromosomal region 6p21, and thus constitute the neoplastic component of the polyp. Although endometrial polyps may occur at any age, they are most common around the time of menopause. Their main clinical significance is that they may produce abnormal uterine bleeding.


Pathology_Robbins

Pathology_Robbins. Benign tumors that arise from the smooth muscle cells in the myometrium are properly termed leiomyomas, but because of their firmness often are referred to clinically as fibroids. Leiomyomas are the most common benign tumor in females, affecting 30% to 50% of women of reproductive age, and are considerably more frequent in black women. These tumors are associated with several different recurrent chromosomal abnormalities, including rearrangements of chromosomes 6 and 12 that also are found in a variety of other benign neoplasms, such as endometrial polyps and lipomas. Mutations in the MED12 gene, which encodes a component of the RNA polymerase transcription complex, have been identified in up to 70% of leiomyomas. The mechanism by which MED12 mutations contribute to the development of leiomyomas is not presently understood. Estrogens and possibly oral contraceptives stimulate the growth of leiomyomas; conversely, these tumors shrink postmenopausally.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig.19.13Uterineleiomyomas.(A)Theuterusisopenedtoshowmultiplesubmucosal,myometrial,andsubserosalgray-whitetumors,eachwithacharacteristicwhorledappearanceoncutsection.(B)Microscopicappearanceofleiomyomashowsbundlesofnormal-lookingsmoothmusclecells. Leiomyomas of the uterus often are asymptomatic, being discovered incidentally on routine pelvic examination. The most frequent presenting sign is menorrhagia, with or without metrorrhagia. Leiomyomas rarely, if ever, transform into sarcomas, and the presence of multiple lesions does not increase the risk of malignancy. Leiomyosarcomas of the uterus virtually always arise de novo from the mesenchymal cells of the myometrium. They are almost always solitary and most often occur in postmenopausal women, in contradistinction to


Pathology_Robbins

Pathology_Robbins. The most common disorder of the fallopian tubes is inflammation (salpingitis), almost invariably occurring as a component of pelvic inflammatory disease. Less common abnormalities are ectopic (tubal) pregnancy and endometriosis. Inflammation of the fallopian tubes is almost always caused by infection. In addition to gonorrhea, nongonococcal organisms, such as Chlamydia, Mycoplasma hominis, coliforms, and (in the postpartum setting) streptococci and staphylococci are the major offenders. The morphologic changes produced by gonococci are similar to those in the male genital tract (Chapter 18). Infections with coliforms, streptococci, and staphylococci can penetrate the wall of leiomyomas, which frequently are multiple and usually arise premenopausally.


Pathology_Robbins

Pathology_Robbins. Recurrence after surgery is common with these cancers, and many metastasize, typically to the lungs, yielding a 5-year survival rate of about 40%. The outlook with anaplastic tumors is less favorable than with well-differentiated tumors. MORPHOLOGYLeiomyosarcomastypicallytaketheformofsoft,hemorrhagic,necroticmasses.Thehistologicappearancevarieswidely,fromtumorsthatcloselyresembleleiomyomatowildlyanaplasticneoplasms.Well-differentiatedtumorsmaylieatthemorphologicinterfacebetweenleiomyomaandleiomyosarcomaandaresometimesdesignatedsmoothmuscletumorsofuncertainmalignantpotential.Thediagnosticfeaturesofleiomyosarcomaincludetumornecrosis,cytologicatypia,andmitoticactivity.Becauseincreasedmitoticactivityissometimesseeninbenignsmoothmuscletumors,particularlyinyoungwomen,anassessmentofallthreefeaturesisnecessarytomakeadiagnosisofmalignancy.


Pathology_Robbins

Pathology_Robbins. the tubes, giving rise to blood-borne infections that seed to distant sites. Tuberculous salpingitis is far less common and is almost always encountered in combination with tuberculous endometritis. All forms of salpingitis may produce fever, lower abdominal or pelvic pain, and pelvic masses, which are the result of distention of the tubes with either exudate or inflammatory debris ( Fig. 19.14 ). Adherence of the inflamed tube to the ovary and adjacent ligamentous tissues may produce a tuboovarian abscess. This may in turn result in adhesions between the ovary and the tubes when the inflammation subsides. Even more serious are adhesions of the tubal plicae, which are associated with increased risk of tubal ectopic pregnancy (discussed later). http://ebooksmedicine.net Fig.19.14Pelvicinflammatorydisease,bilateralandasymmetric.Thetubeandovarytotheleftoftheuterusaretotallyobscuredbyahemorrhagicinflammatorymass.Thetubeisadherenttotheadjacentovaryontheotherside.


Pathology_Robbins

Pathology_Robbins. Fig.19.14Pelvicinflammatorydisease,bilateralandasymmetric.Thetubeandovarytotheleftoftheuterusaretotallyobscuredbyahemorrhagicinflammatorymass.Thetubeisadherenttotheadjacentovaryontheotherside. Follicle and luteal cysts in the ovaries are so commonplace that they may be considered variants of normal physiology. These innocuous lesions originate from unruptured graafian follicles or from follicles that rupture and then immediately seal. Such cysts often are multiple and develop subjacent to the serosa of the ovary. They typically are small (1–1.5 cm in diameter) and are filled with clear serous fluid. Occasionally, they become sufficiently large (4–5 cm) to produce palpable masses and pelvic pain. When small, they are lined by granulosa lining cells or luteal cells, but as fluid accumulates, pressure may cause atrophy of these cells. Sometimes these cysts rupture, producing intraperitoneal bleeding and peritoneal symptoms (acute abdomen).


Pathology_Robbins

Pathology_Robbins. Polycystic ovarian syndrome (formerly called Stein-Leventhal syndrome) is a complex endocrine disorder characterized by hyperandrogenism, menstrual abnormalities, polycystic ovaries, chronic anovulation, and decreased fertility. It usually comes to attention after menarche in teenage girls or young adults who present with oligomenorrhea, hirsutism, infertility, and sometimes with obesity. The ovaries are usually twice the normal size, gray-white with a smooth outer cortex, and studded with subcortical cysts 0.5 to 1.5 cm in diameter. Histologic examination shows a thickened, fibrotic ovarian capsule overlying innumerable cystic follicles lined by granulosa cells with a hyperplastic luteinized theca interna. There is a conspicuous absence of corpora lutea in the ovary. Damage to or obstruction of the tubal lumina may produce permanent sterility.


Pathology_Robbins

Pathology_Robbins. Once thought to be uncommon, primary adenocarcinomas of the fallopian tube may be the site of origin for many of the high-grade serous carcinomas long thought to arise in the ovary. Studies have identified the presence of serous tubal intraepithelial carcinoma (STIC) in the fimbriated ends of fallopian tubes. Like the precursor of uterine serous carcinoma, STICs have mutations in TP53 in more than 90% of cases. These lesions are found frequently in fallopian tubes removed prophylactically from women who carry mutations in BRCA1 and BRCA2 and less commonly in instances where tubes are removed from women without known genetic risk factors. This has led to the idea that sporadic “ovarian” serous carcinomas (discussed later) also originate in the fallopian tube. Because the fimbriated end of the fallopian tube is intimately associated with the ovary and has access to the peritoneal cavity, fallopian tube carcinomas frequently involve the ovary, omentum, and peritoneal cavity at


Pathology_Robbins

Pathology_Robbins. end of the fallopian tube is intimately associated with the ovary and has access to the peritoneal cavity, fallopian tube carcinomas frequently involve the ovary, omentum, and peritoneal cavity at presentation.


Pathology_Robbins

Pathology_Robbins. In the United States it is estimated that there will be over 20,000 ovarian cancer cases diagnosed in 2016 leading to over 14,000 deaths, making ovarian cancer the fifth leading contributor to cancer mortality in women. Tumors of the ovary are remarkably varied as they may arise from any of the three cell types in the normal ovary: the multipotent surface (coelomic) epithelium, the totipotent germ cells, and the sex cord–stromal cells. Neoplasms of epithelial origin account for the great majority of ovarian tumors and, in their malignant forms, account for almost 90% of ovarian cancers ( Table 19.3 ). Germ cell and sex cord–stromal cell tumors are much less frequent; although they constitute 20% to 30% of ovarian tumors, they are collectively responsible for less than 10% of malignant tumors of the ovary. The majority of ovarian tumors arise from the fallopian tube or epithelial cysts in the cortex of the ovary ( Fig.


Pathology_Robbins

Pathology_Robbins. The majority of ovarian tumors arise from the fallopian tube or epithelial cysts in the cortex of the ovary ( Fig. 19.15 ). As mentioned, studies have shown that many of the tumors thought to arise from the coelomic epithelium that covers the surface of the ovary are now thought to arise from the fimbriated end of the fallopian tube ( Fig. 19.15 ). The epithelium lining the cortical cysts may be derived from displaced ovarian surface epithelium or the lining of fallopian tube. These can become metaplastic or undergo neoplastic transformation to give rise to a number of different epithelial tumors. Benign lesions usually are cystic (cystadenoma) and may have an accompanying stromal component (cystadenofibroma). Malignant tumors also may be cystic (cystadenocarcinoma) or solid (carcinoma). http://ebooksmedicine.net Table 19.3 Frequency of Major Ovarian Tumors


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Table 19.3 Frequency of Major Ovarian Tumors Some ovarian epithelial tumors fall into an intermediate category currently referred to as borderline tumors. Although the majority of borderline tumors behave in a benign manner they can recur and some can progress to carcinoma. Important risk factors for ovarian cancer include nulliparity, family history, and germline mutations in certain Fig. 19.15 Derivation, of various ovarian neoplasms. Type I tumors progress from benign tumors through borderline tumors that may give rise to a low-grade carcinoma. Type II tumors arise from inclusions cysts/fallopian tube epithelium via intraepithelial precursors that are often not identified. They demonstrate high-grade features and are most commonly of serous histology. STIC, serous tubal intraepithelial carcinoma.


Pathology_Robbins

Pathology_Robbins. tumor suppressor genes. There is a higher incidence of carcinoma in unmarried women and married women with low parity. Of interest, prolonged use of oral contraceptives reduces the risk. Around 5% to 10% of ovarian cancers are familial, and most of these are associated with mutations in the BRCA1 or BRCA2 tumor suppressor genes. As will be discussed later, mutations in BRCA1 and BRCA2 also are associated with hereditary breast cancer. The average lifetime risk for ovarian cancer is approximately 30% in BRCA1 carriers; the risk in BRCA2 carriers is somewhat lower. In contrast with familial ovarian cancer, mutations in BRCA1 and BRCA2 are found in only 8% to 10% of sporadic ovarian cancers, which appear to arise through alternative molecular mechanisms.


Pathology_Robbins

Pathology_Robbins. Serous tumors are the most common of the ovarian epithelial tumors overall, and also make up the greatest fraction of malignant ovarian tumors. About 60% are benign, 15% are borderline, and 25% are malignant. Benign lesions are usually encountered in patients between 30 and 40 years of age, and malignant serous tumors are more commonly seen between 45 and 65 years of age.


Pathology_Robbins

Pathology_Robbins. There are two types of serous carcinomas, low-grade and high-grade. The former arise from benign or borderline lesions and progress slowly in a stepwise manner to become invasive carcinoma. These low-grade tumors are associated with mutations in genes encoding signaling proteins, such as KRAS, a member of the RAS gene family. The high-grade serous tumors develop rapidly. As already mentioned, many of these high-grade lesions arise in the fimbriated end of the fallopian tube via serous tubal intraepithelial carcinoma, rather than ovarian coelomic epithelium. TP53 mutations are virtually ubiquitous in high-grade serous cancers, being present in over 95% of cases. Other frequently mutated genes include the tumor suppressors NF1 and RB, as well as BRCA1 and BRCA2 in familial ovarian cancers.


Pathology_Robbins

Pathology_Robbins. Most serous tumors are large, spherical to ovoid, cystic structures up to 30 to 40 cm in diameter. About 25% of the benign tumors are bilateral. In the benign tumors, the serosal covering is smooth and glistening. By contrast, the surface of adenocarcinomas often has nodular irregularities representing areas in which the tumor has invaded the serosa. On cut section, small cystic tumors may have a single cavity, but larger ones frequently are divided by multiple septa into multiloculated masses. The cystic spaces usually are filled with a clear serous fluid. Protruding into the cystic cavities are papillary projections, which are more prominent in malignant tumors ( Fig. 19.16


Pathology_Robbins

Pathology_Robbins. Fig. 19.16 On histologic examination, benign tumors contain a single layer of columnar epithelial cells that line the cyst or cysts. The cells often are ciliated. Psammoma bodies (concentrically laminated calcified concretions) are common in the tips of papillae. In high-grade carcinoma the cells are markedly atypical, the papillary formations are usually complex and multilayered, and by definition nests or sheets of malignant cells invade the ovarian stroma. Between clearly benign and obviously malignant forms Fig.19.16Ovarianseroustumors.(A)Borderlineserouscystadenomaopenedtodisplayacystcavitylinedbydelicatepapillarytumorgrowths.(B)Cystadenocarcinoma.Thecystisopenedtoshowalarge,bulkytumormass.


Pathology_Robbins

Pathology_Robbins. Fig.19.16Ovarianseroustumors.(A)Borderlineserouscystadenomaopenedtodisplayacystcavitylinedbydelicatepapillarytumorgrowths.(B)Cystadenocarcinoma.Thecystisopenedtoshowalarge,bulkytumormass. (Courtesy of Dr. Christopher Crum, Brigham and Women’s Hospital, Boston, Massachusetts.) lieborderlinetumors,whichexhibitlesscytologicatypiaandtypicallynostromalinvasion.Borderlinetumorsmayseedtheperitoneum,butfortunatelythetumorimplantsusuallyare“noninvasive.”Ingeneral,malignantseroustumorsspreadthroughouttheperitonealcavityandtoregionallymphnodes,includingperiaorticlymphnodes;distantlymphaticandhematogenousmetastasesareinfrequent.


Pathology_Robbins

Pathology_Robbins. The prognosis for patients with high-grade serous carcinoma is poor, even after surgery and chemotherapy, and depends heavily on the stage of the disease at diagnosis. The 5-year survival for women with carcinoma confined to one ovary is about 90%, but falls precipitously with higher stage tumors to less than 40% depending on the exact stage. In contrast, borderline tumors are associated with nearly 100% survival. Of note, women with tumors containing BRCA1/2 mutations tend to have a better prognosis than women whose tumors lack these genetic abnormalities. Mucinous tumors differ from serous tumors in two respects: the neoplastic epithelium consists of mucin-secreting cells; and mucinous tumors are considerably less likely to be malignant. Overall, only 10% of mucinous tumors are malignant; another 10% are borderline, and 80% are benign.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Rupturedovarianmucinoustumorsmayseedtheperitoneum;however,thesedepositstypicallyregressspontaneously.Stableimplantationofmucinoustumorcellsintheperitoneumwithproductionofcopiousamountsofmuciniscalledpseudomyxomaperitonei;inmostcases,thisdisorderiscausedbymetastaticspreadoftumorsinthegastrointestinaltract,primarilytheappendix(Chapter15). The prognosis of mucinous cystadenocarcinoma is somewhat better than that of its serous counterpart, although stage rather than histologic type (serous versus mucinous) is the major determinant of outcome. Mutations in KRAS are detected in approximately 50% of ovarian mucinous carcinomas, however this does not help distinguish them from metastatic GI tumors, which also have a high frequency of KRAS mutations.


Pathology_Robbins

Pathology_Robbins. These tumors may be solid or cystic; they sometimes develop in association with endometriosis. On microscopic examination, they are distinguished by the formation of tubular glands, similar to those of the endometrium, within the lining of cystic spaces. Although benign and borderline forms exist, endometrioid tumors usually are malignant. They are bilateral in about 30% of cases, and 15% to 30% of women with these ovarian tumors have a concomitant endometrial carcinoma. Similar to endometrioid-type carcinoma of the endometrium, endometrioid carcinomas of the ovary frequently have mutations in the PTEN tumor suppressor gene as well as mutations in other genes that also act by upregulating PI3K-AKT signaling.


Pathology_Robbins

Pathology_Robbins. The Brenner tumor is an uncommon, solid, usually unilateral ovarian tumor consisting of abundant stroma containing nests of transitional-type epithelium resembling that of the urinary tract. Occasionally, the nests are cystic and are lined by columnar mucus-secreting cells. Brenner tumors generally are smoothly encapsulated and gray-white on cut section, ranging from a few centimeters to 20 cm in diameter. These tumors may arise from the surface epithelium or from urogenital epithelium trapped within the germinal ridge. Although most are benign, both malignant and borderline tumors have been described. http://ebooksmedicine.net Fig.19.17Ovarianmucinouscystadenoma.(A)Mucinouscystadenomawithmulticysticappearanceanddelicatesepta.Notethepresenceofglisteningmucinwithinthecysts.(B)Columnarcellliningofmucinouscystadenoma.


Pathology_Robbins

Pathology_Robbins. Fig.19.17Ovarianmucinouscystadenoma.(A)Mucinouscystadenomawithmulticysticappearanceanddelicatesepta.Notethepresenceofglisteningmucinwithinthecysts.(B)Columnarcellliningofmucinouscystadenoma. Many other types of tumors of germ cell and sex cord– stromal origin also arise in the ovary, but only the teratomas of germ cell origin are sufficiently common to merit description. Table 19.4 presents some salient features of other neoplasms of germ cell and sex cord origin. Teratomas constitute 15% to 20% of ovarian tumors. A distressing feature of these germ cell tumors is their predilection to arise in the first 2 decades of life; to make matters worse, the younger the person, the greater the likelihood of malignancy. More than 90% of these germ cell neoplasms, however, are benign mature cystic teratomas; the immature, malignant variant is rare.


Pathology_Robbins

Pathology_Robbins. Benign (mature) cystic teratomas are marked by the presence of mature tissues derived from all three germ cell layers: ectoderm, endoderm, and mesoderm. Usually these tumors contain cysts lined by epidermis replete with adnexal appendages—hence the common designation dermoid cysts. Most are discovered in young women as ovarian masses or are found incidentally on abdominal radiographs or scans because they contain foci of calcification produced by toothlike structures contained within the tumor. About 90% are unilateral, with the right side more commonly affected. Rarely do these cystic masses exceed 10 cm in diameter. On cut section, they often are filled with sebaceous secretion and matted hair that, when removed, reveal a hair-bearing epidermal lining ( Fig. 19.18 ). Sometimes there is a nodular projection from which teeth protrude. Occasionally, foci of bone and cartilage, nests of bronchial or gastrointestinal epithelium, or other tissues are present.


Pathology_Robbins

Pathology_Robbins. For unknown reasons, these neoplasms sometimes produce infertility and are prone to undergo torsion (in 10%–15% of cases), which constitutes an acute surgical emergency. A rare, but fascinating, paraneoplastic complication is limbic encephalitis, which may develop in women with teratomas containing mature neural tissue and often remits with tumor resection. Malignant transformation, usually to a squamous cell carcinoma, is seen in about 1% of cases.


Pathology_Robbins

Pathology_Robbins. Malignant (immature) teratomas are found early in life, the mean age at clinical detection being 18 years. They typically are bulky and appear solid on cut section, and they often contain areas of necrosis; uncommonly, cystic foci are present that contain sebaceous secretion, hair, and other features similar to those of mature teratomas. On microscopic examination, the distinguishing feature is the presence of immature elements or minimally differentiated cartilage, bone, muscle, nerve, or other tissues. As with other tumors, the prognosis depends on grade and stage. A rare subtype of teratoma is composed entirely of specialized tissue. The most common example is struma ovarii, http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. A rare subtype of teratoma is composed entirely of specialized tissue. The most common example is struma ovarii, http://ebooksmedicine.net Twotypesofepithelialcells:cytotrophoblastPrimaryfocusmaydegenerate,andsyncytiotrophoblastleavingonlymetastasesResistanttochemotherapy which is composed entirely of mature thyroid tissue that may actually produce hyperthyroidism. These tumors appear as small, solid, unilateral brown ovarian masses. Other specialized teratomas include ovarian carcinoid, which in rare instances produces carcinoid syndrome.


Pathology_Robbins

Pathology_Robbins. With all ovarian neoplasms, management poses a formidable clinical challenge, because symptoms or signs usually appear only when tumors are well advanced. Ovarian tumors of surface epithelial origin usually are asymptomatic until they become large enough to cause local pressure symptoms (e.g., pain, gastrointestinal complaints, urinary frequency). Indeed, about 30% of all ovarian neoplasms are discovered incidentally on routine gynecologic examination. Larger masses, particularly the common epithelial tumors, may cause an increase in abdominal girth. Smaller masses, particularly dermoid cysts, sometimes twist on their pedicles (torsion), producing severe abdominal pain that mimics an acute abdomen. Metastatic seeding of malignant serous tumors often causes ascites, whereas functioning ovarian tumors often come to attention because of the endocrinopathies they produce.


Pathology_Robbins

Pathology_Robbins. Fig.19.18Maturecysticteratoma(dermoidcyst)oftheovary.Aballofhair(bottom)andamixtureoftissuesareevident.(Courtesy of Dr. Christopher Crum, Brigham and Women’s Hospital, Boston, Massachusetts.) Unfortunately, treatment of ovarian tumors remains unsatisfactory; only a modest increase in survival has been achieved since the mid-1970s. Screening methods that detect early tumors are badly needed, but those evaluated to date are of limited value. One such marker, the protein CA-125, is elevated in the sera of 75% to 90% of women with epithelial ovarian cancer. However, CA-125 is undetectable in up to 50% of women with cancer limited to the ovary; conversely, it often is elevated in a variety of benign conditions and nonovarian cancers. Hence, its usefulness as a screening test in asymptomatic post-menopausal women is limited. Currently, CA-125 measurements are of greatest value in monitoring response to therapy. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Germcelltumorsmaydifferentiatetowardoogonia(dysgerminoma),primitiveembryonaltissue(embryonal),yolksac(endodermalsinustumor),placentaltissue(choriocarcinoma),ormultipletissuetypes(teratoma). Diseases of pregnancy and pathologic conditions of the placenta are important contributors to morbidity and mortality for both mother and child. Discussed in this section are a limited number of disorders in which knowledge of the morphologic lesions contributes to an understanding of clinical disease. Infections may reach the placenta by either of two paths: (1) ascension through the birth canal or (2) hematogenous (transplacental) spread.


Pathology_Robbins

Pathology_Robbins. Infections may reach the placenta by either of two paths: (1) ascension through the birth canal or (2) hematogenous (transplacental) spread. Ascending infections are by far the more common; in most instances they are bacterial and are associated with premature rupture of the fetal membranes. On microscopic examination, the chorioamnion shows neutrophilic infiltration associated with edema and congestion (acute chorioamnionitis). With extension beyond the membranes, the infection may involve the umbilical cord and placental villi, resulting in acute vasculitis of the cord (funisitis). Ascending infections are caused by Mycoplasma, Candida, and bacteria of the vaginal flora.


Pathology_Robbins

Pathology_Robbins. Uncommonly, placental infections may arise by hematogenous spread of bacteria and other organisms; on histologic examination, placental villi are the most frequently affected structures (villitis). Syphilis, tuberculosis, listeriosis, toxoplasmosis, and various viruses (rubella, cytomegalovirus, herpes simplex virus) all can cause placental villitis. Transplacental infections can affect the fetus and give rise to the so-called “TORCH” complex (toxoplasmosis, other infections, rubella, cytomegalovirus infection, herpes) (Chapter 7).


Pathology_Robbins

Pathology_Robbins. Ectopic pregnancy is defined as implantation of a fertilized ovum in any site other than the uterus, which may occur in as many as 1% of pregnancies. In more than 90% of these cases, implantation occurs in the fallopian tube (tubal pregnancy); other sites include the ovaries and the abdominal cavity. Any factor that retards passage of the ovum through the fallopian tube predisposes to ectopic pregnancy. In about half of the cases, slowed passage results from chronic inflammation and scarring in the oviduct; intrauterine tumors and endometriosis may also hamper passage of the ovum. In the other 50% of tubal pregnancies, no anatomic cause is evident. Ovarian pregnancies probably result from rare instances in which the ovum is fertilized just as the follicle ruptures. Gestation within the abdominal cavity occurs when the fertilized egg drops out of the fimbriated end of the fallopian tube and implants on the peritoneum.


Pathology_Robbins

Pathology_Robbins. Until rupture occurs, an ectopic pregnancy may be indistinguishable from a normal pregnancy, with cessation of menstruation and elevation of serum and urinary placental hormones. Under the influence of these hormones, the endometrium (in approximately 50% of cases) undergoes the characteristic hypersecretory and decidual changes of pregnancy. The absence of elevated gonadotropin levels does not exclude the diagnosis because poor attachment and necrosis of the ectopic placenta are common. Rupture of an ectopic pregnancy may be catastrophic, with the sudden onset of intense abdominal pain and signs of an acute abdomen, often followed by shock. Prompt surgical intervention is necessary. http://ebooksmedicine.net Ectopicpregnancyisdefinedasimplantationofthefertilizedovumoutsideoftheuterinecorpus.Approximately1%ofpregnanciesimplantectopically;themostcommonsiteisthefallopiantube. Chronicsalpingitiswithscarringisamajorriskfactorfortubalectopicpregnancy.


Pathology_Robbins

Pathology_Robbins. Chronicsalpingitiswithscarringisamajorriskfactorfortubalectopicpregnancy. Ruptureofanectopicpregnancyisamedicalemergencythat,ifleftuntreated,mayresultinexsanguinationanddeath.


Pathology_Robbins

Pathology_Robbins. Gestational trophoblastic disease refers to an abnormal proliferation of fetal trophoblast cells. The World Health Organization broadly divides these diseases into two categories: molar lesions and nonmolar lesions. The molar lesions are further divided into partial, complete, and invasive hydatidiform moles. The nonmolar category consists of choriocarcinoma and other more uncommon types of trophoblast-derived malignancies. All elaborate human chorionic gonadotropins (hCG), which is detected in the blood and urine at levels considerably higher than those found during normal pregnancy. In addition to aiding diagnosis, hCG levels in the blood or urine can be used to monitor treatment efficacy. Clinicians prefer the umbrella term gestational trophoblastic disease because the response to therapy, as judged by the hormone levels, is significantly more important than pathologic subtyping of lesions. However, the genetics, pathology, and natural history of these disorders are sufficiently


Pathology_Robbins

Pathology_Robbins. as judged by the hormone levels, is significantly more important than pathologic subtyping of lesions. However, the genetics, pathology, and natural history of these disorders are sufficiently distinct to merit discussion of each.


Pathology_Robbins

HydatidiformMole:CompleteandPartial

Pathology_Robbins. HydatidiformMole:CompleteandPartial


Pathology_Robbins

Pathology_Robbins. The typical hydatidiform mole is a voluminous mass of swollen, sometimes cystically dilated, chorionic villi, appearing grossly as grapelike structures. Varying amounts of normal to highly atypical chorionic epithelium cover the swollen villi. There are two distinctive subtypes of hydatidiform moles: complete and partial. Complete hydatidiform moles are not compatible with embryogenesis and rarely contain fetal parts. All of the chorionic villi are abnormal, and the chorionic epithelial cells are diploid (46,XX or, uncommonly, 46,XY). The partial hydatidiform mole is compatible with early embryo formation and therefore may contain fetal parts, has some normal chorionic villi, and is almost always triploid (e.g., 69,XXY) ( 19.5 ). Both types result from abnormal fertilization with an excess of paternal genetic material. In a complete mole the entire genetic content is supplied by two spermatozoa (or a diploid sperm), yielding diploid cells containing only paternal chromosomes, whereas


Pathology_Robbins

Pathology_Robbins. of paternal genetic material. In a complete mole the entire genetic content is supplied by two spermatozoa (or a diploid sperm), yielding diploid cells containing only paternal chromosomes, whereas in a partial mole a normal egg is fertilized by two spermatozoa (or a diploid sperm), resulting in a triploid karyotype with a preponderance of paternal genes.


Pathology_Robbins

Pathology_Robbins. Table19.5FeaturesofCompleteandPartialHydatidiformMole Karyotype46,XX(46,XY)Triploid(69,XXY) hCG,Humanchorionicgonadotropin. The incidence of complete hydatidiform mole is about 1 to 1.5 per 2000 pregnancies in the United States and other Western countries. For unknown reasons, the incidence is much higher in Asian countries. Moles are most common before the age of 20 and after the age of 40 years, and a history of the condition increases the risk for molar disease in subsequent pregnancies. Although molar disease formerly was discovered at 12 to 14 weeks of pregnancy during investigation for a gestation that was “too large for dates,” early monitoring of pregnancies by ultrasound has lowered the gestational age at detection. In both complete and partial moles, elevation of hCG in the maternal blood and absence of fetal heart sounds are typical. MORPHOLOGYInadvancedcasestheuterinecavityisexpandedbyadelicate,friablemassofthin-walled,translucentcysticstructures(


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInadvancedcasestheuterinecavityisexpandedbyadelicate,friablemassofthin-walled,translucentcysticstructures( Fig.19.19 ).Fetalpartsarerarelyseenincompletemolesbutarecommoninpartialmoles.Onmicroscopicexamination,thecompletemoleshowshydropicswellingofpoorlyvascularizedchorionicvilliwithaloose,myxomatous,edematousstroma.Thechorionicepitheliumtypicallyshowsaproliferationofbothcytotrophoblastsandsyncytiotrophoblasts( Fig.19.20 ).HistologicgradingtopredicttheclinicaloutcomeofmoleshasbeensupplantedbymonitoringofhCGlevels.Inpartialmoles,villousedemainvolvesonlyasubsetofthevilli,andthetrophoblasticproliferationisfocalandslight.Inmostcasesofpartialmole,somefetalcellsarepresent,rangingfromfetalredcellsinplacentalvillito,inrarecases,afullyformedfetus. Overall, 80% to 90% of moles do not recur after thorough curettage, but 10% of complete moles are invasive (described next). No more than 2% to 3% give rise to choriocarcinoma.


Pathology_Robbins

Pathology_Robbins. Overall, 80% to 90% of moles do not recur after thorough curettage, but 10% of complete moles are invasive (described next). No more than 2% to 3% give rise to choriocarcinoma. Invasive moles are complete moles that are locally invasive but lack the metastatic potential of choriocarcinoma. An invasive mole retains hydropic villi, which penetrate the uterine wall deeply, possibly causing rupture and sometimes life-threatening hemorrhage. On microscopic examination, the epithelium of the villi shows atypical changes, with proliferation of both trophoblastic and syncytiotrophoblast components. http://ebooksmedicine.net Fig.19.19Completehydatidiformmole,consistingofnumerousswollen(hydropic)villi.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig.19.19Completehydatidiformmole,consistingofnumerousswollen(hydropic)villi. Although the marked invasiveness of this lesion makes removal technically difficult, metastases do not occur. Hydropic villi may embolize to distant organs, such as lungs or brain, but these emboli do not behave like true metastases and may regress spontaneously. Because of deeper invasion into the myometrium, an invasive mole is difficult to remove completely by curettage, so if serum β-hCG remains elevated, further treatment is required. Fortunately, in most cases cure is possible with chemotherapy.


Pathology_Robbins

Pathology_Robbins. Choriocarcinoma, a very aggressive malignant tumor, arises from gestational chorionic epithelium or, less frequently, from totipotential cells within the gonads (as a germ cell tumor). These tumors are rare in the Western Hemisphere (they occur in about 1 per 30,000 pregnancies in the United States), but are much more common in Asian and African countries, reaching a frequency of 1 in 2000 pregnancies. Approximately 50% of choriocarcinomas arise from complete hydatidiform moles; about 25% arise after an abortion, while the remainder manifest following an apparently normal pregnancy. In most cases, choriocarcinoma presents as a bloody, brownish discharge accompanied by a rising titer of β-hCG in blood and urine, in the absence of marked uterine enlargement, such as would be seen with a mole. In general, the β-hCG titers are much higher than those associated with a mole.


Pathology_Robbins

Pathology_Robbins. Fig.19.20Completehydatidiformmole.Inthismicroscopicimage,dis-tendedhydropicvilli(below) andproliferationofthechorionicepithelium(above) areevident.(Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical School,Dallas,Texas.) MORPHOLOGYChoriocarcinomasusuallyappearashemorrhagic,necroticuterinemasses.Sometimesthenecrosisissoextensivethatlittleviabletumorremains.Indeed,theprimarylesionmay“selfdestruct,”andonlythemetastasestellthestory.Veryearly,thetumorinsinuatesitselfintothemyometriumandintovessels.Incontrastwithhydatidiformmolesandinvasivemoles,chorionicvilliarenotformed;instead,thetumoriscomposedofanaplasticcuboidalcytotrophoblastsandsyncytiotrophoblasts( Fig.19.21 Bythetimeachoriocarcinomaisdiscovered,widespreadvascularspreadusuallyhasoccurredtothelungs(50%),vagina(30%–40%),brain,liver,orkidneys.Lymphaticinvasionisuncommon.


Pathology_Robbins

Pathology_Robbins. Fig.19.21 Bythetimeachoriocarcinomaisdiscovered,widespreadvascularspreadusuallyhasoccurredtothelungs(50%),vagina(30%–40%),brain,liver,orkidneys.Lymphaticinvasionisuncommon. Despite the extremely aggressive nature of placental choriocarcinoma, these tumors are remarkably sensitive to chemotherapy. Nearly 100% of affected patients are cured, even those with metastases at distant sites such as the lungs. By contrast, response to chemotherapy with choriocarcinomas that arise in the gonads (ovary or testis) is relatively poor. This striking difference in prognosis may be related to the presence of paternal antigens on placental choriocarcinomas that are lacking in gonadal lesions. Conceivably, a maternal immune response against the foreign (paternal) antigens helps clear the tumor by acting as an adjunct to chemotherapy.


Pathology_Robbins

Pathology_Robbins. Fig.19.21Choriocarcinoma.Thisfieldcontainsbothneoplasticcytotro-phoblastandmultinucleatesyncytiotrophoblast.(Courtesy of Dr. David R. Genest, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Placental site trophoblastic tumors are derived from the placental site or intermediate trophoblast, a cell that has morphologic and functional features that overlap with those of trophoblasts and syncytiotrophoblasts. These uncommon diploid tumors, often XX in karyotype, typically arise a few months after pregnancy. Because intermediate trophoblasts do not produce hCG in large amounts, hCG concentrations are only slightly elevated. More typically, these tumors produce human placental lactogen. An indolent clinical course is typical, with a generally favorable outcome if the tumor is confined to the endomyometrium. Of note, however, placental site trophoblastic tumors are not as sensitive to chemotherapy as are other trophoblastic tumors, and the prognosis is poor when spread occurs beyond the uterus. Molardiseaseisaresultofanabnormalcontributionofpaternalchromosomestotheconceptus.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Placentalsitetrophoblastictumorisanindolenttumorofintermediatetrophoblastthatproduceshumanplacentallactogen.Itcanbecuredsurgicallybutonceitspreadsitdoesnotrespondwelltochemotherapy. The development of hypertension, accompanied by proteinuria and edema in the third trimester of pregnancy, is referred to as preeclampsia. This syndrome occurs in 5% to 10% of pregnancies, particularly with first pregnancies in women older than 35 years. In those severely affected, seizures may occur, and the symptom complex is then termed eclampsia. By long-existing precedent, preeclampsia and eclampsia sometimes are referred to as toxemia of pregnancy. No blood-borne toxin has been identified, and this historically sanctified term is a misnomer. Recognition and early treatment of preeclampsia have now made eclampsia, particularly fatal eclampsia, rare.


Pathology_Robbins

Pathology_Robbins. While exact triggering events initiating these syndromes are unknown, a common feature underlying all cases is insufficient maternal blood flow to the placenta secondary to inadequate remodeling of the spiral arteries of the uteroplacental vascular bed. In normal pregnancy, the musculoelastic walls of the spiral arteries are invaded by trophoblasts, permitting them to dilate into wide vascular sinusoids. In preeclampsia and eclampsia, this vascular remodeling is impaired, the musculoelastic walls are retained, and the channels remain narrow. Decreased uteroplacental blood flow appears to result in placental hypoxia, placental dysfunction, and the altered release of circulating factors that regulate angiogenesis. Specifically, increases in the anti-angiogenic factors soluble Flt1 (sFlt1) and soluble endoglin (sEng) and reductions in proangiogenic factors, such as VEGF, have been noted. These disturbances are hypothesized to result in endothelial cell dysfunction, vascular


Pathology_Robbins

Pathology_Robbins. (sFlt1) and soluble endoglin (sEng) and reductions in proangiogenic factors, such as VEGF, have been noted. These disturbances are hypothesized to result in endothelial cell dysfunction, vascular hyperreactivity, and end-organ microangiopathy. Although the exact basis of preeclampsia remains to be further defined, several serious consequences have been associated with this condition:


Pathology_Robbins

Pathology_Robbins. Placental infarction, stemming from chronic hypoperfusion Hypertension, resulting from reduced endothelial production of the vasodilators prostacyclin and prostaglandin E2 and from increased production of the vasoconstrictor thromboxane A2 Hypercoagulability, due to endothelial dysfunction and release of tissue factor from the placenta End-organ failure, most notably of the kidney and the liver, which occurs in patients with full-blown eclampsia. Approximately 10% of the patients with severe preeclampsia develop the so-called “HELLP syndrome”, characterized by elevated liver enzymes, microangiopathic hemolytic anemia, thrombocytopenia due to platelet consumption, and sometimes fullblown disseminated intravascular coagulation (DIC). disorder.Placentalabnormalitiesinclude Infarcts,whichcanbeafeatureofnormalpregnancy,butaremuchmorenumerouswithseverepreeclampsiaoreclampsia


Pathology_Robbins

Pathology_Robbins. disorder.Placentalabnormalitiesinclude Infarcts,whichcanbeafeatureofnormalpregnancy,butaremuchmorenumerouswithseverepreeclampsiaoreclampsia Prematurematurationofplacentalvilliassociatedwithvillousedema,hypovascularity,andincreasedproductionofsyncytialepithelialknots Preeclampsia presents insidiously during weeks 24 to 25 of gestation with edema, proteinuria, and rising blood pressure. Should the condition evolve into eclampsia, renal function is impaired, blood pressure rises further, and convulsions may occur. Prompt therapy early in the course aborts the associated organ changes, with all abnormalities resolving promptly after delivery or after cesarean section. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Three important features distinguish the breast from other organs. First, rather than being essential for survival, the major function is the nutritional support of another individual, the infant. Second, the structure of the organ undergoes marked changes throughout life: expansion of the lobular system after menarche, periodic remodeling during adulthood, especially during and after pregnancy, and ultimately involution and regression of lobules. Finally, breasts are visible and as a result have a social, cultural, and personal significance not shared by other organs. All of these features play a role when considering the origins, presentations, and treatment of breast disease.


Pathology_Robbins

Pathology_Robbins. The functional unit of the breast is the lobule, which is supported by a specialized intralobular stroma. The inner luminal epithelial cells produce milk during lactation. The basally located myoepithelial cells have contractile function to aid in milk ejection and also help support the basement membrane. The ducts are conduits for milk to reach the nipple. The size of the breast is determined primarily by interlobular stroma, which increases during puberty and involutes with age. Each normal constituent is a source of both benign and malignant lesions ( Fig. 19.22


Pathology_Robbins

Pathology_Robbins. Fig. 19.22 The predominant symptoms and signs of diseases of the breast are pain, inflammatory changes, nipple discharge, “lumpiness,” or a palpable mass (Fig. 19.23A ). However, few symptoms are so severe as to require treatment, and the primary reason for investigating their cause is to evaluate the possibility of malignancy. Most symptomatic breast lesions (>90%) are benign. Of women with cancer, about 45% have symptoms, whereas the remainder come to attention through screening tests ( Fig. 19.23B Pain (mastalgia or mastodynia) is a common symptom often related to menses, possibly due to cyclic edema and swelling. Pain localized in a specific area is usually caused by a ruptured cyst or trauma to adipose tissue (fat necrosis). Almost all painful masses are benign, but for unknown reasons a small fraction of cancers (about 10%) cause pain.


Pathology_Robbins

Pathology_Robbins. Inflammation causes an edematous and erythematous breast. It is rare and is most often caused by infections, which only occur with any frequency during lactation and breastfeeding. An important mimic of Fig.19.22Originsofbreastdisorders.Benignepitheliallesionsincludeintraductalpapillomasthatgrowinsinusesbelowthenippleandepithelialhyperplasiathatarisesinlobules.Malignantepitheliallesionsaremainlybreastcarcinomas,whichmayremaininsituorinvadeintothebreastandspreadbymetastasis.Specializedintralobularstroma(green) cellsmaygiverisetofibroadenomasandphyllodestumors,whereasinterlobularstroma(green) maygiverisetoavarietyofrarebenignandmalignanttumors.Luminal cells (blue) Myoepithelial cells (black) Intralobular stroma (green) Interlobular stroma (red) NORMAL Fibroadenoma Hemangioma Angiosarcoma Papilloma DCIS Epithelial hyperplasia Invasive carcinoma Phyllodes tumor Nipple BENIGN MALIGNANT Normal lobule ing the origins, presentations, and treatment of breast disease


Pathology_Robbins

Pathology_Robbins. A SYMPTOMS OF PATIENTS Nipple discharge Inflammation 7% are cancers 5% are cancers 5% are cancers <1% are cancers 1% are cancers Palpable mass Lumpiness or other symptoms Pain Fig.19.23Presentingsymptomsofbreastdisease.(A)Commonbreast-relatedsymptomsthatbringpatientstoclinicalattention.(B)Presentationsofbreastcancer. inflammation is “inflammatory” breast carcinoma (discussed later). Nipple discharge may be normal when small in quantity and bilateral. The most common benign lesion producing a nipple discharge is a papilloma arising in the large ducts below the nipple ( Fig. 19.22 ). Discharges that are spontaneous, unilateral, and bloody are of greatest concern for malignancy. Lumpiness, or a diffuse nodularity throughout the breast, is usually a result of normal glandular tissue. When pronounced, imaging studies may help to determine whether a discrete mass is present.


Pathology_Robbins

Pathology_Robbins. Lumpiness, or a diffuse nodularity throughout the breast, is usually a result of normal glandular tissue. When pronounced, imaging studies may help to determine whether a discrete mass is present. Palpable masses can arise from proliferations of stromal cells or epithelial cells and are generally detected when they are 2 to 3 cm in size ( Fig. 19.22 ). Most (~95%) are benign; these tend to be round to oval and to have circumscribed borders. In contrast, malignant tumors usually invade across tissue planes and have irregular borders. However, because some cancers grow deceptively as circumscribed masses, all palpable masses require evaluation. Gynecomastia is the only common breast symptom in males. There is an increase in both stroma and epithelial cells resulting from an imbalance between estrogens, which stimulate breast tissue, and androgens, which counteract these effects.


Pathology_Robbins

Pathology_Robbins. Regardless of presenting symptom, the likelihood of malignancy increases with age. For example, the risk of nipple discharge being due to cancer increases from 7% in women younger than 60 years of age to 30% in women older than 60. Similarly, only 10% of palpable masses in women younger than 40 years of age are carcinomas, as compared to 60% in women older than 50. Mammographic screening was introduced in the 1980s as a means to detect early, nonpalpable asymptomatic breast carcinomas before metastatic spread has occurred. Mammography has met this promise, as the average size of invasive carcinomas detected by mammography is about 1 cm (significantly smaller than cancers identified by palpation), and only 15% will have metastasized to regional lymph nodes at the time of diagnosis. In the United States, most cancers in women more than 50 years of age are now detected by mammography (


Pathology_Robbins

Pathology_Robbins. Fig. 19.23B ). As with symptomatic breast lesions, the likelihood that an abnormal mammographic finding is caused by malignancy increases with age, from 10% at age 40 to more than 25% in women older than age 50. Symptomsaffectingthebreastsareevaluatedprimarilytodetermineifmalignancyispresent. Regardlessofthesymptom,theunderlyingcauseisbenigninthemajorityofcases. Breastcancerismostcommonlydetectedbypalpationofamassinyoungerwomenandinunscreenedpopulationsandbymammographicscreeninginolderwomen. Inflammatory diseases of the breast are rare and may be caused by infections, autoimmune disease, or foreign body–type reactions. Symptoms include erythema and edema, often accompanied by pain and focal tenderness. Because inflammatory diseases are rare, the possibility that the symptoms are caused by inflammatory carcinoma should always be considered (discussed later).


Pathology_Robbins

Pathology_Robbins. The only infectious agent to cause breast disease with any frequency is Staphylococcus aureus, which typically gains entry via fissures in nipple skin during the first weeks of breastfeeding. The invading organisms may lead to the formation of “lactational abscesses,” collections of neutrophils and associated bacteria in fibroadipose tissue. If untreated, tissue necrosis may lead to the appearance of fistula tracks opening onto the skin. Most cases are treated adequately with antibiotics and continued expression of milk. Rarely, surgical incision and drainage is required. http://ebooksmedicine.net The two types of stroma in the breast, intralobular and interlobular, give rise to different types of neoplasms ( Fig.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The two types of stroma in the breast, intralobular and interlobular, give rise to different types of neoplasms ( Fig. 19.22 ). Historically, tumors derived from intralobular stroma have been cleanly divided into benign fibroadenomas and more cellular phyllodes tumors, which sometimes recur following excision and rarely pursue a malignant course. It is now appreciated that these tumors share driver mutations in the same genes and appear to be part of a spectrum of related neoplasms. Nevertheless, the old classification is engrained in the medical lexicon and we will follow it here for simplicity’s sake.


Pathology_Robbins

Pathology_Robbins. Lesionsofinterlobularstromaaremonophasic(onlycomprisedofmesenchymalcells)andincludebenignsofttissuetumorsfoundelsewhereinthebody,suchashemangiomas(Chapter10)andlipomas(Chapter21).Theonlymalignancyderivedfrominterlobularstromalcellsofnoteisangiosarcoma(Chapter21),whichmayariseinthebreastafterlocalradiother-apy.Themorphologiesoftheselesionsaredescribedelsewhere. The majority of benign epithelial lesions are incidental findings detected by mammography. Their major clinical significance is their relationship to the subsequent risk of developing breast cancer. Benign changes are divided into three groups, nonproliferative disease, proliferative disease without atypia, and proliferative disease with atypia, each associated with a different degree of breast cancer risk ( Table 19.6 Nonproliferative disease is not associated with an increased risk of breast cancer.


Pathology_Robbins

Pathology_Robbins. Table 19.6 Nonproliferative disease is not associated with an increased risk of breast cancer. Proliferative disease without atypia encompasses polyclonal hyperplasias that are associated with a slightly increased risk of breast cancer. Proliferative disease with atypia includes monoclonal “precancers” that are associated with a modest increase in the risk of breast cancer in both breasts; overall, 13% to 17% of women with these lesions develop breast cancer. MORPHOLOGYNonproliferativediseaseconsistsofthreemajormorphologicchanges:cysts,fibrosis,andadenosis.Itistermed“nonproliferative”becausethelesionscontainsinglelayersofepithelialcells.Themostcommonnonproliferativebreastlesionsaresimplecystslinedbyalayerofluminalcellsthatoftenundergoapocrinemetaplasia(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Germlinetumorsuppressorgenemutation(e.g.,BRCA1 mutation)2.0–45.06%to>90% Ageatmenarche<12years1.34% Ageatmenopause>55years1.5–2.05%–6% Firstlivebirth<20years(protective)0.51.6% Firstlivebirth20–35years1.5–2.05%–6% Firstlivebirth>35years2.0–3.06%–10% Neverpregnant(nulliparous)3.010% Breast-feeding(slightlyprotective)0.82.6% Proliferativediseasewithoutatypia1.5–2.05%–6% Proliferativediseasewithatypia(ALHandADH)4.0–5.013%–17% Carcinomainsitu(ductalorlobular)8.0–10.025%–30% Ionizingradiation1.1–1.43.6%–4.6% Mammographicdensity3.0–7.010%–23% Postmenopausalobesityandweightgain1.1–3.03.6%–10% Postmenopausalhormonereplacement1.1–3.03.6%–10% Alcoholconsumption1.1–1.43.6%–4.6%


Pathology_Robbins

Pathology_Robbins. hyperplasia,increasednumbersofbothspindledmyoepithelialcellsandepithelioidluminalcellsexpandductalandlobularspaces( Fig.19.25B Proliferativediseasewithatypiaincludesatypicallobularhyperplasia(ALH)andatypicalductalhyperplasia(ADH).ALHcloselyresembleslobularcarcinomainsitu(LCIS)andADHcloselyresemblesductalcarcinomainsitu(DCIS)(bothdescribedlater),butaremorelimitedinextent.ThecellsinADHareuniforminappearanceandformsharplymarginatedspacesorrigidbridges( Fig.19.25C Breast carcinoma is the most common malignancy of women globally (excluding nonmelanoma skin cancer) and causes the majority of cancer deaths in women.


Pathology_Robbins

Pathology_Robbins. Fig.19.25C Breast carcinoma is the most common malignancy of women globally (excluding nonmelanoma skin cancer) and causes the majority of cancer deaths in women. Although the incidence in the United States decreased slightly in 2002 and then stabilized (changes attributed to a decrease in the use of postmenopausal hormone therapy and a plateau in the number of women undergoing mammographic screening), the worldwide incidence and mortality is increasing at an alarming rate. The major factors underlying this trend in developing countries are thought to be social changes that increase breast cancer risk—specifically, delayed childbearing, fewer pregnancies, and reduced breastfeeding—combined with a lack of access to optimal health care.


Pathology_Robbins

Pathology_Robbins. Fig.19.25Benignepithelialbreastdisease.(A)Nonproliferativedisease.Anapocrinecystisshownthatisacommonfeatureofnonproliferativebreastdisease.(B)Proliferativebreastdiseaseischaracterizedbyincreasednumbersofepithelialcells,asinthisexampleofepithelialhyperplasia.(C)Proliferativebreastdiseasewithatypia.Theproliferatingepithelialcellsaremonomorphicinappearanceandpileuptoformabnormalarchitecturalstructures. http://ebooksmedicine.net The lifetime risk of breast cancer is 1 in 8 for women living to age 90 in the United States. It is predicted that about 250,000 breast cancers will be diagnosed in 2016 and about 40,000 women will die of the disease—a toll among cancers second only to lung cancer. Since the mid-1980s the mortality rate has dropped from 30% to less than 20%. The decrease is attributed to both improved screening, which detects some cancers before they have metastasized, and more effective systemic treatment.


Pathology_Robbins

Pathology_Robbins. Almost all breast malignancies are adenocarcinomas (>95%). In the most clinically useful classification system, breast cancers are divided based on the expression of hormone receptors—estrogen receptor (ER) and progesterone receptor (PR)—and the expression of the human epidermal growth factor receptor 2 (HER2, also known as ERBB2), into three major groups: ER positive (HER2 negative; 50%–65% of cancers) HER2 positive (ER positive or negative; 10%–20% of cancers) Triple negative (ER, PR, and HER2 negative; 10%–20% of cancers) These three groups show striking differences in patient characteristics, pathologic features, treatment response, metastatic patterns, time to relapse, and outcome ( 19.7 Fig. 19.26 ). Within each group are additional histologic subtypes (discussed later), some of which also have clinical importance. Table19.7SummaryoftheMajorBiologicTypesofBreastCancer Estrogen receptor positive, HER2-negative Estrogen receptor negative, HER2-negative HER2-positive


Pathology_Robbins

Pathology_Robbins. Table19.7SummaryoftheMajorBiologicTypesofBreastCancer Estrogen receptor positive, HER2-negative Estrogen receptor negative, HER2-negative HER2-positive Fig.19.26Ageandtheincidenceofbreastcancersubtypes. An alternative classification system with substantial overlap relies on gene expression profiling. This system, which is currently used mainly in the context of clinical research, divides breast cancers into four major types: Luminal A. The majority are lower-grade ER-positive cancers that are HER2 negative Luminal B. The majority are higher-grade ER-positive cancers that may be HER2 positive HER2-enriched. The majority overexpress HER2 and do not express ER Basal-like. The majority by gene expression profiling resemble basally located myoepithelial cells and are ER-negative, HER2-negative Breast cancer rate (per 100,000 women) HER2Positive(ERPositiveTripleNegative(ER,PR,FeatureERPositive/HER2NegativeorNegative)andHER2Negative)


Pathology_Robbins

Pathology_Robbins. Breast cancer rate (per 100,000 women) HER2Positive(ERPositiveTripleNegative(ER,PR,FeatureERPositive/HER2NegativeorNegative)andHER2Negative) CompleteresponsetoLowgrade(<10%),highergradeERpositive(15%),ERnegative30%chemotherapy(10%)(>30%) MetastaticsitesBone(70%),viscera(25%),brainBone(70%),viscera(45%),brainBone(40%),viscera(35%),brain(<10%)(30%)(25%) SimilargroupdefinedbymRNALuminalA(lowgrade),luminalBLuminalB(ERpositive),HER2-Basal-likeprofiling(highgrade)enriched(ERnegative) CommonspecialhistologictypesLobular,tubular,mucinous,papillaryApocrine,micropapillaryCarcinomawithmedullaryfeatures CommonsomaticmutationsPIK3CA (40%),TP53 (26%)TP53 (75%),PIK3CA (40%)TP53 (85%) PIK3CA encodesphosphoinositide3-kinase(PI3K). http://ebooksmedicine.net A large number of risk factors for breast cancer have been identified ( Table 19.6 ). Some of the more important risk factors are summarized next.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net A large number of risk factors for breast cancer have been identified ( Table 19.6 ). Some of the more important risk factors are summarized next. Age and Gender. Breast cancer is rare in women younger than age 25, but increases in incidence rapidly after age 30 ( Fig. 19.26 ); 75% of women with breast cancer are older than 50 years of age, and only 5% are younger than 40. The incidence in men is only 1% of that in women. Family History of Breast Cancer. The greatest risk is for individuals with multiple affected first-degree relatives with early-onset breast cancer. In most families, it is thought that various combinations of low penetrance, “weak” cancer genes are responsible for increased risk. However, approximately 5% to 10% of breast cancers occur in persons who inherit highly penetrant germline mutations in tumor suppressor genes (discussed later). For these individuals, the lifetime risk of breast cancer may be greater than 90%.


Pathology_Robbins

Pathology_Robbins. Geographic Factors. Significant differences in the incidence and mortality rates of breast cancer have been reported in various countries. The risk is significantly higher in the Americas and Europe than in Asia and Africa. For example, the incidence and mortality rates are five times higher in the United States than in Japan. Some risk factors must be modifiable because migrants from low-incidence to high-incidence areas tend to acquire the rates of their new home countries. Diet, reproductive patterns, and breastfeeding practices are thought to be involved. In line with this, breast cancer rates appear to be rising in parts of the world that are adopting Western habits.


Pathology_Robbins

Pathology_Robbins. Race/Ethnicity. The highest rate of breast cancer is in women of European descent, largely because of a higher incidence of ER-positive cancers. Hispanic and African American women tend to develop cancer at a younger age and are more likely to develop aggressive tumors. Such disparities are thought to result from a combination of differences in genetics, social factors, and access to health care and are an area of intense study. Reproductive History. Early age of menarche, nulliparity, absence of breastfeeding, and older age at first pregnancy are all associated with increased risk, probably because each increases the exposure of “at-risk” breast epithelial cells to estrogenic stimulation.


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Pathology_Robbins. Ionizing Radiation. Radiation to the chest increases the risk of breast cancer if exposure occurs while the breast is still developing. For example, breast cancer develops in 25% to 30% of women who underwent irradiation for Hodgkin lymphoma in their teens and 20s, but the risk for women treated later in life is not elevated. Other Risk Factors. Postmenopausal obesity, postmenopausal hormone replacement, mammographic density, and alcohol consumption also have been implicated as risk factors. The risk associated with obesity probably is due to exposure of the breast to estrogen produced by adipose tissue. In keeping with this, obesity is only associated with an increased risk of tumors that express ER. The three major subtypes of breast cancer defined by differential expression of hormone receptors and HER2 arise through more-or-less distinct pathways that involve the stepwise acquisition of driver mutations in the epithelial cells of the duct/lobular system (


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Pathology_Robbins. Fig. 19.27 ). Factors that contribute directly to the development of breast cancer can be grouped into genetic, hormonal, and environmental categories.


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Pathology_Robbins. Genetic. Driver mutations in cancer genes that contribute to breast carcinogenesis can be divided into those that are inherited and those that are acquired. The major germ-line mutations conferring susceptibility to breast cancer affect genes that regulate genomic stability or that are involved in progrowth signaling pathways. BRCA1 and BRCA2 are classic tumor suppressor genes, in that cancer arises only when both alleles are inactivated or defective (Chapter 6). BRCA1 and BRCA2 encode proteins that are required for repair of certain kinds of DNA damage. They are normally expressed in many different cells and tissues, and why germline mutations in these genes lead mainly to an increased risk of breast and serous ovarian cancer (discussed earlier) remains mysterious. The degree of penetrance, age of onset, and susceptibility to other types of cancers differ among the many BRCA1 and BRCA2 germ-line mutations, but most carriers develop breast cancer by the age of 70 years, as compared to


Pathology_Robbins

Pathology_Robbins. age of onset, and susceptibility to other types of cancers differ among the many BRCA1 and BRCA2 germ-line mutations, but most carriers develop breast cancer by the age of 70 years, as compared to about 12% of women with an average risk of breast cancer. For unclear reasons, BRCA2 mutations are primarily associated with ER-positive tumors, whereas BRCA1 mutations show a strong association with triple-negative cancers (


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Pathology_Robbins. Fig. 19.27 ). Other mutated genes associated with familial breast cancer include TP53 (the so-called “guardian of the genome”, Chapter 6) and PTEN (an important negative regulator of the pro-growth PI3K-AKT pathway), already mentioned earlier as a risk factor for endometrial carcinoma as part of Cowden syndrome. As might be expected, the pathways in which familial breast cancer genes function also are often disturbed in sporadic breast cancers. Somatic mutations in BRCA1 and BRCA2 are rare in sporadic cancers, but BRCA1 is inactivated by methylation in up to 50% of triple-negative cancers. Somatic mutations in TP53 are common in breast cancer, particularly triple-negative and HER2-positive tumors ( Table 19.7 ), whereas mutations that activate PI3KAKT signaling are frequently found in sporadic ER-positive and HER2-positive breast cancers ( Fig. 19.27


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Pathology_Robbins. Table 19.7 ), whereas mutations that activate PI3KAKT signaling are frequently found in sporadic ER-positive and HER2-positive breast cancers ( Fig. 19.27 A common clinically important driver mutation in breast cancer is amplification of the HER2 gene. HER2 is a receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis by stimulating the RASand PI3K-AKT signaling pathways. Cancers that overexpress HER2 are pathogenically distinct and highly proliferative. In the past they had a poor prognosis; however, the availability of therapeutic agents that specifically target HER2 has markedly improved the prognosis for patients with HER2-amplified tumors. http://ebooksmedicine.net (50-65% of cancers) 1q 16q PIK3CA gain loss mutations “Luminal” HER2 Positive (20% of cancers) Normal breast Germline HER2 “HER2 TP53 mutations amplification enriched”


Pathology_Robbins


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Pathology_Robbins. arrow).ThesecancershavelossofBRCA1 andTP53 functionandaregenomicallyunstable.Themajorityoftriple-negativecancersareclassifiedas“basal-like”bygeneexpressionprofiling.


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Pathology_Robbins. Hormonal Influences. Estrogens stimulate the production of growth factors, such as transforming growth factor-α, platelet-derived growth factor, fibroblast growth factor, and others, which may promote tumor development through paracrine and autocrine mechanisms. In addition, ER regulates dozens of other genes in an estrogen-dependent fashion, some of which are important for tumor development or growth. Hormonal influences likely drive proliferation during the development of cancers from precursor lesions (which typically strongly express ER) to fully malignant and even metastatic carcinomas. The clearest measure of the importance of estrogen is found in the therapeutic benefits of estrogen antagonists, which reduce the development of ER-positive cancers in women at high risk and are mainstays in the treatment of established ER-positive tumors.


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Pathology_Robbins. Environmental Factors. Environmental influences are suggested by the variable incidence of breast cancer in genetically homogeneous groups (e.g., Japanese women living in Japan and the United States) and the geographic differences in breast cancer incidence, as discussed earlier. MORPHOLOGYThemostcommonlocationoftumorswithinthebreastisintheupperouterquadrant(50%),followedbythecentralportion(20%).About4%ofwomenwithbreastcancerhavebilateralprimarytumorsorsequentiallesionsinthesamebreast. Breastcancersareclassifiedmorphologicallyaccordingtowhethertheyhavepenetratedthebasementmembrane.Thosethatremainwithinthisboundaryaretermedin situ carcinomas, andthosethathavespreadbeyonditaredesignatedinvasive carcinomas. Inthisclassification,themainformsofbreastcarcinomaareasfollows: A.Noninvasive 1. 2. B.Invasive 1. 2. 3. 4. 5. 6.


Pathology_Robbins

Pathology_Robbins. A.Noninvasive 1. 2. B.Invasive 1. 2. 3. 4. 5. 6. Therearetwomorphologictypesofnoninvasivebreastcarcinoma:ductalcarcinomainsitu(DCIS)andlobularcarcinomainsitu(LCIS).Thetermsductal andlobular aremisleading,asbothtypesofCISarethoughttoarisefromcellsintheterminalductthatgiverisetolobules.LCISusuallyexpandsinvolvedlobules( Fig.19.28A ),whereasDCISdistortslobulesintoductlikespaces( Fig.19.28B ).Bydefinition,both“respect”thebasementmembraneanddonotinvadeintostromaorlymphovascularchannels. DCIShasawidevarietyofhistologicappearances,includingsolid,comedo,cribriform,papillary,micropapillary,and“clinging”types.Nuclearappearancesrangefromblandandmonotonous(lownucleargrade)topleomorphic(highnucleargrade).Thedistinctivecomedosubtypeischaracterizedbyextensivecentralnecrosis,whichproducestoothpastelikenecrotictissuethatextrudesfromtransectedductsonapplicationofgentlepressure.CalcificationsfrequentlyareassociatedwithDCIS(


Pathology_Robbins

Pathology_Robbins. As previously discussed, in unscreened populations (including young women, for whom screening is not indicated) most breast cancers are detected as a palpable mass by the affected patient. Such carcinomas are almost all invasive and are typically at least 2 to 3 cm in size. At least half of these cancers will already have spread to regional lymph nodes. In older screened populations, approximately 60% of breast cancers are discovered before molecular inhibitors of HER2, outcomes were similar to symptoms are present. About 20% are in situ carcinomas. patients with triple-negative carcinomas. However, com-Invasive carcinomas detected by screening in older women plete response rates exceed 60% when targeted therapy is are 1 to 2 cm in size and only 15% will have metastasized combined with chemotherapy, and the outlook for these to lymph nodes. Palpable cancers in the older age group patients has been markedly improved. are often “interval” cancers—cancers that appear suddenly • RNA


Pathology_Robbins

Pathology_Robbins. chemotherapy, and the outlook for these to lymph nodes. Palpable cancers in the older age group patients has been markedly improved. are often “interval” cancers—cancers that appear suddenly • RNA expression profiling is a newer method of subclasbetween screening intervals. Understandably, interval sifying cancers. For breast cancers, many of the genes cancers generally are highly proliferative and usually are that predict prognosis are involved in proliferation. high grade. The greatest clinical value of these assays is their http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. The clinical outcome for a woman with breast cancer ability to identify patients with slow-growing, anti-can be predicted based on the molecular and morphologic estrogen-responsive cancers who can be spared the features of the cancer and its stage at the time of diagnosis. toxicity of chemotherapy. Factors that influence outcome include the following: • Tumor stage. “Stage” is a measure of the extent of tumor • Biologic type. The biologic type of cancer is evaluated by at the time of diagnosis and is important for all biologic a combination of histologic appearance, grade (includ-types of carcinoma. It is based on features of the primary ing proliferative rate), expression of hormone receptors, tumor (T), involvement of regional lymph nodes (N), and expression of HER2. and the presence of distant metastases (M) ( Fig. 19.30


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Pathology_Robbins. Fig. 19.30 Proliferation is evaluated by mitotic count and is The AJCC/UICC staging system, used in the United closely tied to responsiveness to cytotoxic chemother-States and Europe, classifies tumors as T1, T2, and T3 apy. This is because rapidly growing cancer cells are based on the tumor size, whereas T4 tumors have ulcer-more sensitive to agents that damage DNA or otherwise ation of the skin, involvement of the deep muscles of interfere with cell division. the chest wall, or are clinically diagnosed as inflamma-


Pathology_Robbins

Pathology_Robbins. Expression of estrogen or progesterone receptors pre-tory carcinoma. The majority of cancers first metastasize to dicts response to anti-estrogen therapy. The growth of regional nodes, and nodal involvement is a very strong hormone receptor–positive cancers can be inhibited for prognostic factor. Lymphatic drainage goes to one or many years with therapy and it is possible for patients two sentinel lymph nodes in the axilla in most patients. to survive for long periods with distant metastases. If these nodes are not involved, the remaining axillary However, resistance often eventually develops—in nodes are usually free of carcinoma. Sentinel node biopsy some cancers because of mutations in the gene for ER. has become the standard for assessing nodal involve-In contrast, there is no targeted therapy available for ment, replacing more extensive lymph node dissections, triple-negative cancers, which are treated with chemo-which are associated with significant morbidity. Distant therapy.


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Pathology_Robbins. therapy available for ment, replacing more extensive lymph node dissections, triple-negative cancers, which are treated with chemo-which are associated with significant morbidity. Distant therapy. Cancers that do not respond to initial therapy metastases (M) are only detected in 5% of newly diagmetastasize and usually cause the death of the patient. nosed women. Stage 0 is CIS, which is associated with


Pathology_Robbins

Pathology_Robbins. Overexpression of HER2 is seen in about 20% of breast survival rates greater than 95%. Stage I includes women cancers. HER2 remains one of the best-characterized with smaller cancers and nodes either free of carcinoma examples of an effective therapy that is directed against a or with only very small micrometastases. Survival is tumor-specific molecular lesion. Before targeted therapy, ~86% at 10 years. Carcinomas are classified as Stage II which may take the form of blocking antibodies or small either because of larger tumor size or because of up to Fig.19.30Ten-yearbreastcancerspecificsurvivalaccordingtoAJCCstageforER-positiveandER-negativecancers.Bothstageandbiologictypeofcancerareimportantdeterminantsofsurvival.ER-positiveinvasivecancershaveimprovedsurvivaloverER-negativecancersatallstages,butthisadvantagediminishesafter5yearsbecauseoflaterecurrencesofER-positivetumors.(Graph courtesy of Dr. Stephanie Wong; data from SEER-18,1992–2012. http://seer.cancer.gov


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Pathology_Robbins. http://seer.cancer.gov Breast cancer specific survivalEstrogen receptor positive cancers (solid lines) Estrogen receptor negative cancers (dashed lines) Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 0.2 0.4 0.6 0.8 1.0 http://ebooksmedicine.net three positive nodes. Survival declines to ~71% at Stage II. Stage III is the group of locally advanced cancers defined by large size, involvement of skin or chest wall, or by four or more positive nodes. Only ~54% of patients survive 10 years. Stage IV is reserved for patients with distant metastases, and survival is very poor (~11%). The most likely site of a distant recurrence varies with the biologic type of cancer. Triple-negative cancers and HER2 cancers are more likely to metastasize to the brain and viscera, in contrast to ER-positive cancers, which most often metastasize to bones ( Table 19.7


Pathology_Robbins

Pathology_Robbins. Table 19.7 Combining stage and biologic factors may provide a more accurate assessment of outcome. For example, for each cancer stage, the survival of patients with ER-positive cancers is higher than patients with ER-negative cancers 5 years postdiagnosis, especially for Stages III and IV ( Fig. 19.30 ). It must be noted, however, this advantage diminishes with time, with progressively smaller differences being seen at 10 years post-diagnosis and beyond ( Fig. 19.30 ). This narrowing of survival differences is explained by two factors. First, most deaths from ER-negative cancers happen within 5 years of diagnosis ( Fig. 19.31 ). Women who live beyond this point are those whose tumors have had excellent responses to treatment, and many of these women may be cured. Second, although the growth of ER-positive cancers is held in check for years by anti-estrogen therapy, this therapy is not curative and these cancers may eventually become resistant to treatment.


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Pathology_Robbins. Historically, virtually all women with untreated breast cancer died within 3 to 4 years. However, great strides have been made in treatment and now 80% of women with breast cancer who receive optimal therapy will survive. Endocrine therapy with tamoxifen and aromatase inhibitors is very effective for ER-positive cancers, which may remain dormant for many years. Targeted therapy has the promise of being more effective and less toxic than conventional chemotherapy ( Table19.8TargetedTreatmentofBreastCancer Fig.19.31Timetorecurrenceofbreastcancers.Thehazardratioreflectstheriskofrecurrenceofeachmoleculartypeofbreastcanceratvariouspointsintimeafterdiagnosis.ER-negativecancersusuallyrecurwithinthefirst8years.Patientswhosurvivebeyondthisintervalarelikelycured.Incontrast,ER-positivecancershavealowerrateofrecurrence,butremainatriskdecadesaftertheprimarydiagnosis.


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Pathology_Robbins. 19.8 ), as already proven by marked improvement in survival of women with HER2-positive carcinomas following the introduction of therapies that target HER2. Newer approaches to targeted therapy include inhibition of alternative DNA repair pathways in BRCA-mutated cancers and blockage of the PI3K-AKT-signaling pathway. Immune checkpoint blockade therapy (Chapter 6), is under evaluation in patients with breast cancer. It is hoped that such new approaches will improve outcomes in subtypes that currently have a generally poor prognosis, such as triple negative breast cancer. ImmunecheckpointBlockingantibodiestoPD-L1,PD-1,andIHCforimmunecheckpointUnderinvestigationinpatientswithproteinsotherimmunecheckpointproteinsproteins—notyetvalidatedtriple-negativebreastcancer ER, Estrogenreceptor;HRR, homologousrecombinationrepair;IHC, immunohistochemistry;ISH, insituhybridization. http://ebooksmedicine.net ThelifetimeriskofdevelopingbreastcancerforanAmericanwomanis1in8.


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Pathology_Robbins. LCISisbothamarkerofincreasedriskandaprecursorlesion.WhencarcinomadevelopsinawomanwithapreviousdiagnosisofLCIS,two-thirdsareinthesamebreastandone-thirdisinthecontralateralbreast. Invasivecarcinomasareclassifiedaccordingtohistologictypeandbiologictype:ER-positive/HER2-negative,HER2-positive,andER/PR/HER2-negative(triple-negative).Thebiologictypesofcancerhaveimportantdifferencesinpatientcharacteristics,grade,mutationprofile,metastaticpattern,responsetotherapy,timetorecurrence,andprognosis. Prognosisisdependentonthebiologictypeoftumor,stage,andtheavailabilityoftreatmentmodalities. Bulun SE: Mechanism of disease: endometriosis, N Engl J Med 360:268, 2009. [Excellent review of the molecular basis of endometriosis.] Cannistra S: Cancer of ovary, N Engl J Med 351:2519, 2004. [A comprehensive review.] DiCristofano A, Ellenson LH: Endometrial carcinoma, Annu Rev Pathol 2:57, 2007. [A comprehensive discussion of pathogenesis.]


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Pathology_Robbins. DiCristofano A, Ellenson LH: Endometrial carcinoma, Annu Rev Pathol 2:57, 2007. [A comprehensive discussion of pathogenesis.] Ehrmann DA: Polycystic ovary syndrome, N Engl J Med 352:1223, 2004. [A detailed review.] Fox H, Wells M: Recent advances in the pathology of the vulva, Histopathology 42:209, 2003. [A short update on vulvar pathology.] Herrington CS: Recent advances in molecular gynaecological pathology, Histopathology 55:243, 2009. [A review of molecular genetics of cervical, ovarian, and endometrial neoplasia.] Kathleen RC: Ovarian cancer, Annu Rev Pathol Mech Dis 4:287, 2009. [A good review on the subject with discussion of molecular genetics.] Moody CA: Human papillomavirus oncoproteins: pathways to transformation, Nat Rev Cancer 10:550, 2010. [A review of current opinion on cervical carcinogenesis.] Morice P, Leary A, Creutzberg C, et al: Endometrial cancer, Lancet 387:1094, 2016. [A comprehensive review of the subject.]


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Pathology_Robbins. Morice P, Leary A, Creutzberg C, et al: Endometrial cancer, Lancet 387:1094, 2016. [A comprehensive review of the subject.] Rich TA, Woodson AH, Litton J, et al: Hereditary breast cancer syndromes and genetic testing, J Surg Oncol 111:6–80, 2015. [Soon many individuals will know their entire DNA sequence. This review discusses the complexities of detecting lowand moderate-penetrance susceptibility genes.] Seckl MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease, Lancet 376:717, 2010. [A review of gestation trophoblastic including discussion regarding management.] Sonnenblick A, Fumagalli D, Sotiriou C, et al: Is the differentiation into molecular subtypes of breast cancer important for staging, local and systemic therapy, and follow up? Cancer Treat Rev 40:1089– 1095, 2014. [The translation of the biologic types of cancer into clinical practice is discussed.] http://ebooksmedicine.net studentconsult.com Pituitary Adenomas: General Features Other Forms of Thyroiditis


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Pathology_Robbins. Pituitary Adenomas: General Features Other Forms of Thyroiditis Pathogenesis of Type 1 Diabetes Pathogenesis of Type 2 Diabetes Monogenic Forms of Diabetes Other Subtypes of Diabetes Acute Metabolic Complications of Chronic Complications of Diabetes AdrenocorticalHyperfunction:Hyperadrenalism Hypercortisolism: Cushing Syndrome Chronic Adrenocortical Insufficiency: Addison Disease


Pathology_Robbins

Pathology_Robbins. Chronic Complications of Diabetes AdrenocorticalHyperfunction:Hyperadrenalism Hypercortisolism: Cushing Syndrome Chronic Adrenocortical Insufficiency: Addison Disease The endocrine system is conprised of a widely distributed group of organs that work together to maintain the body’s metabolic equilibrium, or homeostasis. The cells of the endocrine system achieve this by secreting molecules, which are frequently called hormones, that act on target cells distant from their site of synthesis. A hormone typically is carried by the blood from the endocrine gland to its target tissues. Most hormones are secreted in response to other, so-called trophic, hormones, which are produced in response to particular metabolic needs. Production of a hormone often downregulates the activity of the gland that secretes the stimulating trophic hormone, a process known as feedback inhibition.


Pathology_Robbins

Pathology_Robbins. Hormones can be classified into several broad categories, based on the nature of their receptors: • Hormones that act by binding to cell surface receptors: This large class of compounds is composed of two groups: (1) peptide hormones, such as growth hormone and insulin, and (2) small molecules, such as epinephrine. Binding of these hormones to cell surface receptors leads to an increase in intracellular second messengers, such as cyclic adenosine monophosphate (cAMP), inositol 1,4,5-trisphosphate (IP3), and ionized calcium. Elevated levels of one or more of these compounds can activate intracellular signaling pathways that may stimulate cell growth or differentiation, or alter cell function.


Pathology_Robbins

Pathology_Robbins. • Hormones that act by binding to intracellular receptors: Many lipid-soluble hormones pass through the plasma membrane by diffusion to interact with receptors in the cytosol or the nucleus. The resulting hormone-receptor complexes bind specifically to regulatory elements in DNA, thereby affecting the expression of specific target genes. Hormones of this type include steroids (e.g., estrogen, progesterone, glucocorticoids), retinoids (vitamin A), and thyroxine. Endocrine diseases generally are caused by: (1) underproduction or overproduction of hormones, with associated biochemical and clinical consequences; (2) end-organ resistance to the effects of a hormone; or (3) neoplasms, which may be nonfunctional or may be associated with overproduction or underproduction of hormones. In many settings, the study of endocrine diseases relies heavily on biochemical measurements of the levels of hormones, their regulators, and other metabolites. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net The pituitary gland is a small, bean-shaped structure that lies at the base of the brain within the confines of the sella turcica. It is intimately related to the hypothalamus, with which it is connected by a stalk, composed of axons extending from the hypothalamus, and a rich venous plexus constituting a portal circulation. Along with the hypothalamus, the pituitary has a central role in the regulation of most of the other endocrine glands. The pituitary is composed of two morphologically and functionally distinct components: the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis). Diseases of the pituitary, accordingly, can be divided into those that primarily affect the anterior lobe and those that primarily affect the posterior lobe.


Pathology_Robbins

Pathology_Robbins. The anterior pituitary, or adenohypophysis, produces trophic hormones that stimulate the production of hormones from the thyroid, adrenal, and other glands. The anterior pituitary is composed of epithelial cells derived embryologically from the developing oral cavity. In routine histologic sections, a colorful array of cells containing basophilic cytoplasm, eosinophilic cytoplasm, or poorly staining (chromophobic) cytoplasm is present ( Fig. 20.1 ). Detailed studies using electron microscopy and immunohistochemical techniques have demonstrated that the staining properties of these cells are related to the presence of different polypeptide hormones within their cytoplasm that control the activity of other endocrine glands. The release of these pituitary hormones is under the control of factors produced in the hypothalamus; while most hypothalamic factors are stimulatory and promote pituitary hormone release, others (e.g., somatostatin and dopamine) are inhibitory (


Pathology_Robbins

Pathology_Robbins. Fig. 20.2 ). Rarely, signs and symptoms of pituitary disease may be caused by overproduction or underproduction of hypothalamic factors, rather than a primary pituitary abnormality. Symptoms and signs of pituitary disease fall into the following categories: Fig.20.1Normalanteriorpituitarygland.Theglandispopulatedbyseveraldistinctcelltypesthatexpressdifferentpeptidehormones.Thesehormonesarebasophilic(blue),eosinophilic(red),ornonstaininginroutinesectionsstainedwithhematoxylinandeosin,whichallowsthevariouscelltypestobeidentified.Notealsothepresenceofafinereticulinnetworkbetweenthecells. Hyperpituitarism related effects: Hyperpituitarism arises from excessive secretion of trophic hormones. It most often results from an anterior pituitary adenoma but also may be caused by other pituitary and extrapituitary lesions, as discussed later. The symptoms and signs of hyperpituitarism are discussed in the context of individual tumors later in the chapter (see Table 20.1


Pathology_Robbins

Pathology_Robbins. Table 20.1 Hypopituitarismrelatedeffects:Hypopituitarismiscaused by deficiency of trophic hormones and results from a variety of destructive processes that may damage the pituitary, including ischemic injury, surgery, radiation, and inflammatory reactions. In addition, nonfunctional pituitary adenomas may encroach upon and destroy the normal anterior pituitary, causing hypopituitarism.


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Pathology_Robbins. Local mass effects: Among the earliest changes associated with pituitary neoplasms are radiographic abnormalities of the sella turcica, including sellar expansion, bony erosion, and disruption of the diaphragma sellae. Because of the close proximity of the optic nerves and chiasm to the sella, expanding pituitary lesions often compress decussating fibers in the optic chiasm. This can give rise to visual field abnormalities, classically in the form of defects in the lateral (temporal) visual fields—a so-called “bitemporal hemianopsia”. As in the case of any expanding intracranial mass, pituitary tumors may produce signs and symptoms of elevated intracranial pressure, including headache, nausea, and vomiting. Pituitary neoplasms that extend beyond the sella turcica into the base of the brain produce seizures or obstructive hydrocephalus; involvement of cranial nerves can result in cranial nerve palsy. On occasion, acute hemorrhage into a pituitary neoplasm is associated with rapid


Pathology_Robbins

Pathology_Robbins. brain produce seizures or obstructive hydrocephalus; involvement of cranial nerves can result in cranial nerve palsy. On occasion, acute hemorrhage into a pituitary neoplasm is associated with rapid enlargement of the lesion and loss of consciousness, a situation termed pituitary apoplexy. Acute pituitary apoplexy may be rapidly fatal and is therefore considered to be a neurosurgical emergency.


Pathology_Robbins

Pathology_Robbins. The most common cause of anterior pituitary disorders are pituitary tumors, most of which are benign adenomas. Some of these produce hormones and result in endocrine abnormalities, and others are nonfunctional and produce mass effects. We discuss first the general features of pituitary adenomas, then specific tumors. PituitaryAdenomas:GeneralFeatures The most common cause of hyperpituitarism is a hormone-producing adenoma arising in the anterior lobe. Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders. Some salient features of pituitary adenomas are as follows: • Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells, which are detected by immunohistochemical stains performed on tissue sections ( Table 20.1 http://ebooksmedicine.net


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Pathology_Robbins

Pathology_Robbins. Pituitary adenomas can be functional (hormone producing) or nonfunctioning (not producing hormone), or silent (i.e., demonstration of hormone production at the tissue level only, without clinical manifestations of hormone excess). Both functional and nonfunctioning pituitary adenomas usually are composed of a single cell type and produce at most a single predominant hormone, but there are exceptions. Some pituitary adenomas secrete two different hormones (growth hormone and prolactin being the most common combination); rarely, pituitary adenomas are plurihormonal. Pituitary adenomas are designated as microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter.