MULTIPLE PRIMARY CARCINOMAS 1

Transcription

1 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 same person. I have recently reviewed the literature on the subject and place on record forty-nine additional cases. This paper is divided into 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 at The Mayo Clinic; (3) an analysis of thirty-one cases in which a clinical diagnosis was made at The Mayo Clinic. REVIEW OF THE LITERATURE Billroth (2) reported a case in 1869 of a patient with carcinoma of the stomach and also one of the external ear. He emphasized the importance of the criteria used as a basis for diagnosis, and established three postulates which he felt were necessary for the diagnosis of multiple primary tumors: (1) each tumor must have an independent histologic appearance; (2) the tumors must arise in different situations; (3) each tumor must produce its own metastasis. Mercanton (9) added a fourth requirement, that there be no recurrence of tumors after their removal. It is quite as unreasonable to demand the fulfillment of the third and fourth postulates in the diagnosis of multiple primary carcinomas as it would be in the diagnosis of a single carcinoma. Egli (3), Harbitz (8) and Puhr (12) objected strenuously to the adoption of Billroth's criteria. Goetze (6) suggested the following requirements for diagnosis: (1) the macroscopic llnd microscopic appearance of the tumors must be that of the usual carcinomas of the organs involved; (2) exclusion of metastasis must be certain; (3) diagnosis may be confirmed 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 Master of Science in Surgery, June Work done in the Section on Pathologic Anatomy, The Mayo Clinic. 2001

2 2002 FRANK ROBERT HANLON The Linacre Lecture of 1927 contained a particularly noteworthy passage. Murray (10), in commenting on the excellent study of Puhr on multiple primary carcinomas, made the following statement: " A certain interest attaches to the fact that in none of Puhr's five cases of multiple malignancies did the combination carcinoma mammae and carcinoma uteri occur... As cancer of these 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 probably significant." I was able to review ten cases in the literature in which 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 for the purpose of determining the frequency of multiple primary carcinomas. These studies have been made, respectively, by v. Hansemann (7), Redlich (13), Feilchenfeld (4), Riechelmann (14), Harbitz (8), Puhr (12), and Gade (5). Excluding the cases of multiple primary carcinomas of the

3 MULTIPLE PRIMARY CARCINOMAS 2003 skin, I have found reports of sixteen cases of multiple primary carcinoma of the same organ or of paired organs, of twenty-four cases of multiple primary carcinoma involving three or more organs, and of 125 other cases of two primary carcinomas in the same patient. 2 Concerning carcinomas of the skin, Owen (11), in a review of 3000 cases of malignant tumors, found 143 (4.7 per cent) of multiple primary 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; the average age of the patient in the group was sixty-six years, and the 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-cell carcinoma. In 1915, Barber (1) reported a series of 200 cases of multiple basal-cell carcinoma. 2 References to these reports, in full, and other references on which this paper is founded, can be found in the library of the University of Minnesota, accompanying the following thesis: Hanlon, F. R.: Multiple Primary Carcinomas.

4 2004 FRANK ROBERT HANLON Many of the 16 cases of multiple primary carcinoma of the same organ or of paired organs that have been referred to, might be subject to debate as to accuracy of diagnosis. Theilhaber and Edelberg (16) have reviewed cases of carcinoma of the same organ or 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 involving three or more organs, the average age of the patients, in cases in which the age was reported, was sixty-three and six-tenths years. This age is greater than that in the cases in which two multiple primary carcinomas existed. The majority of the tumors were situated in the gastro-intestinal tract. Of the 125 other cases of two primary carcinomas in the same patient, the average age of the patients in the 81 cases in which the age was reported, was fifty-eight and eight-tenths years. This age is several years greater than the average age in the cases in which there was only one carcinoma.

5 MULTIPLE PRIMARY CARCINOMAS 2005 The distribution among the various organr corresponded closely with the percentage distribution of carcinoma when it occurs singly. This factor alone would lead to the belief that multiple primary malignant growths are coincidental rather than a response to 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 malignant tumors, of which 710 were carcinomas. The high incidence of tumors (31.7 per cent) in this series is a consequence of the unusually large number of patients afflicted with malignant 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

6 TABLE I Data Concerning Eighteen Cases in Which Necropsy was Performed 1-:> 0 Sex I First tumor Case I and years age. I Situation Histo'ogic appearance Situation -I-151M Stomach Adenocarcinoma Parathyroid gland I 2 157M Stomach Adenocarcinoma, signet-ring cells Colon, splenic flexure 3 72M Sigmoid Adenocarcinoma Right kidney 4 56M Rectum Adenocarcinoma Right kidney 5 60M Mouth (lip) Squamous-cell carcinoma Rectum 6 60M Cecum Adenocarcinoma Right kidney 7 65M Left kidney Adenocarcinoma; large cells, clear Right. kidney 0 0> cytoplasm 8 77M Prostate gland Adenocarcinoma Anal margin 9 41M Rectum Adenocarcinoma Right kidney lot 65F Right ovary Papillary carcinoma Thyroid gland F Left ovary Papillary cystadenocarcinoma Cervix of uterus 12 59F Left breast Scirrhous carcinoma Thyroid gland 13 70M Thyroid gland Adenocarcinoma Right kidney 14 11M Larynx Squamous-cell carcinoma Ileum 15 63M Colon Adenocarcinoma Thyroid gland 16 68F Rectum Adenocarcinoma Kidney 17 63M Nose I Adenocarcinoma Right kidney 18 61M Stomach Adenocarcinoma Rectum I Second tumor Histologic appearance Large pale cells with sharply outlined borders Adenocarcinoma, irregular hyperchromatic cylindric cells Highly cellular tubular carcinoma Hemorrhagic and cystic carcinoma Adenocarcinoma Cuboidal-cell carcinoma Adenocarcinoma; cell growth less active than that in left side Basal-cell carcinoma Tubular carcinoma Adenocarcinoma Squamous-cell carcinoma Highly cellular adenocarcinomas Papillary adenocarcinoma Small round-cell adenocarcinoma Adenocarcinoma Tubular carcinoma Small-cell adenocarcinoma Adenocarcinoma, degeneration of a polyp * Figures 1 and 2. t Figures 3 and 4. ::: Reported by Sussex and Caylor (15).

7 MULTIPLE PRIMARY CARCINOMAS 2007 microscopic appearance of the several tumors in each case. Each tumor was considered in its possible relationship to a metastatic lesion, and an effort was made to rule out the possibility of metastasis. An extensive lapse of time between the appearance of the tumors and the absence of known metastatic lesions, associated with varying histologic appearances, was highly favorable toward the diagnosis of the duality of the tumors. If one of the tumors occurred in an organ which was a common site of metastasis, that tumor was scrutinized most carefully with these criteria in mind, and if an element of doubt remained, it was excluded from the study. Perhaps the most difficult cases to evaluate are the multiple carcinomas of the gastro-intestinal tract. It is a well known fact that metastasis from intestinal tumors takes place in the liver, the regional lymph nodes, or the operative scars. The occurrence of a second tumor at a distant point in the intestine is possibly a second 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 the tumors possess different microscopic appearances before they be adjudged independent primary growths. In the 710 cases of carcinoma, there were 18 cases of multiple primary malignant growths. This represents 0.6 per cent of the entire group of cases studied and 2.5 per cent of the cases of carcinoma. Thirteen patients were males; the remaining 5 were females. The average age of the patients in whom there were two multiple primary carcinomas was sixty-two and six-tenths years. The average age of the group with one carcinoma was fifty-five and two-tenths years. The fact that these dual tumors occurred among patients older than those who had a single tumor already has 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 the organs involved. The high incidence of tumors of the colon is due to the fact that operation on the colon carries with it a rather high mortality, especially because many of the cases necessitate immediate operation for intestinal obstruction. A large number thus come to necropsy. Most of the tumors of kidneys were small,

8 t.::> TABLE II Data Concerning Thirty-one Cases in which Growths Were Recognized Clinically when Case Sex recognized, I Age First tumor I Second tumor Situation Histologic appearance Age when recog- I years Situation Histologic appearance nized. years ---- I M 52 Sigmoid Adenocarcinoma Not recorded Penis Squamous-cell carcinoma 2 F Right breast Adenocarcinoma Not recorded Cervix of uterus Squamous-cell carcinoma 3 F Uterus Adenocarcinoma Not recorded Right breast Adenocarcinoma; marked cellular activity and growth 4 F Rectum Adenocarcinoma Not recorded Uterus Adenocarcinoma 5 M 44 Face Mixed squamous-cell and basal- Not recorded Sigmoid Adenocarcinoma cell carcinoma 6 F 64 Stomach Adenocarcinoma 68 Ovary Adenocarcinoma; no resemblance to gastric carcinoma 7 F 55 Uterus Adenocarcinoma 66 Right breast Adenocarcinoma 8 F 49 Uterus Adenocarcinoma 56 Right breast Adenocarcinoma 9 M 57 Stomach Adenocarcinoma 57 Skin below right Squamous-cell carcinoma ear 10 F 48 Rectum Adenocarcinoma 50 Left breast I Adenocarcinoma 11 M 48 Cecum Adenocarcinoma 56 Splenic flexure Adenocarcinoma; moreactive than first tumor 12 M 26 Right kidney Adenocarcinoma 35 Lung Adenocarcinoma 13 M 61 Esophagus Squamous-cell carcinoma 62 Left hand Squamous-cell carcinoma 14 M 43 Cecum Adenocarcinoma 45 Transverse colon Adenocarcinoma, cells much smaller and growth more rapid 15 F 47 Left orbit Combined squamous-cell and 56 Left breast Adenocarcinoma basal-cell carcinoma

9 t-:l TABLE II-Continued Age First tumor Second tumor when Case Sex recog nized, Age when recogyears Situation Histologic appearance nized, years Situation Histologic appearance M 68 Upper part of left Squamous-cell carcinoma 70 Urinary bladder Squamous-cell carcinoma cheek 17 M 74 Uterus Adenocarcinoma 75 Right shoulder Squamous-cell carcinoma 18 F 56 Uterus Adenocarcinoma 58 Left breast Adenocarcinoma 19 F 56 Left breast Adenocarcinoma 57 Bladder Papillary squamous-cell carcinoma 20 M 57 Sigmoid Adenocarcinoma 57 Penis Squamous-cell carcinoma 21 :\1 48 Cheek Adenocarcinoma; highly malig- 49 Testis Adenocarcinoma; large polyhedral nant hyperchromatic cells 22 F 64 Skin of right ear Mixed basal-cell and squamous- 64 Cervix of uterus Squamous-cell carcinoma cell carcinoma 23 F 81 Left breast Adenocarcinoma 81 Upper lip Basal-cell carcinoma 24 F 50 Left breast Adenocarcinoma 50 Skin of neck Mixed basal-cell and squamouscell carcinoma 25 1\1 78 Lip Squamous-eell carcinoma 80 Stomach Adenocarcinoma 26 F 29 Right oviduct Papillary carcinoma 29 Rectum Adenocarcinoma 27 F 64 Left breast Adenocarcinoma Uterus Adenocarcinoma 28 F 53 Stomach Adenocarcinoma 54 Uterus Adenocarcinoma 29 :M 48 Bladder Papillary squamous-cell carci- 50 Bronchus Papillary carcinoma noma 30 1\1 53 Tongue Squamous-cell carcinoma 53 Urinary bladder Squamous-cell carcinoma 31 1\1 63 Bladder Squamous-cell carcinoma 64 Lip ~quamous-cellcarcinoma I

10 2010 FRANK ROBERT HANLON went unrecognized clinically, but possessed microscopic stigmata of malignancy. Most of them were growing slowly and represented a low degree of malignancy. However, they possessed definite potentialities for growth, and their inclusion in this study is warranted. The carcinomas selected do not represent the benign tumors known as adenomas. These occur either as single or multiple neoplasms on the cortex of the kidney. They are most frequently found in the sclerotic type of kidney. They are classified according to their cellular arrangement as papillary, alveolar, or tubular adenomas. They are distinguished from the carcinomas of the kidney by the completely differentiated cells, the circumscribed limitation of the tumor, and the definite arrangement of the cells in an orderly fashion. The carcinomas, on the other hand, represent an unrestrained growth of cells, lacking in differentiation, and infiltrating the renal substance freely. Of the 18 cases of multiple primary malignant growths, in 2 the growths were recognized clinically as multiple, primary, and malignant; 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. Fifteen were entirely quiescent. The patients dated their symptoms back an average of ten months, with extremes varying between three years and two weeks. Tables I and II contain data on the 18 cases in which necropsy was performed and on the 31 cases in which the growths were recognized clinically. Fourteen of the patients whose cases are recorded in Table II were males; the remaining 17 were females. The average age at the 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 the patients are still living, it is impossible to determine the average span of life of those 31 patients, but it is definitely more than sixty years. The distribution among the various organs of the primary and 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.

11 MULTIPLE PRIMARY CARCINOMAS 2011 SUMMARY AND CONCLUSIONS Multiple primary carcinomas probably represent incidental occurrences rather than a definite response to any law of neoplastic formation. The distribution of the several tumors throughout the body follows closely the frequency of occurrence of single carcinomas. Conclusions cannot be drawn concerning the sex incidence associated with multiple primary tumors. There is, however, a very definite relationship between the occurrence of multiple primary carcinomas and senescence. They occur among persons who are several years older than those who harbor but one carcinoma. This was pointed out previously by Egli, who considered both benign and malignant tumors. The present study confirms his views in regard to carcinomas. This paper adds to the literature 49 new cases of multiple primary tumors; 18 cases were observed in a study of 3,000 consecutive post-mortem examinations; the remaining 31 cases occurred in a large group in which two tumors were removed by operative intervention. BIBLIOGRAPHY 1. BARBER, R. F.: Basal-celled epithelioma, Med. Rec. 87: , BILLROTH: Quoted by Miller, R. T., Jr.: Multiple primary malignant foci in cancer of the colon, Ann. Surg. 80: , EGLI, FRITZ: Ueber Multiplizitat von Geschwiilsten, Cor.-Bl. f. schweiz. Aerzte. 44: , FEILCHENFELD: Quoted by Theilhaber and Edelberg. 5. GADE: Quoted by Siebke, Harald: Uber multiple Carcinome, Ztschr. f. Krebsforsch. 23: 66-81, GOETZE, OTTO: Bemerkungen iiber Multiplizitat primarer Carcinome in Anlehnung an einen Fall von dreifachem Carcinom, Ztschr. f. Krebsforsch. 13: , v. HANSEMANN: Das gleichzeitige Vorkommen verschiedenartiger Geschwiilste bei derselben Person, Ztschr. f. Krebsforsch. 1: , HARBITZ, FRANCIS: Uber das gleichzeitige Auftreten mehrerer selbstandig wachsender (" multipler") Geschwiilste, Beitr. Z. path. Anat. U. Z. aug. Path. 62: , MERCANTON, F.: Quoted by Miller, R. T., Jr.: Multiple primary malignant foci in cancerof the colon, Ann. Burg. 80: , MURRAY, J. A.: Linacre Lecture on multiple new growths, Lancet. 2: ,

12 2012 FRANK ROBERT HANLON 11. OWEN, L. J.: Multiple malignant neoplasms, J. A. M. A. 76: , PUHR, LUDWIG: tjber die Multiplizitat der Geschwiilste, Ztschr. f. Krebsforsch. 24: 38-62, REDLICH, WALTER: Die Sektions-Statistik des Carcinoms am Berliner Stadtischen Krankenhaus am Urban nebst kasuistischen Beitragen, Ztschr. f. Krebsforsch. 5: , RIECHELMANN: Quoted by G6tting: Zur multiplizitiit primarer Carcinome, Ztschr. f. Krebsforsch. 7: , SUSSEX, L. T., AND CAYLOR, H. D.: Epithelioma of the cervix associated with carcinomatous cystadenoma of the ovary, Ann. Surg. 76: , THEILHABER, A., AND EDELDERG, H.: Zur Lehre von der Multiplizitat der Tumoren, insbesondere der Carcinome, Deutsche Ztschr. f. Chir. 117: ,1912.