of the tumor followed by irradiation of thetumor bed and breast. Morphologic studiesof the effects of such irradiation are limited, since post-irradiation tissues becomeavailable for examination only under special circumstances. It has been possible tocollect 100 cases in this laboratory, andboth pre- and post-irradiation specimenswere studied and compared. The study wascarried out against a background of 50years of experience with radiation effectsand tumors in a laboratory with 6,000 casesof mammary carcinoma in its files and acurrent annual case load of 300 to 400women with this disease.

Materialsand MethodsThe pre-irradiation material consisted ofbiopsies,lumpectomies,and quadrantectomiesin casesof histologicallyprovencarcinoma.About one halfofthepost-irradiation specimens were mastectomies,performed because of persistent or recurrent tumor, or suspicion thereof, or for radiation damage. The remainder came fromautopsies, biopsies, and miscellaneouslimited procedures.

In 60 percent of patients, the intervalbetween treatment and the obtaining of thesecond specimen was two years or less.Ninetypercentwere studiedwithinfiveyears, and 10 percent after five years. Thelongest interval was 13 years. Radiationdosages were either 6,000 rad from cobaltunits or 5,000 rad from a 4 Mev linearaccelerator and iridium implantation orother “¿�boosters.―

AbstractThe pathologic changes in tissuesfrom 100women who had received radiation therapy

for breast cancer were studied. It is concluded that carcinoma of the breast cannotbe considered a radiosensitive tumor, thatirradiation should not be considered conservative treatment, and that radiotherapyis not innocuous. More studies of postirradiation breasts are needed, from biopsy, surgical, and autopsy specimens.These studies should evaluate the tissuesfor the presence or absence of tumor, forradiation changes in the breast and thetumor, for evidence of tumor regression,for multicentricity, andfor histologic typesand patterns. Until this is done, the finalresults of radiation therapy for carcinomaof the breast will remain unknown.

Introduction

Increasingz*,@bers of women with breastcancer are being treated by local excision

Dr. Friedman is Senior Consultant to the Department of Pathology and Laboratory Medicineat Cedars-Sinai Medical Center, and ClinicalProfessor in the Department of Pathology at theUniversity of Southern California School ofMedicine, in Los Angeles, California.This article was presented as a poster exhibit atthe Spring 1984 meeting of the American Society of Clinical Pathologists in Las Vegas, Nevada; the 7th Annual San Antonio Breast CancerSymposium in 1984; and Congress WorldAssociation Societies Pathology in Brighton,England in 1985.

368 CA-A CANCERJOURNALFORCLINICIANS

OpinionThe Effects of IrradiationonBreast Cancer and the Breast

Nathan Friedman, MD

All common tumor types were represented. Examples of lobular, ductal, papillary, and squamous carcinomas as well ascomedocarcinoma were present. Tumorswith extensive intraductal disease werepresent only occasionally.'

ResultsIn one half of the patients, tumor waspresent in the post-irradiation specimen(Fig. 1) and appeared essentially unalteredfrom that in the pre-irradiation specimen.Variations in pattern (Figs. 2 and 3) werenot unlike those encountered in breast cancers not subjected to irradiation. Another25 percent of the post-irradiation breastsdemonstrated tumor, but did show radiation change. No particular histologic typeseemed to be especially radioresistant orradioresponsive. Radiation reaction wasmanifested by nuclear enlargement and bizarre nuclei as in anaplasia, but with proportional cytomegaly so that the nuclearcytoplasmic ratio was not increased (Fig.4). Calcific deposits were also noted. Thestromal changes are described below.

The remaining 25 percent of breastsshowed little or no cancer, but considerableradiation change was present in the mammary tissue (Fig. 5). Glandular atrophywith cellular atypia and metaplasia wereconspicuous. Myoepithelial prominencecharacterized both glands and ducts. Basement membranes were thickened and reduplicated. The stromal changes weremore complex than simple fibrosis. Hyalinization of ground substance with relativelyless collagen, reticulin, or elastica wasstriking. Bizarre stellate and spindleshaped radiation fibroblasts were scatteredthroughout the matrix, which containedsmall ectatic vessels, some elastotic, withendothelial atypia. Large vessel sclerosiswas not conspicuous. Where muscle waspresent, striking fiber atrophy with multinucleate atypia and interstitial fibrosis wasapparent, sometimes despite adjacent unaffected tumor (Fig. 6).

In some instances, there was clear evidence of regressed tumor; in others, however, the damaged tissue appeared to becomposed of only mammary parenchyma.

Fig. 1. Recurrent tumor three years after a4.5-cm lumpectomy of 2.4-cm, poorly differentiated adenocarcinoma with uninvolvedsurrounding breast; both internal and externalradiotherapy.

Fig. 3. Post-irradiation status of the same tumor as in Fig. 2, two years after irradiation with5,000 rad by a 4 Mev linear accelerator andiridium implantation. Persistent tumor is seenwith minor radiation alteration; mammary tissue showed distinct radiation reaction (H&E x100).

Fig. 2. Three-cm ductal adenocarcinoma removed by a six-cm tylectomy (H&E x 100).

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Regressed tumor was sometimes characterized by residual bizarre irradiation-alteredneoplasticelements.Intheabsenceofthesechanges, nodular cicatrices displacing residual parenchyma and calcific depositswere the hallmarks of preexisting tumor.

Discussion

The findings in the irradiated tissues do notsupport the view that breast cancer is aradioresponsive tumor. On the contrary,theresultsareconsistentwithautopsydata,which have generally shown the ineffectiveness of irradiation in this disease.

Irradiation ought to be considered radical, rather than conservative, treatment,since tissues heal well after surgery and arenot increasingly vulnerable to subsequenttrauma, infection, or surgery, as they areafter irradiation. Once an area has beenirradiated, it undergoes changes similar tothoseofagingandbecomesmore susceptible to damage.

It is not generally appreciated that combinations of external irradiation and intramammary radioactive materials have beenused in the past.24 The hiatus of one generation in the widespread use of radiotherapy for breast cancer would probably nothave occurred had the results been satisfactory. One famous radiologist even avoidedusing the word “¿�cure―because of laterdevelopments.5 It is impossible to irradiateany tissue without permanent side effects.With modern techniques, changes in thedeep tissues can be severe even though theskin may appear almost normal.

If surgical “¿�salvage―becomes necessary after radiation failure, the mastectomymust be performed in an irradiated field,and time has been lost. In addition, although it may be speculated that spread wasaverted by irradiation, some claim thatbreast cancer is actually “¿�systemic―rightfrom the onset. Does this mean that tumorcells spread beyond the breast at inception?And after how many cell divisions? Whatabout the well-known in situ cancers,which may be present for long periods before invasion? Radiation therapy does notnecessarily prevent spread.6 There must besome period during which a tumor remains

Fig. 4. Post-irradiationspecimen showsconsiderable carcinoma as well as marked radiation change with cytomegaly and bizarre nuclei (H&E x 100).

Fig. 5. Portionof a breast removed for radiation damage two years aftera four-cm lumpectomy for a 2.2-cm infiltrating ductal carcinoma.The patient received 5,000 rad from a 4 Mevlinear accelerator. No carcinoma was identified, but there were fibrous nodules suggesting regressed tumor.

- - .@- ,-- -.-@---.@ .c—.-— - --@

Fig. 6. PapillaryAdenocarcinoma. Thetumorwas removed by quadrantectomy that enveloped a 2.8-cm tumor. The post-irradiationmastectomy three years after radiotherapywith 6,000 rad shows badly damaged muscleadjacent to unaltered tumor (H&E x 100).

370 CA-A CANCERJOURNALFORCLINICIANS

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localized. A small tumor may not be early,but if “¿�small―or “¿�minimal―cancers are“¿�early,―surgical extirpation would seemto offer the best hope.

Multicentricity cannot be ignored, despite the fact that the National SurgicalAdjuvant Project for Breast and BowelCancers reported a rate of multicentricityof only 13.4 percent;7 numerous studieshave documented incidences double, triple, and quadruple this figure.8-― Somehave indicated that papillary and intraductal lesions, particularly if extensive andwith involvement of the ducts away fromthe main mass, have a tendency to recurearly.'2 The data in this report do not substantiate this. Parenthetically, radiotherapists have traditionally maintained thatpapillary tumors generally respond well toirradiation. Since multicentric disease inother quadrants and in subareolar locationsis present in approximately one half of cancerous breasts, which patients should beirradiated? One half may not require furthertreatment. On the other hand, since theremaining breast epithelium may be at risk

References

for later neoplasia, irradiation might increase this hazard.

It should be made clear, however, thatpathologistsdo nothaveaccesstotissuesfrom presumably successfully irradiatedpatients but only to specimens from patients in whom there was suspicion ofpersistentor recurrenttumor or radiationdamage. Autopsy studies could yield considerable information, but in view of themassive decline in autopsy rates, such material will be scanty. The present reportcannot be viewed as a follow-up study, andonly time will tell if these findings are representative or exceptional. Follow-ups willhave to be longer than traditional, in viewof the increased incidence of early lesions,such as the possibly not in situ intraductalcarcinomas disclosed by mammography.

Nevertheless, it is still incumbent uponthose of us who study such tissues to raisethe issues of radiosensitivity, conservativeversus radical surgery, and the innocuousness of irradiation for breast cancer, whichhave not been given enough seriousthought and consideration.'3

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AdjuvantBreastProject(protocolno. 4). I: Observations concerning the multicentricity ofmammarycancer.Cancer35:247—254,1975.8. MorgensternL, KaufmanPA, FriedmanNB:Thecaseagainsttylectomyforcarcinomaof thebreast:The factorof multicentricity.AmI Surg130:251—258,1975.9. Shah IP, Rosen PP, Robbins OF: Pitfalls oflocal excision in the treatment of carcinoma ofthe breast. Surg Oynecol Obstet 136:721—725,1973.10. Rosen PP, FracchiaAA, Urban IA, et al:Residualmammary carcinomafollowingsimulated partial mastectomy. Cancer 35:739—747,1975.11. Carter D: Margins of “¿�lumpectomy―forbreast cancer. Hum Pathol 17:330—332,1986.12. Harris IR, Connolly IL, Schnitt SI, et al:Clinical-pathologic study of early breast cancertreated by primary radiation therapy. I Clin Oncol 1:184—189,1983.13. Friedman NB: Mammary carcinoma andradiation therapy (editorial). Arch Surg122:753, 1987.

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