British JOWMI of Urology (1983), 55, 440-444 0 1983 British Association of Urological Surgeons

Occult Germ-cell Testicular Tumours

S. POWELL, W. F. HENDRY and M. J. PECKHAM

Institute of Cancer Research and Royal Marsden Hospital, 1 ondon and Sutton

Summary-Eighteen men presenting with metastatic germ-cell malignancy in whom no primary tumour could be palpated in either testis are described. All patients had both testes in the scrota1 sac and none had a history of maldescent. All had abdominal node involvement, in most cases associated with metastases at other sites. Ten men presented with Stage 4 disease, five with Stage 3 and three with Stage 2.

The most common histological sub-type associated with an occult primary testicular tumour was trophoblastic malignant teratoma (9/18 patients). Abdominal pain (12 patients) and systemic symptoms (10 patients) were common presenting features. There was a history of testicular atrophy in eight patients and seven had experienced episodes of transient testicular pain up to 18 months before presentation.

In three of four patients in whom the testis was examined histologically following a history of atrophy and/or pain, there was evidence of a primary tumour, manifest as spontaneous turnour regression (one), differentiation (one) or a small micro-primary trophoblastic teratoma (one). In a fifth patient an ultrasonic scan showed a 1-cm echogenic mass in an atrophic testis. In 10 patients the diagnosis of germ-cell malignancy was established by laparotomy. Obstructive uropathy was present in six patients, associated with haematuria in four patients.

In 1961, Azzopardi et al. described a series of patients dying of widespread metastatic germ-cell malignancy in whom no primary tumour could be palpated in the testes. In these patients the testes showed characteristic lesions composed of well defined fibrous scars, often with ghosted remnants of seminiferous tubules. In some cases there were small foci of differentiated teratoma or micro-foci of seminoma cells. The appearance of these scars suggested spontaneous resolution of a primary testicular tumour associated with progression of metastatic disease.

Subsequent reports have drawn attention to the importance of considering a diagnosis of meta- static germ-cell testicular malignancy in young men with widespread tumour in whom no primary site can be identified (Fox et a/., 1979). Several clinical situations may occur in male patients where there are metastases of germ-cell malignancy with an apparent absence of primary tumour. These in-

Accepted for publication 30 November 1982.

clude primary extragonadal site of origin, malig- nant change in an undescended intra-abdominal testis and occult tumour in a descended testis. The latter group includes small impalpable malignant tumours, small impalpable tumours composed of mature differentiated tissue and testes in which there are histological changes suggestive of sponta- neous regression. There is a further group of patients who present with palpable but very small primary testicular tumours which may be missed unless the patient is examined with great care.

The present report describes 18 patients seen between 1972 and 1981 at the Royal Marsden Hospital in whom, on the basis of the pattern of tumour spread and/or histological confirmation, it is assumed that metastatic tumour had originated from a primary germ-cell testicular tumour al- though in no case was a primary tumour palpable.

Patients and Methods Details of approach to investigation and manage- ment of testicular tumour patients have been described elsewhere (Peckham, 1981).

440

OCCULT GERM-CELL TESTICULAR TUMOURS 44 1

Staging Methods The following investigations were performed : lymphography, chest radiography and whole lung tomography, intravenous urography, renal and hepatic function tests and full blood count. Ultra- sonic scanning of the liver and retroperitoneum was employed routinely prior to the availability of CAT scanning facilities in mid-1977. Since that time all patients have had CAT scans of the liver, retroperitoneum and lungs unless the presence of obvious metastatic disease rendered this unnecessary.

All patients had sequential serum sampling for AFP and P-HCG levels from the time of presentation.

Staging Class8cation This describes extent of tumour, site(s) of involvement and tumour volume.

(1) Lymphogram negative, no evidence of metastases.

(2) Lymphogram positive, metastases confined to abdominal nodes, 3 sub-groups are recognised : A. Maximum diameter of metastases < 2

cm B. Maximum diameter of metastases 2-5 cm C. Maximum diameter of metastases > 5

cm (3) Involvement of supra- and infradiaphrag-

matic lymph nodes. No extralymphatic metastases.

(4)

Abdominal status : A, B, C as for Stage 2 Extralymphatic metastases. Suffixes as follows: 0-lymphogram negative, A, B, C as for Stage 2 Lung status: L, < 3 metastases L2 multiple, none exceeding 2 cm maximum diameter L3 multiple, one or more exceeding 2 cm diameter Liver status: H+-liver involvement Criteria for liver involvement: Of the four following parameters, three should be positive before liver involvement is diagnosed. (i) Abnormal liver function tests (ii) Positive CT scan (iii) Positive ultrasonic or isotopic scan (iv) Clinical enlargement.

Histological Classijication. As much of the primary tumour as possible was obtained for histological review, which was carried out in all patients. Patients were classified according to the criteria of the British Testicular Tumour Panel (Pugh, 1976) into teratoma differentiated (TD), malignant tera- toma intermediate (MTI), malignant teratoma undifferentiated (MTU) or malignant teratoma trophoblastic (MTT). The presence of associated seminoma or yolk sac components was noted but did not modify the classification.

Criteria for Diagnosis of Occult Testicular Primary Only patients with both testes in the scrotum were included ; tumours arising in intra-abdominal testes were excluded from the study group. Patients with small palpable primary tumours were also excluded even though in some cases the diagnosis was missed initially and patients treated inappropriately.

Patients in whom a primary extragonadal origin of tumour was considered certain were excluded. These included mediastinal germ-cell tumours.

Criteria for inclusion in the study group were as follows :

(1) Both testes present in the scrotum. (2) No palpable tumour in either testis. ( 3 ) Diagnosis of germ-cell malignancy (histo-

logical and/or raised blood levels of alpha- fetoprotein and/or human chorionic gonadotrophin).

(4) Metastatic involvement of retroperitoneal lymph nodes draining the testis.

To provide further evidence in favour of a primary testicular origin the following aspects were docu- mented : a history of testicular pain and/or atrophy, histological evidence from the testes of testicular malignancy, differentiated teratoma or scarring considered to indicate spontaneous resolution of primary tumour, or ultrasonic scan evidence of an intratesticular mass.

Results Eighteen patients fulfilled the criteria for inclusion in the study. Their details are summarised in Table 1, Half of the group (9/18) had either histologically proven MTT (eight patients) or MTT diagnosed on the basis of a high HCG blood level (one patient). Eight patients presented with advanced stage group (ASG) I1 disease*. During the period 1976 to 1981 the total number of ASG I1 patients seen at

* Stages 4A, B, C, L3, H,.

Tabl

e 1

Occ

ult

Pri

mar

y T

esti

cula

r G

erm

Cel

l T

umou

rs:

Sum

mar

y of

Cli

nica

l D

ata

(Roy

al M

arsd

en H

ospi

tal

1972

-198

1)

Patie

nr

His

tolo

gy@

Sta

ge a

t Pr

e-tr

eatm

ent

Met

hod

of

Tesr

icul

ar h

isro

ryifi

ndin

gs

Year

oj~

O

utco

me

pres

enta

tion

seru

m m

arke

rs

diag

nosi

s pr

esen

tatio

n (m

onth

s)

His

tory

H

isto

logy

U

ltras

ound

A

FP

H

CG

(n

gIm

0 (i

u/O

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

MTT

4C

Lz

150

MTT

4

C L

3z H

, 20

5

MTT

3B

M

TT

4CL

, M

TT

3C

MTT

4

CH

+

MT

T

3C

MTT

4C

L3

(MTT

O)

4C L

, M

TU

2C

M

TU

jYS

4C L

, M

TU

4BL

3 M

TU

/YS

3C

MTI

4

c L

* Y

S 4C

H,

Sem

3

c

-

< 25

<

25

180

< 25

38

00

18

<5

17,5

00

2400

10

,000

<

25

40,0

00

<5

-

Sem

2

c

Sem

2B

<

5

21,0

00

136,

000

-

19,0

00

36,0

00

5318

68

0 49

,000

68

1,00

0 <

2

64

42

<3

<

2 (4

56

LA

P A

troph

y (R

) L

AP

Abn

orm

al (

R)

N (

L)

Pain

(L)

L

AP

Pain

/atr

ophy

(L)

N

(L)

A

troph

y (R

) L

AP

Pain

/sw

ellin

g (R)

LA

P Sm

all (

R&

L)

LA

P Pa

in (

R)

HC

G

Pain

/sw

ellin

g (R)

LA

P Pa

in (R)

LA

P A

troph

ylpa

in (

R)

Lung

Sm

all (R)

LA

P Sm

all (R)

N (

L)

LA

P B

ulky

(L)

N

eedl

e bi

opsy

A

troph

y (R)

LA

P B

iops

y pr

osta

te

Tend

erne

ss (R)

test

is a

et 5

(Abd

.)

MT

T (

R)

TD

" (R)

Scar

(L)

T

D/S

car

His

tolo

gy - ve

Tub

ular

atro

phy+

Sc

ar (

L)

Scar

(L)

1978

19

80

1972

19

80

1978

19

76

1979

19

79

1981

Sc

ar (R)

1980

19

80

1981

19

79

I979

19

77

1 cm

ech

ogen

ic

1981

1974

19

81

mas

s (R)

D 5

.5

D2

D 1

2 D

12

NE

D 4

3 D

32

NE

D 3

3 N

ED

20

A+

D 8

N

ED

20

D 1

2 N

ED

11

D 2

7 N

ED

29

D 4

.5

NE

D 1

1

D 3

3 W

E 2 N

ED

13

I s

Key

: =

For

hist

olog

y abb

revi

atio

ns se

e tex

t; a

= A

utop

sy;

= B

iops

y onl

y; D

= D

ead

of tu

mou

r; N

ED

= A

live

with

no

evid

ence

of d

isea

se; A

+ D =

Aliv

e with

di

seas

e; L

AP

= L

apar

otom

y; N

(L)

= L

eft c

ervi

cal n

ode

biop

sy.

7a z $

OCCULT GERM-CELL TESTICULAR TUMOURS 44 3

Table 2 Occult Germ-Cell Testicular Turnours: Summary of Symptoms and Findings at Presentation

Symptomlsign

Abdominal pain Systemic symptoms (sweats,

weight loss) Obstructive uropathy Haematuria Cervical mass Neurological impairment* Haemoptysis Haematospermia, dysuria Unilateral leg oedema

Number of patients

12

10 6 4 3

* Sensory loss, anterior surface of thigh. Ejaculatory impotence.

the Royal Marsden Hospital was 27. Hence 8/27 (29.9%) of ASG I1 patients presented with occult primary tumours.

A history of testicular atrophy and/or bouts of pain experienced intermittently over the months (up to 18 months) before presentation was obtained in 15 patients. Histological material from the testis was obtained in eight cases. Biopsy revealed bilateral tubular atrophy associated with fibrosis and necrosis in one patient. A sperm count showed azoospermia in this patient, who had previously fathered two children. Testicular scars were demonstrated in three patients, differentiated teratoma in two and a small 2-mm diameter MTT primary in one. Ultrasonic scans of the testes were carried out in two patients; one showed a 1-cm diameter echogenic lesion and the other an area of scarring. The histological nature of these abnor- malities was not established. Histological abnor- malities correlated well with the side in which testicular symptoms and signs were described.

The diagnosis of germ-cell malignancy was established at laparotomy in 11 patients, by percutaneous CT-guided fine needle biopsy of retroperitoneal nodes in one, by cervical node biopsy in three, biopsy of a lung metastasis in one, prostatic biopsy in one and by high HCG blood levels (681,000 iu/l) in one patient.

The symptoms and signs (other than testicular) present at diagnosis are summarised in Table 2. Systemic symptoms of weight loss, sweats and general debilitation were prominent in 10 patients and abdominal pain (leading to laparotomy) in 12. The advanced stage of presentation is underlined by the finding that 6/18 patients were shown to have obstructive uropathy. Neurological impair-

ment was present in two patients: one presented with ejaculatory impotence and one with sensory loss over the upper anterior thigh.

Discussion It is important to distinguish occult primary testicular tumour associated with metastases from primary extragonadal presentations which are best documented in the suprasellar region, mediastinum and sacrococcygeal region. In the absence of testicular histology prior to therapy a conclusive diagnosis of a primary testicular tumour cannot be proven. In patients with extensive metastatic tumour, orchiectomy for a suspected but clinically impalpable primary tumour is generally undesir- able since prompt treatment needs to be instituted. So long as the diagnosis of germ-cell malignancy is established, the proof of primary origin will not influence choice of treatment or its outcome. In the present series of 18 patients, a small trophoblas- tic teratoma was proven in one patient, a differen- tiated teratoma in two and testicular scars in three. In one patient ultrasonic scanning demonstrated a 1-cm diameter lesion but this was not biopsied. In another patient ultrasound suggested an intratesti- cular scar. In the remainder a primary testicular origin for metastases was considered highly prob- able because of the invariable presence of extensive retroperitoneal lymph node metastases, and a history of testicular atrophy and episodes of pain in 15 patients. i t is of interest that bouts of pain and tenderness were described as long as 18 months before the patient finally presented.

The series shows several striking features. Nine of I8 patients had trophoblastic tumours (histologi- cally proven in eight and assumed in one because of a serum beta-HCG titre of 681,000 iu/l). This compares with an overall frequency of 3.6% of MTT in the British Testicular Tumour panel series of 569 patients (Pugh, 1976). Secondly, as noted above, there was an association between testicular atrophy and/or testicular pain with occult primary malignancy; thirdly, and perhaps not unexpec- tedly, patients with occult primary tumours pre- sented with advanced disseminated bulky disease and hence carry a poor overall prognosis.

The explanation for the observation that in some patients rapid metastatic progression may occur, with spontaneous resolution or differentiation of the primary tumour or persistence of a very small primary tumour, is unknown. Several possibilities may be advanced. Many of these patients present with massive abdominal disease which may result

444 BRITISH JOURNAL OF UROLOGY

unpublished data). The relationship, if any, of occult primary tumours and tubular atrophy to in situ carcinoma is unknown. However, it is possible that the germinal epithelium in patients with occult testicular tumour will remain unstable following chemotherapy and such patients should be kept under observation because of the possible risks of developing a second tumour. It is known that patients who have been treated successfully with chemotherapy for one testicular tumour may develop a second tumour in the contralateral testis (Fowler et al., 1979).

The role of testicular ultrasound in identifying small clinically-impalpable primary tumours with- in the substance of the testis remains to be established. Techniques have improved consider- ably over the past few years and in one patient in the present series, presenting with a large abdomi- nal mass of seminoma, a 1-cm diameter echogenic lesion was identified, although its histological nature was not verified.

in ureteric obstruction and less commonly with neurological involvement. It is possible, although unlikely, that the transient episodes of testicular pain followed by testicular atrophy may result from interference with the vascular supply to the testis. In those patients where histological confirmation of a testicular primary was obtained, a preceding history of atrophy and/or pain accurately predicted the side of tumour involvement. It is therefore tempting to associate presence of the tumour with atrophy. It is known from the work of Skakkebaek (1978) that a proportion of men with small atrophic testes develop carcinoma in situ which may then go on to become invasive tumours. The relatively short history of atrophy in many of the patients in the present series, when compared with the longer time scale reported for in situ carcinoma and its evolution into invasive tumour, suggests that atrophy is not a primary event anteceding tumour formation in patients with occult presentations.

An alternative explanation is that the tumour provokes tubular atrophy. This hypothesis would require a tumour product or products to influence adversely growth of germinal epithelium and primary tumour but not of metastases. There is no evidence in the present series that high levels of alphafetoprotein or human chorionic gonado- trophin were associated preferentially with testicu- lar atrophy.

Finally, it is possible that infarction in haemor- rhagic trophoblastic tumour (where vascular inva- sion is common) might occur preferentially in the primary site due to the constraining effect of the tunica albuginea. In this context it is of interest that episodes of testicular pain had been experienced by seven men in the present series.

Occult primary testicular cancer should be con- sidered in the differential diagnosis of metastatic malignancy in young men. Serum levels of AFP and beta-HCG assays should always be measured. Although normal marker levels argue against such a diagnosis, they do not exclude it, and a tissue diagnosis should always be sought from metastatic tumour. In 10 out of 18 patients in the present series, the diagnosis was established at laparotomy. CT-guided fine needle aspirate is a less invasive alternative. Once the diagnosis is established on the basis of high marker levels and/or histology from metastatic tumour, there is probably no need to perform an orchiectomy, although the testes should be observed carefully after treatment since the evidence that chemotherapy deals effectively with primary testicular tumours is inconclusive (Fowler and Whitmore, 1981 ; Calvo and Peckham,

References Azzopardi, J. G., Mostofi, F. K. andTheiss, E. A. (1961). Lesions

of testes observed in certain patients with widespread choriocarcinoma and related tumors. American Journal o j Pathology, 38, 207-225.

Fowler, J. E., Vugrin, D., Cvitkovic, E. and Whitmore, W. F. (1979). Sequential bilateral germ-cell tumors of the testis despite interval chemotherapy. Journal of Urology, 122, 421- 425.

Fowler, J. E. and Whitmore, W. F. (1981). Intratesticular germ cell tumors: observations on the effect of chemotherapy. Journal of Urology, 126, 412-414.

Fox, R. M., Woods, R. L., Tattersall, M. H. and McGovern, V. J. (1979). Undifferentiated carcinoma in young men: the atypical teratoma syndrome. Lancet, I, 1316-1318.

Peckham, M. J. (1981). Investigation and staging: general aspects and staging classification; non-seminomas: current treatment results and future prospects. In The Management of Tesficular Tumours, ed. Peckham, M. Pp. 89-101 and 218-239. London: Arnold.

Pugh, R. C. B. (1976). Testicular tumours-introduction. In Pathology of the Testis, ed. Pugh, R. C. B. Pp. 139-159. Oxford, London, Edinburgh, Melbourne : Blackwell.

Skakkebaek, N. E. (1978). Carcinoma in situ of the testis: frequency and relationship to invasive germ-cell turnours in infertile men. Hisropathology, 2, 157-170.

The Authors S. Powell, MB, BS, Senior House Officer in Radiotherapy,

W. F. Hendry, ChM, FRCS, Consultant Urologist. M. J. Peckham, MD, MRCP, FRCP(G), FRCR, Professor of

Hammersmith Hospital, London.

Radiotherapy.

Requests for reprints to: M. J. Peckham, Division of Radio- therapy, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PX.