CIHRT Exhibit P-2625 Page 1

PATHOLOGYOF THE BREAST

SECOND EDITION

Fattaneh A. Tavassoli, 1\10, AFlPChairman

Department of Gynecologic & Breast PathologyArmed Forces Institute of Pathology

Washington, DC

Adjunct Professor or PathologyGeorge Washington University

Washinglon, DC

Consultant in PathologyNational Cancer Institute

Bethesda, Maryland

APPLETON & LANGEStamford, COllnecticul

CIHRT Exhibit P-2625 Page 2

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Librar)' of Congress Cataloging-ill-Publica! ion Data

Tavassoli, Fattaneh A., 1949-Pathology of the breast / Fatl:aneh A. Tavassoli. - 2nd ed.

p. cm.Includes bibliographical references and index.1SBN 0-8385-770'1-0 (case: aile paper)1. Breast-Cancer-Diagnosis. 2. Breast-Histopathology.

3. Breast-Diseases. I. Tille.IDNLJVJ: 1. Breast Diseases-pathology. 2. Breast-pathology.

3. Breasl" Neoplasms-pathology. WI' 840 T231p 1999JHC280.B8T39 J999616.99'249-dc2 L

DNI.JVJ/DLC1'01' Library of Congress 98-50680

CipISBN 0-8385-7704-0

Acgllisitions Editor: Michael P. MedinaProduction Editor: Sondra GreenfieldDesigner: Janice Barsevich BielawaCover Design: Aimee Nordin

PHINTED IN liaNG KONG

CIHRT Exhibit P-2625 Page 3432 • PATHOLOGY OF Til E BREAST

A B

Figure 9-22. Infilliating lobular carcinoma, alveolar variant. (A & B) Closely packed islands of uniform small cells [11M, (A) x 120; (B) x240)

Axillary Node MetastasesIn Haagensen's series2980f 76 Columbia stage A small-cell carci­nomas (comparable to infiltrating lobular carcinoma), the fre­quency of axillary node metastases was 39.7%, compared wilh30.8% for similar stage carcinomas of all types. Two other stud­ies also found a lower frequency of nodal metastases (32% inboth studies) for lobular carcinoma compared with 37%321 and35%317 for infiltrating ductal carcinoma. Fechner292 has sug­gested that the variant patterns may be associated with a 10IVerfrequency of axillary node metastases.

Infiltrating lobular carcinoma is notorious for simulatinghistiocytes in metastatic foci andlVhen populating subcapsularand medullary sinuses in axillary lymph nodes.279.30' The sheet­like aggregation of the tUlllor cells and subt"le distortion of thenodal archilecture are helpful in arriving at the accural"e diag­nosis. When a distinction is difl1cult, special staining for mucinor imlllunostains for cytokeratin helps resolve the issue; a posi­tive reaction for mucin or cytokeratin establishes the diagnosisof carcinoma. In the eyelids, the histiocytic appearance of themetastatic tumor cells Illay cause misinterpretation of the le­sion as a chalazion.301.333

The metastatic pattern of lobular invasive carcinoma differsfrom that of invasive ductal carcinoma with a higher frequencyof skeletal, gaslTointestinal tract, uterine, ovarian, meningeal,genitourinary, skin, diffuse serosal, peritoneal and retroperi­toneal metastases observed in lobular carcinomas.281.283.299,317.

324.325 The gastrointestinal, gynecologic, and peritoneal-retroperi-

toneal mel aslases are markedly more prevalent in lobular carci­noma 281 In the central nervous system, melasl'ases from invasivelobular carcinoma form meningeal intillrales, whereas. ductalcarcinomas sholV parenchymal deposits.212.322 Other investiga­tors, however, found an eqlla[ proportion of lobular and ductalcarcinomas among patients lVilh meningeal carcinomalosisfrom breast cancer.212 Metastases 10 the ovary and u ten IS arecommon. In the endometrium, metastases cause bleeding, butbecause of the small cell size and diffuse pal tern of infiltration inthe endometrium, these metastases are easily overlooked. Fur­thennore, even when the cells are larger wil"h pink cytoplasm,they are often misinterpreted as a decidual reaction to prog­estins, which many of the patients receive for their irregularbleeding prior to the cllret tage. Bone mnrrolV mel"aslases are par­ticularly common,322 and constil"uted the most common site ofmetastases in DiCostanzo and colleagues' series.286

Hormone Receptors and PloidyAbout 70-92% of lobular carcinomas are EH_positive.s.JlI6.120.317 EH

positivity is observed in the classic form and all other variants,309with the alveolar variant appearing to have a greal"er likelihood ofEH positivity.3()" Progesterone recept.ors are fonnel in 63-67% ofthe tUlllors317.508.511 Carcinoembryonic ant igen (CEA) has beenreported in 33-63% of cases.85.309 Milk-related proleins, SIIch asladalbumin and casein, have been detected in some cases.29 J.327Also, 60% of these tumors sholV a positive reaction (or 5-] 00 pro­tein, underscoring the lack of specificity of5-100 protein.36

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Figure 9-23. Infiltrating lobular carcinoma, pleomorphic varian!. (A) At low magnification the lesion resembles typical infiltrating lobular carcinomawith isolated cells sometimes arranged in cords. (B) The nuclei display significant pleomorphism, and more variation is generally evident in cell size. [H&E,(A) x240; (B) x480j

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CIHRT Exhibit P-2625 Page 5434 • PATHOLOGY OF Til E BREAST

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Figure 9-23. (C) Pleomorphic lobular neoplasia (LN3) shows some highly atypical nuclei; curiously, this tumor was ER positive even in the highly atypi­cal cells. (H&E, x300j

Approximately 22% of infiltrating lobular carcinomas areaneuploid. Among ER-positive tumors, ploidy does not appearto influence the likelihood of PR positivityS08

Treatment and Prognosis

Treatment of infiltrating lobular carcinoma should parallel thatof infiltrating mammary carcinomas in general and depends onthe stage of the lesion. Conservative treatment of invasive lobu­lar carcinoma has been sholVn to be an appropriate alternativein selected cases302,312 The results of limited excision and radio­therapy for "19 lobular carcinomas were compared with those of561 cases of inf1ltrating duct carcinoma. The 5-year actuarialrisk of local recurrence was similar for patients with infiltratinglobular or ductal carcinoma: 12% versus 11%. \J\lhen the groupwith infiltrating duct carcinoma was di\rided into those with anextensive DClS component and those without such a compo­nent, the 5-year actuarial survival of 12% for lobular carcinomafell between the 5% rate for infiltrating duct carcinomas withextensive DClS component and the 23% for those infiltratingduct carcinomas without extensive DClS. 117

Another study comparing clinicopathologic features of in­filtrating lobular carcinoma (726 cases), mixed inl1ltrat-ing lobu­lar/invasive ductal carcinoma (249 cases), and nonlobular infil­trating carcinomas (10,061 cases) also evaluated response of thethree groups to conservative therapy.317 Conservative treatmentwas used in 480 cases (66%) of pure lobular carcinoma, 6797cases (68%) of nonJobular infiltrating carcinomas, and 43 casesof mixed infiltrating lobular/invasive ductal carcinoma. 'vVith amedian follow-up of 82 months, the overall survival rate, locore-

gional control, disease-free interval, and metastaLic spread ratewere not different among the three groups by eiLher univariateor mult-ivariaLe analysis; the investigaLors concluded t.hat con­servative therapy may be appropriate treatment for infiltratinglobular carcinoma.317

The 5- and 10-year survival rate for node-negative women,is 86% and 74%, respectively.280 Following radical mastectomy,approximat ely 5.4% of the women develop local recurrenceswithin ]0 years.298 About 50% of patients with positive nodeseventually die from the disease compared with 14% of the node­negative women.310

Although some studies have suggested a worse prognosisfor infiltrating lobular carcinoma than for ductal cancer,306 sev­eral studies have found no significant. difference in sur­vival,280.285.317.323 or even a more favorable outcome for infiltratinglobular carcinoma.321 ,326 In some studies, the observed differ­ences are not substant-ial; about 6% of women with 1'1 OMO in­filtrating lobular carcinomas treated by mastectomy died of thedisease within 10 years, compared with 14% of those with infil­trating ductal carcinoma. 133 In Haagensen's experience298 andfollowing radical mastectomy, wOlllenwith Columbia stage A in­l1Itrating small-cell carcinomas had a 75% probability ofl O-yearsurvival, compared with 72% for patient·s ""ilh all other types ofbreast carcinoma. In a comparison of sUI-vival between 217women with invasive lobular carcinoma and 1121 women withinfiltrating duct carcinoma, Toikkanen and coworkers326 found5- and 3D-year corrected sUlvival rates of 78% and 50% respec­tively, among women with lobular carcinoma, compared with63% and 37% survival rates. respectively, for those with infiltrat­ing ductal carcinoma.326 Women with small pTINOIVIO infiltrat-