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Crouching tiger, hidden dragon
  1. Daniel Hopkins,
  2. Murali Varma
  1. Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK
  1. Correspondence to Dr Murali Varma, Department of Histopathology, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK; varmam{at}Cardiff.ac.uk

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Clinical question

A 34-year-old man presented with a history of bilaterally undescended testes since birth. A bilateral orchidectomy was performed. Macroscopic examination of the specimen demonstrated multiple pale nodules within both testes, the largest of which measured 3 mm in diameter.

Review the high-quality, interactive digital Aperio slide at http://virtualacp.com/JCPCases/jclinpath-2017-204691/ and consider your diagnosis.

What is your diagnosis?

  1. Germ cell neoplasia in situ (GCNIS)

  2. Leydig cell hyperplasia

  3. Seminoma

  4. Sertoli cell nodule

  5. Sertoli cell tumour

Discussion

The submitted section demonstrates features of cryptorchidism, with marked hyalinisation of the tubular basement membrane, germ cell atrophy and Leydig cell hyperplasia (figure 1A,B). Most of the seminiferous tubules are lined only by Sertoli cells. However, there are also multiple small nodular aggregates of Sertoli cells that correspond to the macroscopically described abnormality (figure 1A,C,D). These have been occasionally referred to by the misnomer ‘Pick’s Adenomas’ but have been shown to be polyclonal and best referred to as Sertoli cell nodules.

Figure 1

The testis (A) shows germ cell atrophy with basement membrane thickening and Leydig cell hyperplasia in keeping with cryptorchidism (B) as well as Sertoli cell nodules (C,D). (A–D: H&E).

On low-power examination some of the atrophic tubules contain peripherally located cells with clear cytoplasm that on closer examination show cytological atypia with prominent nucleoli (figure 2). This represents in situ malignancy that has been referred to as ‘carcinoma in situ’ or ‘intratubular germ cell neoplasia’. However, these cells are germ cells rather than epithelial cells and are located adjacent to the basement membrane rather than within the tubules. Hence, the preferred terminology adopted by WHO 2016 is GCNIS.1 2 Like invasive germ cell tumours, GCNIS is characterised by isochromosome 12p abnormality and despite its morphological similarity to seminoma cells is recognised as the precursor of most malignant germ cell tumours. In contrast, absence of GCNIS is a diagnostic feature of spermatocytic tumour, prepubertal-type testicular teratoma and prepubertal type yolk sac tumour. Intratubular spread of germ cell tumour that is commonly seen in spermatocytic tumour is characterised by tumour cells filling tubular lumina and should not be confused with GCNIS.

Figure 2

Some atrophic tubules contain peripherally located cells with clear cytoplasm and cytological atypia with prominent nucleoli (A–D) that on immunostaining are immunoreactive for PLAP (E) and OCT3/4 (F), confirming diagnosis of germ cell neoplasia in situ (GCNIS). GCNIS may be closely mimicked by vacuolated germ cells that lack cytological atypia and are immunonegative for PLAP and OCT3/4 (G–I). (A–D: H&E; E: PLAP; F: OCT3/4; G–H: H&E; I: OCT3/4).

As compared with benign Sertoli cells, nuclei of GCNIS are larger and hyperchromatic with more prominent nucleoli. The immunoprofile of GCNIS is like seminoma (positive for PLAP, c-KIT and OCT3/4) (figure 2E,F). However, c-KIT should not be used to confirm diagnosis of GCNIS as it may be expressed by benign seminiferous cells. Vacuolated germ cells can closely mimic GCNIS on low-power but lack cytological atypia and are immunonegative for PLAP and OCT3/4 (figure 2G–I). OCT3/4 is now generally accepted as the most sensitive marker for seminoma and embryonal carcinoma; yolk sac tumours are OCT3/4-negative.

Patchy lymphocytic chronic inflammation is noted within the intertubular testicular stroma, and careful examination demonstrates clustered and individual atypical large cells associated with this inflammation. The cells show clear cytoplasm and hyperchromatic nuclei with prominent nucleoli (figure 3). These cells showed positive immunohistochemical staining for PLAP, c-KIT (CD117) and OCT3/4 (figure 3E,F). The final diagnosis is seminoma with a pure intertubular (interstitial growth) pattern. WHO 2016 has adopted the nomenclature ‘spermatocytic tumour’ for tumours previously designated ‘spermatocytic seminoma’ so it is not necessary to use the prefix ‘classical’ for the more common seminomatous germ cell tumour.1

Figure 3

Testis (A) also shows foci of chronic inflammation containing individual atypical large cells with clear cytoplasm and hyperchromatic nuclei with prominent nucleoli (B–D) that are immunoreactive for OCT3/4 (E–F), confirming diagnosis of intertubular pattern seminoma. Invasive tumour is particularly difficult to identify when obscured by Sertoli cell nodules (G), inflammation (H) or Leydig cells (I). (A–D: H&E; E–F: OCT3/4; G–I: H&E).

Correlating microscopic findings with macroscopy is a well-recognised axiom in histopathology, but one should always watch out for dual pathology. While the crouching tiger (Sertoli cell nodule) is readily identified, the invasive seminoma camouflaged by lymphocytes and Leydig cells could represent the hidden dragon that may seriously burn the fingers of an unwary pathologist. Cryptorchidism is associated with an increased incidence of both Sertoli cell nodules and germ cell tumours so this dual pathology is not coincidental.

An intertubular or interstitial growth pattern is a characteristic feature of lymphoma or metastatic tumour involving the testis. This growth pattern is not uncommonly seen at the edge of a usual mass forming seminoma, but seminoma with a pure intertubular (interstitial) growth pattern is rare with only about 13 cases reported to date in the English literature.3 4 The latter does not present as a testicular tumour and may be discovered during investigation of infertility, pain or metastatic disease with no distinct tumour apparent on radiological or gross examination. Intertubular seminoma can be particularly difficult to identify in cryptorchid testis, where the tumour cells are obscured by hyperplastic Leydig cells (figure 3I).

An important clue to the diagnosis is the association with patchy chronic inflammation,3 although this may also somewhat mask the tumour cells (figure 3H). The identification of areas of chronic inflammation within the interstitium of a cryptorchid testis should prompt closer examination and consideration of immunohistochemistry if any atypical cells are identified. The clinical significance of intertubular growth pattern in a grossly evident seminoma is uncertain but could result in underestimation of tumour size and therefore inaccurate staging. It has been suggested by Browne et al5 that intertubular growth pattern seminoma may also indicate an increased risk of rete testis involvement.

Identification of pure intertubular seminoma is important as it may be associated with metastasis and hence mandates radiological staging and appropriate follow-up.

Answer

C. Seminoma (with pure intertubular (interstitial) growth pattern).

Take home messages

  • Cryptorchidism is associated with Sertoli cell nodules and germ cell neoplasia.

  • An interstitial (intertubular) growth pattern is the characteristic feature of lymphoma or metastatic tumour involving the testis, but rarely seminoma may not present as mass forming tumour and show an exclusively interstitial growth pattern.

  • Malignant cells of pure interstitial pattern seminoma are easily missed, especially when associated with lymphoid or Leydig cells.

  • WHO 2016 nomenclature for precursor lesion of germ cell tumours is ‘Germ Cell Neoplasia In-Situ (GCNIS)’.

  • Vacuolated germ cells can closely mimic GCNIS on low-power but lack cytological atypia and are immunonegative for PLAP and OCT3/4.

References

View Abstract

Footnotes

  • Handling editor Iskander Chaudhry

  • Contributors The case was identified by MV. Both authors contributed equally to writing the manuscript.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Provenance and peer review Commissioned; internally peer reviewed.

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