MULTIPLE PRIMARY CARCINOMAS 1

FRANK ROBERT HANLON, M.D.

Fellow in Surgery, The Mayo Foundation, Rochester, Minnesota

Two or more primary carcinomas rarely occur in the sameperson. I have recently reviewed the literature on the subject andplace on record forty-nine additional cases. This paper is dividedinto three sections: (1) a partial record of my survey of the litera­ture; (2) an analysis of eighteen cases of multiple primary carci­nomas occurring in 3000 consecutive post-mortem examinations atThe Mayo Clinic; (3) an analysis of thirty-one cases in which aclinical diagnosis was made at The Mayo Clinic.

REVIEW OF THE LITERATURE

Billroth (2) reported a case in 1869 of a patient with carcinomaof the stomach and also one of the external ear. He emphasizedthe importance of the criteria used as a basis for diagnosis, andestablished three postulates which he felt were necessary for thediagnosis of multiple primary tumors: (1) each tumor must havean independent histologic appearance; (2) the tumors must arisein different situations; (3) each tumor must produce its ownmetastasis. Mercanton (9) added a fourth requirement, that therebe no recurrence of tumors after their removal.

It is quite as unreasonable to demand the fulfillment of thethird and fourth postulates in the diagnosis of multiple primarycarcinomas as it would be in the diagnosis of a single carcinoma.Egli (3), Harbitz (8) and Puhr (12) objected strenuously to theadoption of Billroth's criteria.

Goetze (6) suggested the following requirements for diagnosis:(1) the macroscopic lLnd microscopic appearance of the tumorsmust be that of the usual carcinomas of the organs involved;(2) exclusion of metastasis must be certain; (3) diagnosis may beconfirmed by the character of the metastasis in each case.

1 Abstract of thesis submitted to the Faculty of the Graduate School of the Uni­versity of Minnesota in partial fulfillment of the requirements for the degree of Masterof Science in Surgery, June 1929. Work done in the Section on Pathologic Anatomy,The Mayo Clinic.

2001

2002 FRANK ROBERT HANLON

The Linacre Lecture of 1927 contained a particularly note­worthy passage. Murray (10), in commenting on the excellentstudy of Puhr on multiple primary carcinomas, made the followingstatement: " A certain interest attaches to the fact that in none ofPuhr's five cases of multiple malignancies did the combinationcarcinoma mammae and carcinoma uteri occur.... As cancer ofthese two sites make up nearly half the total female cancer mortal­ity, it is hardly possible such a combination could be consistently

FIG. 1. ADENOCARCINOMA OF THE CECUM, CASE 6, TABLE I. X 120

overlooked, and its absence from the casuistic literature is probablysignificant." I was able to review ten cases in the literature inwhich this combination occurred.

In only seven instances, so far as I have been able to determine,has a large series of post-mortem examinations been studied forthe purpose of determining the frequency of multiple primarycarcinomas. These studies have been made, respectively, byv. Hansemann (7), Redlich (13), Feilchenfeld (4), Riechelmann(14), Harbitz (8), Puhr (12), and Gade (5).

Excluding the cases of multiple primary carcinomas of the

MULTIPLE PRIMARY CARCINOMAS 2003

skin, I have found reports of sixteen cases of multiple primarycarcinoma of the same organ or of paired organs, of twenty-fourcases of multiple primary carcinoma involving three or moreorgans, and of 125 other cases of two primary carcinomas in thesame patient.2

Concerning carcinomas of the skin, Owen (11), in a review of3000 cases of malignant tumors, found 143 (4.7 per cent) of multipleprimary growths. In these 143 cases, 113 of the growths involved

FIG. 2. CARCINOMA OF THE KIDNEY, CASE 6, TABLE 1. X 120

the skin only. There were 86 cases of basal-cell carcinoma; theaverage age of the patient in the group was sixty-six years, andthe duration of the disease, eight years. In 20 of the 113 cases,a squamous-cell and a basal-cell tumor existed in the same patient.The average age of the patients in this group was sixty-five years.Seven of the 113 cases were examples of multiple squamous-cellcarcinoma. In 1915, Barber (1) reported a series of 200 casesof multiple basal-cell carcinoma.

2 References to these reports, in full, and other references on which this paper isfounded, can be found in the library of the University of Minnesota, accompanyingthe following thesis: Hanlon, F. R.: Multiple Primary Carcinomas.

2004 FRANK ROBERT HANLON

Many of the 16 cases of multiple primary carcinoma of thesame organ or of paired organs that have been referred to, mightbe subject to debate as to accuracy of diagnosis. Theilhaber andEdelberg (16) have reviewed cases of carcinoma of the same organor of paired organs, and, in addition to the 16 cases mentioned,

.FIG. 3. CARCINOMA OF THE OVARY, CASE 10, TABLE I. X 120

they have listed cases reported by Klebs, Ribbert, Handford,Rotter, and Tanberg.

Concerning the cases of multiple primary carcinoma involvingthree or more organs, the average age of the patients, in cases inwhich the age was reported, was sixty-three and six-tenths years.This age is greater than that in the cases in which two multipleprimary carcinomas existed. The majority of the tumors weresituated in the gastro-intestinal tract.

Of the 125 other cases of two primary carcinomas in the samepatient, the average age of the patients in the 81 cases in whichthe age was reported, was fifty-eight and eight-tenths years. Thisage is several years greater than the average age in the cases inwhich there was only one carcinoma.

MULTIPLE PRIMARY CARCINOMAS 2005

The distribution among the various organR corresponded closelywith the percentage distribution of carcinoma when it occurssingly. This factor alone would lead to the belief that multipleprimary malignant growths are coincidental rather than a responseto a definite law of formation of tumors.

FIG. 4. CARCINOMA OF THE THYROID GLAND, CASE 10, TABLE 1. X 120

MULTIPLE PRIMARY CARCINOMAS DISCLOSED IN 3000 CONSECUTIVE

POST-MORTEM EXAMINATIONS MADE AT THE MAYO CLINIC

In this entire group, 950 deaths were attributable to malignanttumors, of which 710 were carcinomas.

The high incidence of tumors (31.7 per cent) in this series is aconsequence of the unusually large number of patients afflicted withmalignant disease who present themselves at the clinic for examina­tion. In a similar survey in a fairly large metropolitan center,malignant tumors were responsible for only 9 per cent of the'deaths.

In establishing the diagnosis of multiple primary carcinoma,the greatest reliance has been placed on distinct variation in the

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MULTIPLE PRIMARY CARCINOMAS 2007

microscopic appearance of the several tumors in each case. Eachtumor was considered in its possible relationship to a metastaticlesion, and an effort was made to rule out the possibility of metas­tasis. An extensive lapse of time between the appearance of thetumors and the absence of known metastatic lesions, associatedwith varying histologic appearances, was highly favorable towardthe diagnosis of the duality of the tumors. If one of the tumorsoccurred in an organ which was a common site of metastasis, thattumor was scrutinized most carefully with these criteria in mind, andif an element of doubt remained, it was excluded from the study.

Perhaps the most difficult cases to evaluate are the multiplecarcinomas of the gastro-intestinal tract. It is a well known factthat metastasis from intestinal tumors takes place in the liver, theregional lymph nodes, or the operative scars. The occurrence ofa second tumor at a distant point in the intestine is possibly asecond primary growth. The frequency of intestinal polyps under­going malignant degeneration offers strong support for this theory.However, in the cases appended it has been required that thetumors possess different microscopic appearances before they beadjudged independent primary growths.

In the 710 cases of carcinoma, there were 18 cases of multipleprimary malignant growths. This represents 0.6 per cent of theentire group of cases studied and 2.5 per cent of the cases ofcarcinoma. Thirteen patients were males; the remaining 5 werefemales.

The average age of the patients in whom there were twomultiple primary carcinomas was sixty-two and six-tenths years.The average age of the group with one carcinoma was fifty-fiveand two-tenths years. The fact that these dual tumors occurredamong patients older than those who had a single tumor alreadyhas received emphasis. The organs involved were as follows:colon, 9; kidney, 9; thyroid gland, 4; stomach, 3; ovary, 2; para­thyroid, 1; mouth, 1; prostate gland, 1; anal margin, 1; uterus, 1;breast, 1; larynx, 1; ileum, 1; nose, 1.

It will be noted that there is widespread distribution of theorgans involved. The high incidence of tumors of the colon is dueto the fact that operation on the colon carries with it a rather highmortality, especially because many of the cases necessitate immedi­ate operation for intestinal obstruction. A large number thuscome to necropsy. Most of the tumors of kidneys were small,

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went unrecognized clinically, but possessed microscopic stigmataof malignancy. Most of them were growing slowly and representeda low degree of malignancy. However, they possessed definitepotentialities for growth, and their inclusion in this study iswarranted. The carcinomas selected do not represent the benigntumors known as adenomas. These occur either as single ormultiple neoplasms on the cortex of the kidney. They are mostfrequently found in the sclerotic type of kidney. They areclassified according to their cellular arrangement as papillary,alveolar, or tubular adenomas. They are distinguished from thecarcinomas of the kidney by the completely differentiated cells, thecircumscribed limitation of the tumor, and the definite arrange­ment of the cells in an orderly fashion. The carcinomas, on theother hand, represent an unrestrained growth of cells, lacking indifferentiation, and infiltrating the renal substance freely.

Of the 18 cases of multiple primary malignant growths, in 2the growths were recognized clinically as multiple, primary, andmalignant; in 2 others the diagnosis was made at necropsy only,and in the other 14 cases one tumor was recognized clinically,whereas the second was first noted at necropsy.

Twenty-one tumors gave rise to definite symptoms. Fifteenwere entirely quiescent.

The patients dated their symptoms back an average of tenmonths, with extremes varying between three years and two weeks.

Tables I and II contain data on the 18 cases in which necropsywas performed and on the 31 cases in which the growths wererecognized clinically.

Fourteen of the patients whose cases are recorded in Table IIwere males; the remaining 17 were females. The average age atthe time when the first tumor was removed was fifty-four years,and the average age at the time when the second tumor was re­moved was fifty-seven and eight-tenths years. Since some of thepatients are still living, it is impossible to determine the averagespan of life of those 31 patients, but it is definitely more than sixtyyears. The distribution among the various organs of the primaryand secondary tumors, taken together, was as follows: breast, 11;colon and rectum, 10; uterus, 10; skin, 9; urinary bladder, 5;stomach, 4; lip and tongue, 4; lung and bronchus, 2; penis, 2;kidney, 1; esophagus, 1; testis, 1; fallopian tube, 1; ovary, 1.

MULTIPLE PRIMARY CARCINOMAS 2011

SUMMARY AND CONCLUSIONS

Multiple primary carcinomas probably represent incidentaloccurrences rather than a definite response to any law of neoplasticformation.

The distribution of the several tumors throughout the bodyfollows closely the frequency of occurrence of single carcinomas.

Conclusions cannot be drawn concerning the sex incidenceassociated with multiple primary tumors. There is, however, avery definite relationship between the occurrence of multipleprimary carcinomas and senescence. They occur among personswho are several years older than those who harbor but one carci­noma. This was pointed out previously by Egli, who consideredboth benign and malignant tumors. The present study confirmshis views in regard to carcinomas.

This paper adds to the literature 49 new cases of multipleprimary tumors; 18 cases were observed in a study of 3,000consecutive post-mortem examinations; the remaining 31 casesoccurred in a large group in which two tumors were removed byoperative intervention.

BIBLIOGRAPHY

1. BARBER, R. F.: Basal-celled epithelioma, Med. Rec. 87: 753-754,1915.

2. BILLROTH: Quoted by Miller, R. T., Jr.: Multiple primary malignantfoci in cancer of the colon, Ann. Surg. 80: 456-472, 1924.

3. EGLI, FRITZ: Ueber Multiplizitat von Geschwiilsten, Cor.-Bl. f.schweiz. Aerzte. 44: 449-462, 1914.

4. FEILCHENFELD: Quoted by Theilhaber and Edelberg.5. GADE: Quoted by Siebke, Harald: Uber multiple Carcinome, Ztschr.

f. Krebsforsch. 23: 66-81, 1926.6. GOETZE, OTTO: Bemerkungen iiber Multiplizitat primarer Carcinome

in Anlehnung an einen Fall von dreifachem Carcinom, Ztschr. f.Krebsforsch. 13: 281-302, 1913.

7. v. HANSEMANN: Das gleichzeitige Vorkommen verschiedenartigerGeschwiilste bei derselben Person, Ztschr. f. Krebsforsch. 1:183-198, 1904.

8. HARBITZ, FRANCIS: Uber das gleichzeitige Auftreten mehrererselbstandig wachsender (" multipler") Geschwiilste, Beitr. Z. path.Anat. U. Z. aUg. Path. 62: 503-579, 1916.

9. MERCANTON, F.: Quoted by Miller, R. T., Jr.: Multiple primarymalignant foci in cancer of the colon, Ann. Burg. 80: 456-472, 1924.

10. MURRAY, J. A.: Linacre Lecture on multiple new growths, Lancet.2: 800-803, 1927.

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2012 FRANK ROBERT HANLON

11. OWEN, L. J.: Multiple malignant neoplasms, J. A. M. A. 76: 1329­1333, 1921.

12. PUHR, LUDWIG: tJber die Multiplizitat der Geschwiilste, Ztschr. f.Krebsforsch. 24: 38-62, 1926-1927.

13. REDLICH, WALTER: Die Sektions-Statistik des Carcinoms am BerlinerStadtischen Krankenhaus am Urban nebst kasuistischen Bei­tragen, Ztschr. f. Krebsforsch. 5: 261-325, 1907.

14. RIECHELMANN: Quoted by G6tting: Zur multiplizitiit primarerCarcinome, Ztschr. f. Krebsforsch. 7: 675-681, 1909.

15. SUSSEX, L. T., AND CAYLOR, H. D.: Epithelioma of the cervixassociated with carcinomatous cystadenoma of the ovary, Ann.Surg. 76: 949-952, 1927.

16. THEILHABER, A., AND EDELDERG, H.: Zur Lehre von der Multi­plizitat der Tumoren, insbesondere der Carcinome, DeutscheZtschr. f. Chir. 117: 457-489,1912.