“Misleading features of a testicular tumour”

Authors of the case: 
Rokas Stulpinas MD; Consultant: Ugnius Mickys MD

BACKGROUND
A 43 year old male patient was admitted to the urology department complaining of a painless lump (size 3x3 cm) in his left testicle. The lump had a heterogeneous appearance on ultrasound and a tumour was suspected, but due to the history of a possible previous trauma, the decision was made to perform a partial resection ("biopsy") instead of orchiectomy and a fragment 0,9x0,7x0,4 cm of brownish tissue was removed and sent for examination. It was not specified whether this tumour was in the testicular parenchyma itself, in the epididymal tissues or in the coverings.

HISTOLOGY
The tumor is composed of a hypocellular collagenous stroma and solid, nested, serpentine, trabecular structures (with scant small tubule formation and lumina containing homogenous eosinophilic secretions) of small to medium calibre cells with pale eosinophilic, finely vacuolated cytoplasm and monotonous centred round nuclei with a small peripheral nucleolus, finely dispersed chromatin and unidentifiable mitotic activity. There are few medium sized veins in the stroma. No normal testicular parenchyma is present.

FIRST THOUGHTS
Usually, when an indolent epithelioid testicular tumour (most probably primary) is seen in a middle aged patient, sex cord – stromal tumour group is the first one to turn to. Hence, an initial array of immunohistochemistry stains was ordered:

PanCytokeratin – negative;
Inhibin – negative;
Calretinin – negative;
CD99 (+/++) 90% membranous reaction; 
MelanA – negative;
Beta-Catenin (+++) 100% nuclear and cytoplasmic reaction; 
Ki67 proliferative activity ~1% (0.987% using Aperio “Nuclear v9” algorithm).

INTERMISSION
Leydig cell tumours account for 1-2% of all testicular tumours and are the most common neoplasms in the sex cord-stromal group, but PanCytokeratin, lnhibin, Calretinin are typically positive in these cases and nuclear Beta-Catenin is usually absent. Both WHO Classification and Pathology Outlines mention a usual positivity for MelanA clone A103 only (and this specific clone is used in our lab).
Sertoli cell tumours are the second most common testicular sex cord- stromal tumours, which (according to WHO Classification) “most often show a nodular growth of tubules in a scant but occasionally more abundant stroma. The tubules vary from round and hollow to solid and elongated, and from small to large and cystically dilated. A diffuse growth of cells is much less common, but when seen, may be traversed by fibrous septa. Nests, cords, clusters, and (rarely) individual cells may be seen.” This is not exactly the picture we see in our case and also lnhibin is usually positive in about 50% of these tumours; PanCytokeratin, Calretinin are also typically positive. What is interesting is that Sertoli cell tumours are positive for nuclear Beta-catenin in 60-70% of cases, which we clearly have.
As CD99 was the only typical positive “sex-cord” marker, additional stains were ordered to clarify the case and exclude other malignancies.

EXPANDED IMMUNOHISTOCHEMISTRY
Vimentin(+++) 100% cytoplasmic reaction; 
SF1(+) 95% cytoplasmic (and possible nuclear?) reaction; 
CD56(+) 30% weak, intermittent membranous reaction; 
S100(+) 30% weak heterogeneous cytoplasmic reaction; 
EMA(+/-) 30% uncertain reaction, barely distinct from background; 
Synaptophysin(++) 5% focal cytoplasmic reaction (in a corner of the sample); 
CD34(-), Cam5.2(-), SMA(-), PLAP(-), Desmin(-), SALL4(-), Pax8(-), OCT4(-), HMB45(-), ChromograninA(-).

PROPOSED DIAGNOSIS AND EPILOGUE
Histologic pattern and immunophenotype are not entirely typical, but most closely resemble a Sertoli cell tumour. No criteria for malignant behaviour (size >5cm, extratesticular spread (must be excluded clinically!), prominent cytological atypia, necrosis, high mitotic activity, lymphovascular invasion) are present. 
The case was uploaded to INCTR iPath (https://www.ipath-network.com/ipath/object/view/1053695) and reviewed by Prof. em. Klaus Dietmar Kunze (University Hospital Dresden Germany, Institute for Pathology), who commented: 
“I agree with you and prefer the diagnosis of a mixed testicular sex cord stromal tumour with predominant features of a Sertoli cell tumour and annular tubules.”
I would tend to disagree with the term of “mixed” tumour as only the epithelioid component is clearly identifiable with no stromal counterpart. In this case a term of “unclassified sex cord tumour” could be more appropriate, as WHO lists them under such a description: “The unclassified tumours have variable components of epithelial cells of sex cord type with patterns that do not end themselves to subclassification as Sertoli or granulosa cell tumour. There is often conspicuous fibrous stroma. Their immunohistochemical profile parallels that of Sertoli or granulosa cell tumours, but unclassified tumours may be less positive for typical sex cord-stromal markers”.
Sex cord tumor with annular tubules (SCTAT) is a distinctive neoplasm with indifferent cells of sex cord derivation in a characteristic arrangement of ring-like tubules. SCTAT has also been placed under an "unclassified sex cord-stromal" category in the World Health Organization (WHO) Classification of ovarian tumours (and is not listed among testicular tumours at all).
So, it seems that a specific formulation of diagnosis remains a matter of personal decision, but a term of “unclassified sex cord tumour with predominant features of a Sertoli cell tumour” is a fine consenssus in this case.
As orchiectomy is treatment of choice (and usually sufficient) in such a case, this procedure will soon be performed with simultaneous implantation of a testicular prosthesis.

1. WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4^th ed. 2016
2. WHO Classification of Tumours of Female Reproductive Organs, 4^th ed. 2014
3. A Contemporary Review of Common Adult Non-germ Cell Tumours of the Testis and Paratestis. Mooney KL, Kao CS. Surg Pathol Clin. 2018 Dec;11(4):739-758. doi: 10.1016/j.path.2018.07.002. Epub 2018 Oct 17.
4. A testicular tumor resembling the sex cord with annular tubules in a case of the androgen insensitivity syndrome. Ramaswamy G, Jagadha V, Tchertkoff V. Cancer. 1985 Apr 1;55(7):1607-11.
5. http://www.pathologyoutlines.com