HISTOPATHOLOGIC CLASSIFICATION AND NATURAL HISTORY OF MALIGNANT TESTIS

TUMORS I N NORWAY, 1959-1963 ASHTON MILLER, MA, MD, FRCS, * AND ROLF SEL JELID M D ~

All malignant testis tumors which occurred in a single country, Norway, during a 5-year period, 1959-1963 inclusive, have been collected and classified according to a simple histopathologic system containing 4 groups-seminoma, embryonal carcinoma, teratoma, and choriocarcinoma. T h e population in the various age-groups was known accurately and registration of cancer cases was compul- sory, so it has been possible to produce reliable incidence figures. The frequency of malignancy in maldescended testis is shown to be 10 times that i n normal descent. T h e results of treatment vary according to the differing natural history of the 4 pathologic groups.

EVEIWL OTHERWISE EXCELLENT STUDIES OF S malignant tumors of the testis have suf- fered from the fact that the patients were de- rived from a selected age-gro~p,~~l5 while others may have been selected in other ways.3 Therefore, there is insufficient exact knowl- edge of the incidence of these tumors in a large total population.

Classification according to histopathology has always been difficult, so comparative stud- ies have been without meaning. For example, Blandy? quotes a list of the estimated fre- quencies of seminoma ranging from 23% to 870/, of all testis tumors. Such figures clearly de- pend upon definition as well as selection, so we have made an attempt to produce a simple classification which can be easily used by the pathologist and which has at the same time some clinical prognostic significance.

From the Norwegian Radium Hospital and Norsk Hydro’s Institute for Cancer Research, Oslo, Norway.

* Research Fellow, Norsk Hydro‘s Institute for Can- cer Research, and Consultant in Urology, Norwegian Radium Hospital, Oslo.

t Norsk Hydro’s Institute for Cancer Research, and Senior Pathologist, Norwegian Radium Hospital, Oslo.

Address for reprints: A. Miller, MD, Norwegian Ra- dium Hospital, Montebello, Oslo 3, Norway.

The authors are grateful to the heads of the pathol- ogy laboratories in Norway for making histologic mate- rial available to them. They are also appreciative to the Norwegian Cancer Registry for providing statistics and follow-up detail and to Miss Anna Hougen, Ac- tuary to the Registry, for help with the analysis of re- sults. The investigation was undertaken while Ashton Miller was holder of a stipend from Norsk Hydro’s Fund for Cancer Research.

Received for publication March 29, 1971.

MATERIAU AND IMETHODS

Details concerning the 314 patients whose malignant testis tumors were diagnosed dur- ing the years 1959-1963 inclusive were taken from the records of the Norwegian Cancer Reg- istry. In a high proportion (272), i t was possi- ble to collect additional detail from the hospi- tal clinical notes. Histologic preparations were available for 305 of the 314 cases (97.2%). The other 9 patients died at home untreated or died shortly after admission to hospital in a moribund condition. Survival information was obtained from the hospitals concerned and from the Cancer Registry. Population statis- tics were taken from the publications of the Central Bureau of Statistics in Norway.

HISTOPATHOLOGIC CLASSIFICATION

All the histologic material was fixed in for- maldehyde and examined after staining with liemotoxylin and eosin. A classification was ar- rived at which basically resembles that of Dixon and Moore.5 Four varieties are recog- nized:

Seminoma: This group contains uniform large cells with clear cytoplasm which resem- ble spermatogonia (Fig. 1). They are round or polyhedral and have characteristically distinct cell borders. The nuclei are round or oval and stain deeply. Thin strands of eosinophilic ma- terial join them to the cell border. T h e chro- matin is evenly dispersed, beaded, and the nu- clear membrane sharply defined, with 1 or 2

1054

No. 4 TESTIS TUMORS IN NORWAY Miller and Seljelid 1055

distinct nucleoli. Giant cells with many nuclei are occasionally seen, and mitoses are moder- ately frequent. Tightly packed groups of cells are separated by a vascular stroma which is variable both in extent and composition. In some, there is little stroma with collections of lymphocytes or lymphocyte-like cells around the vessels, while in others a granulomatous or fibrous reaction is found with comparatively few lymphocytes to be seen.

Areas of ischemic necrosis are common but hemorrhages are unusual.

Transition varieties between seminoma and other varieties have not been found, though it is fairly common to find small islands of semi- noma at the edge of and distinct from another variet).

A histologic variation containing sheets of cells with rather darker-staining cytoplasm, many giant cells, and minimal lymphocyte infiltration described as a spermatocytic seminomal0J4 was occasionally seen.

Embryonal carcinoma: This is composed of large pleomorphic cells with amphophilic cy- toplasm without distinct cell borders (Fig. 2). The nuclei are irregular with a light chroma- tin pattern and often contain more than one nucleolus. Giant cells are common, and mi- toses are frequent and sometimes bizarre. The cells are uwally found in large masses, but when they form the lining of spaces they often show the characteristics of dedifferentiated cu- boidal or columnar epithelium and may have a tendency to papilla formation. Cells can be found which resemble cytotrophoblast or syn- cytiotrophoblast, but there is never villus for- mation.

There is no regular stromal pattern, and lymphocyte infiltration is minimal. Both hem- orrhage and necrosis are common features.

Teratomn: This tumor can contain cells representative of all three germ layers, but the essential diagnostic point is that cells related to more than one recognizable adult tissue type can be found (Fig. 3). T h e degree of de- differentiation is variable. Characteristically, there is a random mixture of adult and fetal tissues, without evidence of organization to- wards a total organism.

ChoTiocarcinoma: This is distinguished by the presence of 2 types of cells: 1. Closely packed masses of cells with large nuclei and light cytoplasm resembling cytotrophoblast, and 2. Cells with darker, smaller nuclei and eosinophilic or amphophilic cytoplasm which resemble syncytiotrophoblast (Fig. 4).

The essential diagnostic point is that there should be a demonstrable attempt at villus formation, with the two cell types described above forming adjacent layers. T h e vascular core of the normal chorionic villus is not seen. Hemorrhage and necrosis are constant fea- tures.

RESULTS

The total male population of Norway in 1960 was 1,789,406. This figure is taken to be the population at risk during the period 1959-1963, for there was very little variation from year to year at that time. 'The total num- ber of malignant testis tumors in Norway dur- ing the 5 years was 314, an average of 63 per year (Table 1). T h e average incidence was therefore 3.5 per 100,000 males per year (Table 2). T h e proportion of tumors in the different pathologic groups is shown in Table 3, and the incidence of the different varieties of tumor in the various age-groups can be seen in Table 4.

NATURAL HISTORY

Clinical presentation and diagnosis: In this series, there was no deviation from the well- known generalization that 80% of malignant testis tumors present to the doctor with en- largement of a testis which is more often than not painless.

T h e length of history is different in the three common types:

Seminoma 8.6 mos. 1-90 mos. Embryonal Ca. 5.3 mos. 1-60 mos. Teratoma 4.3 mos. 1 4 8 mos.

Within all 3 groups, there is a relationship between a longer history and a longer sur- vival, but the converse-that a short history indicates short survival-is not demonstrable.

Misdiagnosis: The most important cause of delay in initiating treatment in this series was misdiagnosis as epididymitis; no less than 54 out of 289 (19yo), maldescent being excluded, received initial treatment with antibiotics.

This led to delays ranging from 1 to 18 months. There was a preponderance of em- bryonal carcinoma among those cases treated as epididymitis; 23 out of the total of 65 were so treated (35y0), as compared with 24 out of 157 seminomas (15%) and 7 out of 51 terato- mas (14%). This implies that about one third of all embryonal carcinomas present with

Average length Range

1056 CANCER October 1971 Vol. 28

FIG. 1 (top). Seminoma. Solid groups of clear cells with dark, fairly uniform nuclci ( ~ 9 0 ) . FIG. 2 (bottom). Embryonal carcinoma. Plroniorphic cells in solid groups or forming gland-like structures. A couplc ol mitoses ale seen ( ~ 9 0 ) .

No. 1 T E s m TCMORS IN NORWAY - Miller and Seljelicl

FIG. 3 (top,). Teratomd. Various types of differentiation are scen (x90). FIG. 4 (boftomj. Choriocarcinoina. Villi are seen; in many places one can easily distinguish between cells re- sembling cytotrophohlast and syncytiotrophoblast ( ~ 9 0 ) .

1058 CANCER October 1971 Vol. 28

-- TABLE 1. Varieties of Malignant Testis Tumors in Norway, 1959-1963

___~ Einb.ryoiial Chorio-

Year Seminoma carcinoma Teratoma carcinoma Lymphoma No histology Total - . -.

1959 31 12 8 1 0 1 53 1960 31 16 12 1 0 3 66 1961 3 5 11 7 I 0 3 57 1962 13 1 1 16 0 3 2 78

7 0 0 60 1963 3 3 17 8

176 70 51 5 3 9 314 - - - __ - - -

symptoms and signs which suggest an inflam- matory process. This red herring has been em- phasized previously by Gordon-Taylor and Wyndhams and by Stevens,l5 who called it the “pseudo-inflammatory” presentation. In spite of the fact that misdiagnosis obviously led to delay in initiating correct treatment, there was no difference in the survival of these cases treated as epididymitis compared with those treated in the usual way; 9 of the 23 patients with embryonal carcinoma were alive at 5 years (40%) compared with 14 out of the re- maining 42 (337,).

The underlying cause of this pseudo-inflam- matory presentation may be related to in- creased vascularity of the testis and neighbor- ing tissues, even involving redness of the over- lying skin. Histologically, however, it was im- possible to demonstrate any connection be- tween this type of presentation and a more than usually pronounced inflammatory re- sponse or lymphocyte infiltration in the tumor itself.

TABLE 2. Population of Norway, November 1, 1960, with Incidence of Malignant Testis Tumors in Each

Age Group (Population Figures from Cancer Registration in Norway, 1959-1961 :

Oslo, 1964)

Age group

under 14 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 45 to 49 50 to 54 55 to 59 60 to 64 65 to 69 70 to 74 75 & over

Population

176,065 135,336 107,062 100,895 113,727 129,549 128,827 122,199 111,159 98,313 86,133 68,495 49,007 62,609

Annual incidence per 100,000 males

0 3 1 .1 4.1 8.4 7 1 7 . 4 4 . 5 4 . 5 2 . 5 2 . 2 1 . 6 1 . 2 1 2 1.0

Locatzon: For some unknown 1 eamn there is a preponderance of tumors on the right side; in our series, this was in the proportion of 166: 142 or approximately 8:7. This cliffer- ence occurs in normally descended as well as in maldescended testes.2

Two patients developed bilateral tumors, one having maldescent on both sides and the other having normally descended testes. A cor- responding figure-that 2% of all testis tu- mors are bilateral-is given by Collins and Pugh.3

Presentation by metastasis: In this $cries, 4 out of 314 patients presented with lymph node enlargement, 1 supraclavicular, 2 abdom- inal, and 1 inguinal. In all of these, the diag- nosis was made as a result of histologic exami- nation of a lymph node, after which the af- fected testis was removed.

Afnlignnnt testis tumors in children: Six out of the total number of 314 occurred in chil- dren of 14 years or under. There was no ex- ample of seminoma, which in fact did not occur under the age of 25, and the majority (4) were embryonal carcinomas and the re- maining 2 were teratomas. The ages of the pa- tients with embryonal carcinoma were be- tween 6 months and 3 years, while the pa- tients with teratoma were older, 6 and l l years, respectively. No histologic difference could be seen between the tumors in children and those of a similar type in adults.

Maldescent Out of the total of 314 tumors, 25 (7.9%) were associated with maldescent of

TABLE 3. Proportions of the Various Groups in the 305 Tumors Which Were Histologically Classified

Pathological group Number Percentage of total

Seminoma 176 57.7% Embryonal carcinoma 70 23.0% Teratoma 51 16.7% Choriocarcinoma 5 1.6% LvmDhoma 3 1.07”

xo, 4 TESTIS TUMORS IN NORWAY - Miller and Seljelid 1059

the testis. The frequency of the various varie- ties is as follows:

Seminoma 18 72% Embryonal Ca. 5 20%

- Tera toma 1 Choriocarcinoma 1 -

The preponderance of seminoma (72%) as compared with its frequency in normally de- scended testis (57.7%) in this series is striking, and the comparative rarity of teratoma is in- teresting.

Age at diagnosis of tumor in maldescent: Gilbert and Hamilton7 found that there was no difference in the age at diagnosis of tumors in the maldescended as compared with the normally descended testis. In this series, the mean age a t diagnosis was as follows:

Maldescen t Normal descent Seminoma 44 yrs. 44 yrs. Embryonal Ca. 26 yrs. 31 yrs. Teratoma insuff. 27 yrs.

All cases 40 yrs. 38 yrs.

Bilateral tumors in maldescent: One pa- tient, age 35, developed 2 seminomas with a gap of 3 years.

Frequeucy of malignancy in mnldescent: To arrive at a realistic estimate of the fre- quency of malignant tumor in maldescent it is necessary to know the frequency of maldescent in the general population. Investigations in Western Europeans have shown that there is no difference between the frequency in boys and men provided that the retractile testis is excluded.4 The proportion of the male popu- lation at age 3 was found to be 0.8% by Vil- lumsen and Zachau-Christiansen.19 Scorer13 found a frequency of 0.7% at 12 months. There are no similar data available for Nor- way, so for the purpose of this investigation the frequency in Norway was therefore taken to be 0.75% of the male population.

The number of males in Norway with mal- descent during 1960 at this rate would be 13,420. The average number of testis tumors occurring each year (taken from the years 1959-1963 inclusive) in maldescent was 5, so the incidence is 5 in 13,420 or 37 per 100,000 males. Malignancy is therefore about 10 times as frequent as in normally descended testes (Table 5).

Effect of m-chiopexy on development of malignancy: Placing the maldescended testis in the scrotum is said to have no influence on the develoDment of malignant tumors. It was

TABLE 4. Age-specific Incidence per 100,000 Males of the Three Main Varieties

Embryonal Age group Seminoma Ca. Teratoma

14 and under 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75 & over

- -

3.6 3.6 4.7 4 .3 3.6 2.5 2.2 1.6 1.2 1.2 1 .6

0.2 0.6 1.1 2 . 0 3.2 2.0 0.2 0 . 9 - - - - - -

0.1 0.5 3.0 2.8 0 .9 0 . 7 - - - -

- - - -

done in one-fourth of 58 cases3 and in 77 of 840 cases.' Dow and Mostofis suggest that or- chiopexy must be done before the age of 6 years to have a chance of preventing malig- nant change. In this series, 9 out of 25 had had orchiopexy, but only 2 of these had been done before puberty and none before the age of 6.

T h e site of metastases is said to be influ- enced by orchiopexy done before the onset of malignancyls*1 because after surgery cells can pass to the inguinal lymph nodes rather than the para-aortic group. However, both Thackrayl? and Howat and MassarellaQ de- scribe extension to inguinal lymph nodes without previous involvement of the superfi- cial scrota1 structures and in the absence of any previous operation in the area. We found 7 examples of histologically proven metastasis

TABLE 5. Incidence of Malignancy in Maldescended Testis According to Age Group, Expressed per 100

Males with Maldescent

Estimated Incidence Tumors Population per 100 per year with males with

Age group 1959-1963 maldescent maldescent 14 & under - 3570 - 15-19 0.2 1015 0,002 20-24 0 . 4 803 0.05 25-29 0.2 757 0.03 30-34 1.0 853 0.12 35-39 1 .o 97 1 0.10 40-44 0.4 966 0.04 45-49 0.8 914 0.08 50-54 0.4 834 0.05 55-59 0 . 4 73 7 0.05 60-64 0.2 646 0.03 65 & over - - -

"

1060 CANCER October 1971 Vol. 28

TABLE 6. Five-year Survival of Serninorna

Total Alive 5 Years 9% survival

176 135 77.3

a t diagnosis 141 125 88.6

at diagnosis 35 10 28.6

No metastases

With metastases

to inguinal lymph nodes. One occurred after orchiopexy and herniorrhaphy, 2 followed in- volvement of scrota1 skin by direct extension from the testis, and the remaining 4 occurred as the first manifestation of metastasis, with- out involvement of para-aortic nodes as judged by urography and cavography.

Possible relationship of malignancy to hypo- plasia and atrophy: In this series, either atro- phy or hypoplasia is a probability in 8 of the 25 patients with maldescent, as compared with 8 out of the 289 patients with normally de- scended testes. Strayla and Torgersenls both put forward the idea that malignant clevelop- ment might be related to hypoplasia rather than to maldescent.

Intra-abdominal maldew-ent: The incidence of intra-abdominal testis in the general popu- lation must be a small fraction of 0.75%, for it is a rare variety. Nevertheless, in this series, there were 4 examples out of 25 cases of mal- descent.

Trentmmt: During the period under re- view, 1959-1963, treatment of malignant testis tumors was almost standardized. Those treated a t the Norwegian Radium Hospital (60%) had orchidectomy followed by high vol- tage radiotherapy with 3,500 rads to each of two fields. inguinal and lumbar. More distant areas of spread were only treated if metastases were demonstrated. Patients treated elsewhere received after orchidectomy similar therapy from conventional 250 KV machines with a slightly smaller dosage. Ten apparently local- ized cases, including 6 children, received no ir- radiation, and 10 patients had an orchidec- tomy with para-aortic lymph node dissection of variable extent.

TABLE 7. Five year Survival of Embryonal Carcinoma

Total Alive 5 years survival

70 24 38.5 No metastases

Metastases present a t diagnosis 38 19 50

at diagnosis 32 5 16

In the great majority, orchidectomy was performed by the inguinal route after prelimi- nary ligation and division of the cord before the testis was disturbed. In 7 cases, there was doubt about the diagnosis and some form of biopsy, either by needle or excision, was per- formed. Two of these needed radical excision of the biopsy scar because of local metastasis. This danger has been stressed by Stevens,lS Prossor,12 and Blandy.2

SURVIVAL

The overall 5-year survival rate was 193 out of 314 (61y0). This figure only becomes mean- ingful when it is broken down into groups ac- cording to type of tumor and presence or ab- sence of metastases (Tables 6-8).

Seminoma: T h e survival rate for seminoma (88.6%) is comparable with other recent re- ported figures-Collins and Pugh, 1964: 8.5% and National Cancer Institute Monographs, 1964: 84y0 (Table 6).

In 7 patients, invasion of spermatic cord or inguinal lymph node was demonstrated by his- tology, but there was no evidence of spread further afield. Six of these are alive and well 5 years after treatment. This suggests that semi- noma at an early stage of metastasis is emi- nently treatable, and that the finding of cells in the spermatic cord is not necessarily a bad prognostic sign.

Embryonal carcinoma (Table 7) has an en- tirely different life history in that metastasis occurs earlier and more frequently by the bloodstream to the lungs, often with over- whelming dissemination.

Invasive embryonal carcinoma was demon- strated histologically at the cut end of the spermatic cord in 8 out of the 32 who were ex- amined. Only 1 of these did not have metas- tasis further afield, and all 8 died of their tumor. The numbers are, however, too small for any conclusion to be drawn.

Teratoma (Table 8) also has a natural his- tory which is different from the other two main groups. A proportion metastasize early

TABLE 8. Five-year Survival of Teratoma

Total Alive 5 years % survival ~

51 31 63

at diagnosis 41 32 78 No metastases

Metastases present at diagnosis 10 0 0

No. 4 TESTIS TUMORS IN NORWAY Miller and Seljelid 1061

and extensively and give the patient no chance whatever the treatment, while others can have a long history and a long life after diagnosis. There is much variation in malig- nancy so that unpredictability is a feature. Ex- amination of the cord revealed malignant cells in only 2 out of 27 examined: both of these had extensive spread to abdomen and thorax.

Choriocarcinoma is represented by so few cases that analysis is fruitless.

Lymphomas are represented by 3 exam- ples--2 lymphosarcomas which occurred con- comitant with a widely disseminated lymph node involvement in almost moribund pa- tients, and the other was bilateral testicular reticulosarcoma which appeared to be the only manifestation of the condition.

DISCUSSION

Theoretically, it is possible to find a suita- ble tissue origin for all testis tumors by refer- ring them to the whole spectrum of develop- ing embryonic cells, ranging from the ovum, in which no primitive germ layers are yet identifiable, to organoid elements formed from more than one germ layer. This is the basis of the “germ cell theory” proposed by Dixon and Moore.5 It has been criticized by Willis20 and others on the grounds that the histogenesis of neoplasms in the adult cannot realistically be related to the primitive cellu- lar situation in the early embryo since it is un- known whether such primordial cells persist in the fully developed normal individual. Col- lins and Pugh’s clas~ification,~ in which the seminoma is a separate entity and all other common malignant tumors come under the heading of teratoma, can be applied without difficulty by the pathologist, but it appears to us to have the important failing that the groups of teratoma are distinguished by the most differentiated element and therefore lack clinical significance, for it is often the less-dif- ferentiated cell type which metastasizes.

We suggest, therefore, that suitable patho- logic classification of testis tumors will have the smallest number of groups which show appre- ciable histologic differences provided that

these groups can be shown to reflect differ- ences in the life history.

There is general agreement that seminoma should be in a group by itself. If all other ma- lignant tumors are to be included under the heading of teratoma, it becomes neither a pathologic nor a clinical entity, containing tu- mors of widely different histologic appearance and clinical behavior. We believe there is a case for considering the embryonal carcinoma as a separate entity. We have retained the old name because it has become well known, but it is not intended to have any implications as to histogenesis. Collins and Pug113 discarded the term “embryonal carcinoma” because it had led to much confusion, but the confusion only arises when a definition of its histogene- sis is attempted: there is no argument about its existence.

The teratoma group distinguishes itself by its lack of prognostic predictability, so there is little point in subdividing it at our present state of knowledge. It is not even thought jus- tifiable to separate the type in which all ele- ments are apparently fully differentiated, for it is well known that the truly benign tera- toma rarely, if ever, exists in the testis. Small, less-differentiated regions that may not appear in the sections that are examined are the ones that give rise to metastasis and decide the prognosis.

Seminoma is quite frequently combined with other tumors as a separate collection of cells lying adjacent to the main tumor. We do not find that it alters the clinical characteris- tics of the main tumor, so there seems little reason to put these combined tumors into a separate group. Many have noted this combi- nation of seminoma and other tumors; n e body, except Collins and Pugh, has proposed a separate group.

T h e lymphoma is occasionally a difficult differential diagnostic problem. It is rare and only occurs in elderly patients. The histologic similarity to seminoma and embryonal carci- noma can be striking. Special reticulum stains and the characteristic local infiltration with- out destruction will often give the clue to its identity.

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2. Blandy, J. P.: Surgical management of testiclar tu- mors. Hosp. Medicine 1:133-146, 1966.

3. Collins, D. H.,and Pugh, R. C. B.: The pathology

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5. Dixon, F. J., and Moore, R. A.: Tumors of the

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8. Gordon-Taylor, G., and Wyndham, N. R.: On ma- lignant tumors of the testicle. Brit. J . Surg. 35:6-14, 1947.

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Norwegian M e d . Ass. 75:339-341, 1955. 19. Villumsen, A. L., and Zachau-Christiansen, B.:

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