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Leydig Cell Tumor

Definition

Sex cord stromal tumor composed of or recapitulating steroid producing Leydig cells.

Clinical Features

Gross Pathology

  • Generally:
    • small (average size 3 cm) sharply delimited solid nodule within the testis
    • brown color (one of its most distinguishing features) (Figs 1 and 2
      Gross appearance of Leydig cell tumor. The tumor, which has replaced most of the testis, has a granular yellowish appearance.

      Fig. 1: Gross appearance of Leydig cell tumor. The tumor, which has replaced most of the testis, has a granular yellowish appearance.

      Gross appearance of Leydig cell tumor. This tumor, occurring in a child, is solid, well circumscribed, and dark brown.

      Fig. 2: Gross appearance of Leydig cell tumor. This tumor, occurring in a child, is solid, well circumscribed, and dark brown.

      )
  • Rarely outside testis proper6

Malignant Leydig Cell Tumor

  • Larger than benign variety (average size 7.5 cm)
  • More commonly infiltrative

Histopathology

  • Tumor cells:
    • well-defined outlines
    • deeply acidophilic cytoplasm (occasionally clear) (Figs 3 and 4
      Leydig cell tumor of testis. The neoplasm is characterized by solid growth of polygonal cells with abundant granular acidophilic cytoplasm.

      Fig. 3: Leydig cell tumor of testis. The neoplasm is characterized by solid growth of polygonal cells with abundant granular acidophilic cytoplasm.

      Leydig cell tumor of testis. The tumor cells have a cytoplasmic clear quality, reminiscent of that seen in tumors of the adrenal cortex.

      Fig. 4: Leydig cell tumor of testis. The tumor cells have a cytoplasmic clear quality, reminiscent of that seen in tumors of the adrenal cortex.

      )
    • round or oval (occasionally grooved) nucleus
    • sometimes:
      • plasmacytoid appearance
      • lipochrome pigment
      • Reinke's crystalloids (well demonstrated with Masson's trichrome stain)
    • may be:
      • marked variation in size and shape
      • bizarre forms with giant nuclei
    • ultrastructurally:
      • abundant smooth endoplasmic reticulum and mitochondria with tubulovesicular cristae7 (Fig. 5
        Ultrastructural appearance of Leydig cell tumor. These steroid-producing cells contain prominent smooth endoplasmic reticulum. Cytoplasmic microvilli fill the intercellular space. (Courtesy of Dr JH Lin, East Meadow, NY)

        Fig. 5: Ultrastructural appearance of Leydig cell tumor. These steroid-producing cells contain prominent smooth endoplasmic reticulum. Cytoplasmic microvilli fill the intercellular space. (Courtesy of Dr JH Lin, East Meadow, NY)

        )
      • rarely, Reinke's crystalloids (Fig. 6
        Ultrastructural appearance of Leydig cell tumor. Numerous Reinke's crystalloids are seen in the cytoplasm of a tumor cell. (Courtesy of Dr JH Lin, East Meadow, NY)

        Fig. 6: Ultrastructural appearance of Leydig cell tumor. Numerous Reinke's crystalloids are seen in the cytoplasm of a tumor cell. (Courtesy of Dr JH Lin, East Meadow, NY)

        )
      • occasionally, reminiscent of fetal-type Leydig cells8
    • Growth pattern:
      • generally solid
      • may be trabecular, myxoid, pseudofollicular, and microcystic formations9,10 (Fig. 7
        Leydig cell tumor with myxoid features.

        Fig. 7: Leydig cell tumor with myxoid features.

        )
    • Occasionally:
      • prominent spindling of tumor cells
      • metaplastic ossification
      • adipose metaplasia11–13

Special Stains and Immunohistochemistry

Differential Diagnosis

Nodular Leydig Cell Hyperplasia

  • As seen in cryptorchid testes and other conditions
  • Distinction is made on the basis of:
    • size (>0.5 cm for tumors)
    • nodular hyperplasia is characteristically multiple
    • true Leydig cell tumors are not accompanied by hyperplasia of Leydig cells in the remaining testis21

Large Cell Calcifying Sertoli Cell Tumor

  • May have a component with a Leydig cell-like appearance

Testicular ‘Tumor’ of the Adrenogenital Syndrome

  • Perhaps the most important and difficult differential diagnosis
  • Usually discovered during early adult life as a palpable mass
  • In children tends to be smaller and found incidentally
  • The adrenogenital syndrome is ‘salt-forming type’ in two-thirds
  • Testicular masses are:
    • usually bilateral and at the hilum
    • well-circumscribed brown–green masses separated into lobules by prominent fibrous bands17
    • microscopically, sheets, nests, and cords of cells with abundant eosinophilic cytoplasm (Fig. 8
      So-called ‘testicular tumor’ of the adrenogenital syndrome. Multiple nodules are present, having an appearance compatible with adrenal cortical origin.

      Fig. 8: So-called ‘testicular tumor’ of the adrenogenital syndrome. Multiple nodules are present, having an appearance compatible with adrenal cortical origin.

      ) that may contain lipochrome pigment, but no Reinke's crystalloids
  • Most important features in differential diagnosis:

Genetics

  • An activating mutation of the gene encoding luteinizing hormone receptor detected in one case23
  • Compared with the non-metastasizing tumors, metastasizing Leydig cell tumors have:
    • a higher MIB-1 index
    • a much higher incidence of aneuploidy24,25

References

1 Sugimura J, Suzuki Y, Tamura G, Funaki H, Fujioka T, Satodate R. Metachronous development of malignant Leydig cell tumor. Hum Pathol. 1997;28:1318–1320.

2 Dieckmann KP, Loy V. Metachronous germ cell and Leydig cell tumors of the testis. Do testicular germ cell tumors and Leydig cell tumors share common etiologic factors? Cancer. 1993;72:1305–1307.

3 Freeman DA. Steroid hormone-producing tumors of the adrenal, ovary, and testes. Endocrinol Metab Clin North Am. 1991;20:751–766.

4 Gabrilove JL, Nicolis GL, Mitty HA, Sohval AR. Feminizing interstitial cell tumor of the testis. Personal observations and a review of the literature. Cancer. 1975;35:1184–1202.

5 Mahon FB, Gosset F, Trinity RG, Madsen PO. Malignant interstitial cell testicular tumor. Cancer. 1973;31:1208–1212.

6 Maurer R, Taylor CR, Schmucki O, Hedinger CE. Extratesticular gonadal stromal tumor of the testis. A case report with immunoperoxidase findings. Cancer. 1980;45:985–990.

7 Sohval AR, Churg J, Gabrilove JL, Freiberg EK, Katz N. Ultrastructure of feminizing testicular Leydig cell tumors. Ultrastruct Pathol. 1982;3:335–345.

8 Ekfors TO, Martikainen P, Kuopio T, Malmi R, Nurmi MJ. Ultrastructure and immunohistochemistry of a fetal-type Leydig cell tumor. Ultrastruct Pathol. 1992;16:651–658.

9 Billings SD, Roth LM, Ulbright TM. Microcystic Leydig cell tumors mimicking yolk sac tumor: a report of four cases. Am J Surg Pathol. 1999;23:546–551.

10 Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol. 1985;9:177–192.

11 Balsitis M, Sokal M. Ossifying malignant Leydig (interstitial) cell tumour of the testis. Histopathology. 1990;16:599–601.

12 Santonja C, Varona C, Burgos FJ, Nistal M. Leydig cell tumor of testis with adipose metaplasia. Appl Pathol. 1989;7:201–204.

13 Ulbright TM, Srigley JR, Hatzianastassiou DK, Young RH. Leydig cell tumors of the testis with unusual features: adipose differentiation, calcification with ossification, and spindle-shaped tumor cells. Am J Surg Pathol. 2002;26:1424–1433.

14 Gulbahce HE, Lindeland AT, Engel W, Lillemoe TJ. Metastatic Leydig cell tumor with sarcomatoid differentiation. Arch Pathol Lab Med. 1999;123:1104–1107.

15 Kurman RJ, Andrade D, Goebelsmann U, Taylor CR. An immunohistological study of steroid localization in Sertoli-Leydig tumors of the ovary and testis. Cancer. 1978;42:1772–1783.

16 Czernobilsky H, Czernobilsky B, Schneider HG, Franke WW, Ziegler R. Characterization of a feminizing testicular Leydig cell tumor by hormonal profile, immunocytochemistry, and tissue culture. Cancer. 1985;56:1667–1676.

17 McLaren K, Thomson D. Localization of S-100 protein in a Leydig and Sertoli cell tumour of testis. Histopathology. 1989;15:649–652.

18 Augusto D, Leteurtre E, de la Taille A, Gosselin B, Leroy X. Calretinin: a valuable marker of normal and neoplastic Leydig cells of the testis. Appl Immunohistochem Mol Morphol. 2002;10:159–162.

19 Busam KJ, Iversen K, Coplan KA, Old LJ, Stockert E, Chen YT, et al. Immunoreactivity for A103 and antibody to Melan-A (Mart-1) in adrenocortical and other steroid tumors. Am J Surg Pathol. 1998;22:57–63.

20 McCluggage WG, Shanks JH, Whiteside C, Maxwell P, Banerjee SS, Biggart JD. Immunohistochemical study of testicular sex cord-stromal tumors, including staining with anti-inhibin antibody. Am J Surg Pathol. 1998;22:615–619.

21 Grem JL, Robins HI, Wilson KS, Gilchrist K, Trump DL. Metastatic Leydig cell tumor of the testis. Report of three cases and review of the literature. Cancer. 1986;58:2116–2119.

22 Knudsen JL, Savage A, Mobb GE. The testicular ‘tumour’ of adrenogenital syndrome—a persistent diagnostic pitfall. Histopathology. 1991;19:468–470.

23 Liu G, Duranteau L, Carel JC, Monroe J, Doyle DA, Shenker A. Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med. 1999;341:1731–1736.

24 Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM. Leydig cell tumor of the testis: a clinicopathologic, DNA content and MIB-1 comparison of nonmetastasizing and metastasizing tumors. Am J Surg Pathol. 1998;22:1361–1367.

25 McCluggage WG, Shanks JH, Arthur K, Banerjee SS. Cellular proliferation and nuclear ploidy assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell tumours. Histopathology. 1998;33:361–368.

26 Bercovici JP, Nahoul K, Ducasse M, Tater D, Kerlan V, Scholler R. Leydig cell tumor with gynecomastia. Further studies—the recovery after unilateral orchidectomy. J Clin Endocrinol Metab. 1985;61:957–962.

Last updated: 30 Mar 2006

Leydig Cell Tumor

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