retrogression in testicular seminoma viable metastases · retrogression in testicular seminoma with...

J. clin. Path. (1965), 18, 135

Retrogression in testicular seminoma withviable metastases

J. G. AZZOPARDI AND A. V. HOFFBRAND

From the Depairtment of Morbid Anatomy, Postgraduate Medical School ofLondon

SYNOPSIS Stages in the retrogression of testicular seminoma are described. Eosinophilic necrosisfringed by palisaded histiocytes may be followed by fibrous replacement. Oxidation of unsaturatedphospholipids in necrotic tumour may lead to deposition of lipofuscin around the lesion. Searchfor partially or completely scarred lesions is essential before contemplating a diagnosis of primaryretroperitoneal seminoma.

Retrogressed seminoma can often be distinguished from retrogressed teratoid tumours. Appar-ently paradoxical teratoid metastases in association with a testicular seminoma are explained on thebasis of misinterpreted retrogressed teratoid tumours in association with the seminoma.

Inguinal node metastases from testicular seminoma may be the result of abnormal lymphaticdrainage following previous scrotal operations, testicular torsion etc.

Testicular scars representing a fibrosed source oforigin of extragenital chorioncarcinoma and otherteratomatous metastases have been recognized sincePrym's (1927) description. Stowell, Sachs, andRussell (1945), however, when reporting one of themost thoroughly documented instances of primaryextragenital chorioncarcinoma, disputed the signifi-cance of these testicular scars, and Lynch andBlewett (1953) went so far as to suggest that thescars themselves might be the consequence ofprimary extragenital growths. The speculative viewof the latter workers has been quoted by others(e.g., Ainsworth and Gresham, 1960). Azzopardi,Mostofi, and Theiss (1961), on the basis of 17 casesin the files of the Armed Forces Institute ofPathology, Washington, D.C., strongly supportedthe contention that testicular scars can representsites of fibrosed primary gonadal tumours and drewattention to the significance of haematoxyphildeposits in the seminiferous tubules in retrogressedtesticular teratoid neoplasms. They cautioned againstan uncritical acceptance of cases of allegedly primaryextragenital, and especially retroperitoneal, embry-onal carcinoma and chorioncarcinoma. Thatretrogression with scarring occurs also in testicularseminoma is not generally appreciated.The purpose of this paper is to report a case

illustrating the pattern of regression in a testicularseminoma accompanied by viable metastases and todiscuss the implications of these findings.

Received for publication 19 June 1964.

CASE HISTORY

E.H., a man aged 45, a civil engineer, noticed swelling ofthe left leg three days before admission to hospital inJuly 1963. The leg throbbed and gradually became morepainful. On the night before admission he had an episodeof shortness of breath lasting 10 minutes. The onlyrelevant past history was painful swelling of the left testisin 1961 which, according to the patient, was caused by'orchitis': this was said to have been treated by manipula-tion after which the pain subsided. In view of this and thesubsequent findings, this might well have been atesticular torsion.On examination, the patient was a well-built man with

a mild pyrexia up to 100°F. and a rapid, regular pulse; hisblood pressure was 120/70 mm.Hg, he had a normaljugular venous pressure, and no abnormalities werefound in the cardio-respiratory systems. Abdominal andrectal examination was normal. No abnormal neuro-logical signs were present. The left leg was swollen, redand hot. Peripheral pulses were palpable on both sides.In the left inguinal region there was a mass of enlargedlymph nodes which were not tender. The left spermaticcord was thickened and the epididymis felt harder thanits opposite number. The left testis felt normal but waspossibly slightly reduced in size. No abnormality of theright scrotal contents was detected. He was thought tohave a deep vein thrombosis in the left leg due to femoralvein pressure associated with the mass in the left groin.Tuberculosis and neoplasm were considered as potentialcauses of the genital lesion.Haemoglobin was 13 2 g./100 ml., white blood count

15,000/c.mm. with 84% polymorphs, E.S.R. (Westergren)23 mm./hour. The blood urea level was 24 mg. %, and theWassermann and Kahn reactions were negative. No acid-

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J. G. Azzopardi and A. V. Hoffbrand

fast bacilli were seen in the urine and no tubercle bacillifound on culture. A chest radiograph was normal, as wasan E.C.G.The patient was treated with bed rest, anticoagulants,

and antibiotics; the pain and swelling in the legdiminished. On 20 August an excision biopsy of aninguinal lymph node was carried out and, as the left cordwas thickened and hard, a left orchidectomy wasperformed with removal of the spermatic cord. He made agood post-operative recovery and was discharged on30 August. On 16 September the left leg was found to beswollen again and the left inguinal nodes were palpable.In view of the pathological findings (see below) he wasgiven a course of radiotherapy on a Cobalt machine,treating the left groin and iliac fossa with an incident doseof 6,000 r over 24 days; the lumbar region received anincident dose of 3,600 r through an anterior field over thesame period. When seen on 21 December 1963 he hadimproved and was feeling well.

PATHOLOGY

INGUINAL LYMPH NODE This was received in twofragments, the larger measuring 2-5 x 1 5 x 1P0 cm.The node is largely replaced by metastatic seminoma(Figs. 1 and 2). There is a histiocytic granulomatousreaction in the stroma of the type frequentlyassociated with seminoma. Staining with Best'scarmine reveals abundant glycogen in the tumourcells, a feature of the classical variety of seminoma.

ORCHIDECTOMY SPECIMEN This consists of the lefttestis, 4 x 2-5 x 2 5 cm., and the spermatic cord,6 x 1-5 x 10 cm. There is fibrous thickening of thetunica vaginalis. On section the testis is firm, fibrousand white. On its posterior aspect, slightly to oneside of the rete, there is a group of circular, yellowamorphous areas up to 0 5 cm. diameter and togetherinvolving an area 1-4 x 0-8 cm. On serial section ofthis zone it measures 2 to 3 mm. in depth.Numerous blocks show fibrosis and hyalinization

of the testicular parenchyma with only occasional,barely visible ghosts of seminiferous tubules. Theepididymis shows slight tubular atrophy andmoderate interstitial fibrosis with occasional lymph-oid foci; it is firmly bound to the testis. The caputis relatively well preserved as is the appendixepididymis. There is dense fibrosis around the vasdeferens.The most significant findings are in the block

containing the yellow amorphous foci. In addition tofibrosis this contains irregular areas of eosinophilicnecrotic tissue (Fig. 3): these foci vary in numberfrom two to six at different levels. On closer inspec-tion each focus is found to consist of closely aggre-gated, large, rounded, degenerate tumour cells whichhave lost their nuclear staining, a feature commonly

if-WWrw'I''&'. *7FIG. 1. Metastatic seminoma in lymph node with histio-cytic stromal reaction best seen at the top. Haemalum andeosin x 120.

FIG. 2. Higher magnification of tumour cells in lymphnode. Large nucleoli and a punctate chromatin pattern arevisible. Haemalum and eosin x 750.

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Retrogression in testicular seminoma with viable metastases

FIG. 3. FIG. 4.

FIG. 3. Foci of eosinophilicnecrotic tissue containingclefts of cholesterol esters.Calcification has resulted inthe artefactual line acrossthe photograph. Haeinalumand eosin x 38.

FIG. 4. Edge of necroticfocus showing outlines ofindividual degeneratetumour cells. Massontrichrome x 370.

FIG. 5. Palisade ofhistiocytes and fibrohlastsat edge of necrotic seminoma.Heidenhain's azocarminex 100.

FIG. 5.

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seen in the necrotic areas of seminoma. The obscuredcytological details are rendered a little clearer bystaining with Masson's trichrome (Fig. 4). Serialsections, staining every fourth slide, show noevidence of viable seminoma. The necrotic focihave sharp edges and are ringed by a layer ofhistiocytes and fibroblasts which tend to a perpen-dicular orientation (Fig. 5), the whole appearance ata low magnification bearing a superficial resembl-ance to a subcutaneous rheumatoid nodule (Fig. 3).Occasional foamy macrophages, lymphocytes, anda few plasma cells complete the composition of thecellular infiltrate. Many of the arteries around thenecrotic foci show marked intimal fibrous thickening.

In paraffin sections, the necrotic tissue stainsmoderately deeply with Sudan black B and isnegative with P.A.S.: this indicates its phospholipidcontent. Since a small amount of phospholipid ispresent in the viable metastatic seminoma, thephospholipid at the site of the primary tumour mayrepresent a concentration of intrinsic phospholipidby removal of protein, glycogen, and other moresoluble constituents. It is not possible, however, toexclude the addition of phospholipid to the necroticmaterial from extraneous sources.

Haematoxyphilic deposits are present in largemasses in the centre and in smaller aggregates at theedges of the necrotic foci. The Feulgen reaction isnegative; the absence of deoxyribonucleic acid is notsurprising in view of the ease with which it appearsto be removed from necrotic seminomatous tissue.Calcium carbonate or phosphate is present in thehaematoxyphilic deposits as demonstrated bynaphthochrome green B and Von Kossa; thesestains also show a fine sprinkling of calcium saltsin the necrotic tissue as a whole. A haematoxyphilicreaction has often been erroneously attributed tocalcium salts when it is in fact caused by substanceslaid down before or together with calcium (Azzo-pardi, 1959). In the present case large amounts ofmucopolysaccharide are present in the haematoxy-phil deposits as shown by Southgate mucicarmineand by Alcian green, provided nuclear counterstainsare omitted in both methods so as not to obscurethe red or green staining. A small amount ofgreenish-yellow pigment, probably haematoidin, ispresent in one necrotic zone.The histiocytes bordering the necrotic foci (Fig. 6)

give a strongly positive Sudan black reaction and apositive P.A.S. reaction. On close inspection of thehaemalum-eosin sections, these cells are found tocontain a finely granular, pale yellow pigment. Thiscontains no stainable iron and the suspicion that itmight be lipofuscin is confirmed by the golden-yellow autofluorescence in ultra-violet light. Thepigment is also acid-fast and identifiable as lipo-

FIG. 6. Histiocytes containing finely granular lipofuscin.Haemalurm and eosin x 370.

fuscin of ceroid type. A very small amount ofhaemosiderin is present in histiocytes adjacent to oneof the necrotic foci.

DISCUSSION

This case illustrates the stages in the regression of aprimary testicular seminoma. Necrosis of tumourresults in accumulations of ghosts of neoplastic cellsin which cytological detail is lost and specificnuclear staining no longer possible. The degeneratedtissue excites a histiocytic reaction at the periphery.Cholesterol and its esters may appear in the necrotictumour and foam cells may be seen in the peripheralreactive zone. More important is the presence ofphospholipid in the necrotic tumour; auto-oxidationof unsaturated fatty acids of phospholipids leads tothe appearance of a lipofuscin pigment, of ceroidtype, in the histiocytes fringing the necrosis. In theabsence of specific staining, this pigment is easilymistaken for haemosiderin. Beyond the histiocyticzone there is a band of dense fibrosis. In someinstances, possibly because of the large quantity ofnecrotic tissue and its high fat content, necrotic

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tumour may remain for long periods of time andbecome calcified. In other cases necrotic tumour maybe completely removed with loss of the more specificfeatures and replacement by a fibrous scar ofvariable size. In the case reported here, it is possiblethat the episode of probable testicular torsionsuffered by the patient at an earlier date may havebeen an important factor in precipitating tumournecrosis. It must, however, be stressed that torsionis by no means an essential prelude to regression oftesticular seminoma. In other cases seen by one of

us and summarized in Table I, there was no indica-tion of torsion in the clinical histories and inthese patients the scarring and necrosis did notinvolve the entire testis but was limited to a part ofthe gonad. While radiotherapy might possibly havecontributed to the scarring of the testicular lesionsin some of these patients, it certainly was notresponsible in cases 4 and 6 who had palliativetreatment only.Because of these findings, great caution is

necessary before making a diagnosis of primary

Case Age (yr.) Clinical PresentationNo. and Findings

TABLE 1

SUMMARY OF OTHER CASES

Operative or Necrops*y Macroscopic Finding'Findings, Progress and in TestisTherapy

Histology of Testisand Metastases

Additional Data andComment

42 Pain left flank with Massive retroperitoneal Large dense scar

radiation to groin and node involvement; affecting about 2/3 oftestis. T.V.P. showed L. nephrectomy and cut surface. Specimengross L. hydronephrosis nodal excision; radio- step-sectioned

therapy. A ?metastatic seminoma.L. orchidectomy.

(a) No special features Histiocytic reactionin testis scar in metastatic(b) Seminoma in lymph seminomanodes and peri-ureterictissue

2 40 Epigastric mass Biopsy: seminoma. Scar, 2 cm. max. diam., (a) At one end of scar,

Radiotherapy to retro- involving mediastinum necrotic focus withperitoneal mass; acicular clefts,indurated area palisaded by foamyL. testis 3 months histiozytes. Pigmentedlater; orchidectomy histiocytes +

Some calcification(b) Seminoma inlymph nodes

3 25 Back pain, loss of Biopsy node: seminoma. Fibrous nodule, 0-3 cm. (a) No special featuresweight, painless mass Radiotherapy to diam., near in testis scar

central abdomen, mediastinal mass; mediastinum L. testis (b) Seminoma inenlarged Virchow nitrogen mustard metastaseslymph node therapy; further

courses radiotherapyand mustard. Necropsy:massive mediastinal andretroperitoneal tumour,metastases in liver,R. adrenal, calvarium,vertebrae

4 30 Low back pain, Necropsy: metastases in Wedge of firm white (a) Densely localized Only palliativeL. lower quadrant para-aortic nodes, tissue, 2 x 2 cm., in scar. Pigmented therapyabdominal pain, fever, lungs, liver, peri- L. testis, equidistant histiocytes +. In one

cough, loss of weight. cardium between the 2 poles and section, minute focusChest radiograph: subcapsular in position of intratubularbilateral lung seminoma with some

metastases extratubular tumourcells. 'G' cells + +I(b) Seminoma withabundant necrosis inmetastases

5 31 Anorexia and weight Nitrogen mustard L. testis mostly fibrous (a) Densely fibrous,loss, visible swelling in therapy. Necropsy: with a small residue of poorly defined scar.

L. upper abdominal mass in region of recognizable 'G' cells +quadrant duodenum, para-aortic parenchyma (b) Seminoma in

and hepatic metastases metastases6 Unknown Anorexia and weight Necropsy: metastases Ill-circumscribed (a) Dense fibrous scar. Only palliative

loss, low back pain, lungs, liver, nodes, etc. greyish mass replacing Necrotic focus with therapyswelling L. neck, hard upper 2/3 of R. testis 'ghost' cells, acicularmass to R. of umbilicus, and merging with clefts and some D.N.A.mass in R. inguinal residual parenchyma debris. Pigmentedregion. Chest radio- histiocytes +graph: mediastinal mass (b) Seminoma in

metastases"G' cells is an abbreviation for the altered hyperchromatic germ cells, probably spermatogonia, found within seminiferous tubules and possiblyrepresenting the earliest seminoma in situ. They are more fully described in the paper by Azzopardi et al. (1961).

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retroperitoneal seminoma. One cannot postulateorigin in a third testis (Auvert, 1960) unless thetestes are serially sliced and carefully examined.These difficulties apply also to primary extragenitalchorioncarcinoma (Azzopardi et al., 1961). Thisis not to be taken as implying that primary extra-genital chorioncarcinoma in the male does not occur,since there are several well-documented accounts ofprimary tumours of this nature arising in themediastinum (Laipply and Shipley, 1945; Lynch andBlewett, 1953) and in the pineal region. Seminomamay also originate in the anterior mediastinum.The testicular lesion in this case illustrates the

difference between regression and healing ofseminoma and regression in the teratoid group oftumours. Thirteen of 17 teratoid tumours of thetestis (Azzopardi et al., 1961) contained haematoxy-phil deposits in the scar tissue; these formed sharplycircumscribed foci because of their localizationwithin seminiferous tubules and were characterizedby their high D.N.A. content (Fig. 7). Necrosis in

~~~~~~~~~~~~1~~~~~~~~~~P

FIG. 7. Retrogression in teratoid testicular tumour.Purplish granular debris occupies distended seminiferoustubules situated in fibrous scar. This was associated withchorioncarcinomatous metastases. Haemalum and eosinx 38.

seminoma is mainly a feature of extratubular tumourand discrete haematoxyphil deposits are not seen.Previous authors have drawn no distinction betweenretrogression in seminoma and in the teratoidneoplasms of the testis. If only a fibrous scar ispresent in the testis, the nature of the primary tumourcan only be surmised from the character of themetastases. In the presence of intratubular haema-toxyphil deposits, one is justified in diagnosing aretrogressed teratoid tumour. Ghost neoplastic cellsringed by palisaded histiocytes sometimes containinglipofuscin are characteristic of the pattern ofregression in seminoma, but this appearance is notspecific and can be seen occasionally in othertumours. Nevertheless, where the testis containsconglomerates of 'shadow cells' associated with ahistiocytic reaction we can, in the presence ofseminomatous metastases, fairly assume the existenceof a primary testicular seminoma. This view issupported by the present case report, by the othercases (Table I) one of us has had the opportunity ofstudying, and by analysis of a few cases in theliterature. Quenu's (1960) patient had a fibrosedprimary seminoma and cases 2 and 3 of Rather,Gardiner, and Frerichs (1954) are probably of thisnature. Friedman (1951) recognized the occurrenceof healing in testicular tumours. His Figs. 18 and 19,showing necrosis and sclerosis in an unspecifiedtype of testicular tumour, very probably represent aseminoma: there is even a suggestion of palisadedhistiocytes around the lesion.The distinction between the two forms ofregression

has important applications and leads us to disagreewith one of Friedman's fundamental conclusions.Friedman believes that the seminoma is the pre-cursor of the embryonal carcinoma. His mainevidence is that embryonal carcinomatous andchorionepitheliomatous metastases may appearwhen the primary testicular tumour is a 'germinoma',i.e., seminoma. Four germinomas with non-germinomatous metastases studied by the multiple-block method were found by Friedman to be puregerminomas, a finding which might tempt one to theconclusion he draws. However, if one studies hisFig. 22 it shows a good example of a seminomaalongside a retrogressed teratoma and it is lesions ofthe latter type that are responsible for the apparentlyparadoxical character of the metastases. Therecognition of differences between the two types ofregressed testicular tumour has histogenetic implica-tions since it removes one of the main planks for theerroneous belief that seminoma may show transitionto the teratomatous group of tumours.A point of surgical interest in this patient, not

related to the main theme, is the unusual develop-ment of and presentation with inguinal metastases

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from a testicular seminoma. Bowles (1962) hassuggested that where there has been a previousscrotal operation, e.g., on a varicocele, or orchiopexy,a testicular tumour may metastasize to inguinalnodes because of alterations in the lymphaticdrainage. Witus, Sloss, and Valk (1959) reported on

two patients with testicular tumours developingafter orchiopexy that metastasized to inguinal nodesand did not involve the retroperitoneal nodes. In thecase reported here, there was an episode of probabletorsion two years before the last hospital admission.Whatever the precise nature of this episode may havebeen, at orchidectomy the tunica vaginalis was partlyobliterated by firm adhesions; this may well haveresulted in variations in the normal drainage mechan-ism that led to the development of inguinal meta-stases. This case offers some support for Bowles'view of the circumstances in which testicularseminoma may involve the inguinal before thelumbar nodes. This hypothesis needs confirmation ona large series of testicular tumours.

We are grateful to Mr. A. G. Young and Dr. K. A.Misch of the Lister Hospital, Hitchin, for the use of theirclinical data and pathological material, and to Dr. G.Picciotto of Mount Vernon Hospital, Northwood, fordetails of post-operative treatment. We wish to thankProfessor C. V. Harrison and Dr. A. G. E. Pearse for theircriticism, Mr. B. Chalk for technical assistance, and MissS. Lee for typing the manuscript.

REFERENCES

Ainsworth, R. W., and Gresham, G. A. (1960). J. Path. Bact., 79, 185.Auvert, M. J. (1960). J. Urol. med. chir., 66, 800.Azzopardi, J. G. (1959). J. Path. Bact., 78, 513.

, Mostofi, F. K., and Theiss, E. A. (1961). Amer. J. Path., 38, 207.Bowles, W. T. (1962). J. Urol. (Baltimore), 88, 266.Friedman, N. B. (1951). Cancer (Philad.), 4, 265.Laipply, T. C., and Shipley, R. A. (1945). Amer. J. Path., 21, 921.Lynch, M. J. G., and Blewett, G. L. (1953). Thorax, 8, 157.Prym, P. (1927). Virchows Arch. path. Anat., 265, 239.Quenu, L. (1960). J. Urol. med. chir., 66, 861.Rather, L. J., Gardiner, W. R., and Frerichs, J. B. (1954). Stanf. med.

Bull., 12, 12.Stowell, R. E., Sachs, E., and Russell, W. 0. (1945). Amer. J. Path., 21,

787.Witus, W. S., Sloss, J. H., and Valk, W. L. (1959). J. Urol. (Baltimore),

81, 669.

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