Cord-Stromal Tumors

and Pilar González-Peramato2



(1)
Department of Anatomy, Histology and Neuroscience, Universidad Autónoma de Madrid, Madrid, Spain

(2)
Department of Pathology, University Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain

 




Keywords

Testicular neoplasmsSex cord-stromal tumorLeydig cell tumorSertoli cell tumorSertoli cell adenomaCalcifying sclerosing Sertoli cell tumorIntratubular large cell hyalinizing Sertoli cell neoplasiaLarge cell calcifying Sertoli cell tumorGranulosa cell tumorThecomaMyoid gonadal stromal tumor


This category includes tumors that present complete or incomplete differentiation towards Leydig cells, Sertoli cells, granulosa cells, and theca cells. In the prepubertal age, they are the most frequent (25%) of all testicular tumors, but much less frequent in adults (2–5%). These data are probably related to the high incidence of germ cell tumors in adulthood. The most frequent ones are Leydig cell tumors, followed in decreasing order of frequency by Sertoli cell tumors, granulosa cell tumors, unclassified sex cord-stromal tumors, and theca tumors. Cases have been chosen taking into account that they represented all ages, different forms of clinical presentation and different biological behavior. Eight cases of Leydig cell tumor are included, among which there are functioning cases (precocious puberty, gynecomastia, infertility), non-functioning with infrequent morphological findings (bone and adipose metaplasia, microcystic and myxoid patterns, associated with Leydig cell nodular hyperplasia) and with malignant behavior. Eight cases of Sertoli cell tumors (adenoma, NOS, sclerosing, large Sertoli cells with calcifications, intratubular large cell hyalinizing Sertoli cell neoplasia). Three granulosa cell tumors, two juvenile-type with different patterns (follicular and solid) and one adult-type granulosa cell tumor, a fibrothecoma, a myoid gonadal stromal tumor, and three mixed and unclassified sex cord stromal tumors.


3.1 Leydig Cell Tumors



Case 52. Leydig Cell Tumor with Precocious Puberty


Clinical case. An 8-year-old patient who sought consultation for precocious pseudopuberty. During the physical examination, the penis was observed to have increased in size; also an increase in scrotal pigmentation and in the size and the consistency of the left testicle were verified. Serum levels of FSH and LH and adrenal androgens within normal limits. Serum testosterone levels were similar to those of an adult.


Pathological findings. A 1.1-cm oval yellowish tumor, moderately defined from the adjacent testicular parenchyma, located in the vicinity of the rete testis. It consists of polyhedral cells, eosinophilic cytoplasm with spherical nucleus, eccentric, without mitosis. Some nuclei are larger and show marginalization of the chromatin and ground-glass appearance. In the cytoplasm of some cells, we find two types of spherical, eosinophilic inclusions that correspond to concentric laminar formations of smooth and elongated endoplasmic reticulum suggesting Reinke crystals. The seminiferous tubules located around the tumor have an advanced pubertal maturation, which contrasts with the prepubertal aspect of the more distant parenchyma.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figa_HTML.jpg

Fig. 1

The tumor shows a shiny surface and a yellowish-brown color. It is not encapsulated and the limits with the testicular parenchyma are not defined


../images/471462_1_En_3_Chapter/471462_1_En_3_Figb_HTML.jpg

Fig. 2

A ring of seminiferous tubules larger than those located under the albuginea is observed in the periphery of the tumor


../images/471462_1_En_3_Chapter/471462_1_En_3_Figc_HTML.jpg

Fig. 3

Several tumoral nodules are located in the testicular mediastinum between the rete testis cavities


../images/471462_1_En_3_Chapter/471462_1_En_3_Figd_HTML.png

Fig. 4

Proliferation in sheet of cells of broad eosinophilic cytoplasm and eccentric nuclei


../images/471462_1_En_3_Chapter/471462_1_En_3_Fige_HTML.jpg

Fig. 5

Tumor cells have spherical nuclei, peripheral nucleolus, and broad eosinophilic cytoplasm. In the cytoplasm of the cells close to the seminiferous tubule, several spherical and other elongated formations resembling Reinke crystals are observed


../images/471462_1_En_3_Chapter/471462_1_En_3_Figf_HTML.jpg

Fig. 6

Several tumor cells have a larger nucleus and peripheral arrangement of the chromatin, the central part adopting a ground-glass appearance. Absence of mitosis. Abundant intracytoplasmic spherical inclusions can be seen


../images/471462_1_En_3_Chapter/471462_1_En_3_Figg_HTML.jpg

Fig. 7

Electron microscopy shows part of several cells, one with lipofuchins, another one with abundant smooth endoplasmic reticulum and yet another one with concentric laminated formations of smooth endoplasmic reticulum


../images/471462_1_En_3_Chapter/471462_1_En_3_Figh_HTML.jpg

Fig. 8

Seminiferous tubules located at the periphery of the tumor, surrounded by tumor cells. They show complete spermatogenesis


../images/471462_1_En_3_Chapter/471462_1_En_3_Figi_HTML.png

Fig. 9

Seminiferous tubules away from the tumor, under the albuginea, whose size and cellularity are consistent with the patient’s prepubertal age


Comments. Leydig cell tumors represent between 4 and 9% of pediatric testicular tumors. They are responsible for 10% of all cases of early pseudopuberty in children. The peculiarities of this case are four: (a) the location of part of the tumor in the testicular mediastinum between the rete testis cavities, (b) the ground-glass appearance of the nuclei of some cells, (c) the spherical eosinophilic inclusions (concentric laminar smooth endoplasmic reticulum), and (d) the potential presence of Reinke crystals in a tumor at this age. The differential diagnosis that can be issued is with a tumor of the adrenogenital syndrome (see representative cases of these entities later on). To complicate the differential diagnosis, a Leydig cell tumor associated with adrenogenital syndrome has been reported. Other Leydig cell tumors are associated with acquired missense mutations in codon 578 of the gene for LHCGR and in the FH gene.




References



  1. 1.

    Gracia R, Nistal M, Gallego ME, Lledo G, Oliver A, Utrilla J, Gancedo P. Leydig cell tumor with pseudoprecocious puberty. An Esp Pediatr. 1980, 13:593–8.


     

  2. 2.

    Méndez-Gallart R, Bautista A, Estevez E, Barreiro J, Evgenieva E. Leydig cell testicular tumour presenting as isosexual precocious pseudopuberty in a 5 year-old boy with no palpable testicular mass. Clin Pediatr Endocrinol. 2010;19:19–23.


     

  3. 3.

    Olivier P, Simoneau-Roy J, Francoeur D, Sartelet H, Parma J, Vassart G, Van Vliet G. Leydig cell tumors in children: contrasting clinical, hormonal, anatomical, and molecular characteristics in boys and girls. J Pediatr. 2012;161:1147–52.


     

  4. 4.

    O’Grady MJ, McGrath N, Quinn FM, Capra ML, McDermott MB, Murphy NP. Spermatogenesis in a prepubertal boy. J Pediatr. 2012;161:369–369 e1.


     

  5. 5.

    Santos-Silva R, Bonito-Vítor A, Campos M, Fontoura M. Gonadotropin-dependent precocious puberty in an 8-year-old boy with leydig cell testicular tumor. Horm Res Paediatr. 2014;82:133–7.


     

  6. 6.

    Mameli C, Selvaggio G, Cerini C, Bulfamante G, Madia C, Riccipetitoni G, Zuccotti GV. Atypical Leydig cell tumor in children: report of 2 cases. Pediatrics. 2016;138(5). pii: e20160151.


     


Case 53. Leydig Cell Tumor with Gynecomastia


Clinical case. A 26-year-old patient with painless enlargement of the left testicle. He presents bilateral gynecomastia and moderate elevation of estradiol levels (E2) and low testosterone levels.


Pathological findings. The testicle measured 5 × 4 × 3.5 cm. There was a well-defined, reddish lobed tumor at the upper pole. A marked varicocele was associated. The tumor is constituted by large polygonal cells, with eosinophilic and granular cytoplasm, separated by fibrous septa. The nuclei are central, spherical, and the nucleolus is prominent. The proliferation index is less than 2%. One or several optically empty rectangular formations are observed in some cytoplasms. There is neither necrosis nor vascular infiltration. The cells are positive for inhibin and Melan-A but do not express calretinin. The peripheral parenchyma shows very poor spermatogenesis and few Leydig cells.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figj_HTML.jpg

Fig. 1

Tumor located at the upper pole of the testicle, with nodular surface and brown coloration. Great thickening of the vessels of the pampiniform plexus due to the presence of a varicocele is observed


../images/471462_1_En_3_Chapter/471462_1_En_3_Figk_HTML.jpg

Fig. 2

Well-defined solid tumor of the testicular parenchyma is shown


../images/471462_1_En_3_Chapter/471462_1_En_3_Figl_HTML.jpg

Fig. 3

Cell proliferation in sheets interrupted by thin connective tissue septa


../images/471462_1_En_3_Chapter/471462_1_En_3_Figm_HTML.png

Fig. 4

Tumor cells have spherical nuclei, one or two peripheral nucleoli and an eosinophilic cytoplasm


../images/471462_1_En_3_Chapter/471462_1_En_3_Fign_HTML.png

Fig. 5

Tumor cells have low cellular pleomorphism and in their cytoplasm there are rectangular spaces corresponding to dissolved Reinke crystals after fixation with formaldehyde


../images/471462_1_En_3_Chapter/471462_1_En_3_Figo_HTML.jpg

Fig. 6

Leydig cell with eccentric nucleus, many lipofuchins and smooth endoplasmic reticulum hyperplasia (electron microscopy)


../images/471462_1_En_3_Chapter/471462_1_En_3_Figp_HTML.jpg

Fig. 7

Electron microscopy shows part of a nucleus of a Leydig cell and a cytoplasm with the characteristic mitochondria of tubular ridges and the abundant smooth endoplasmic reticulum of functioning tumors


../images/471462_1_En_3_Chapter/471462_1_En_3_Figq_HTML.png

Fig. 8

Strong immunoexpression for inhibin in the cytoplasm of all tumor cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figr_HTML.jpg

Fig. 9

Seminiferous tubules away from the tumor show diminished size and deficient spermatogenesis. The Leydig cells are very rare in the intertubular interstitium


../images/471462_1_En_3_Chapter/471462_1_En_3_Figs_HTML.jpg

Fig. 10

The seminiferous epithelium of two adjacent tubules shows a decrease in the number of all germ cells. A hypertrophic spermatogonia is recognized. Immunostaining for inhibin


Comments. It is a typical case of Leydig cell tumor. Leydig cell tumors incidence ranges from 1 to 3% of all adult testicular tumors. They are the most frequent neoplasms of the sex cord stromal tumor group. About 12.5% of the tumors, as in this case, present with gynecomastia or are discovered in an infertility study. Situations secondary to the hormonal production of estrogen (in this case) or androgen by the tumor cells, and the consequent inhibition of the hypothalamic-pituitary-testicular axis give rise to a certain degree of hypogonadotropic hypogonadism. The fact that only the beds of the Reinke crystals are observed and not the crystals themselves is due to formaldehyde fixation. The expression of calretinin in these tumors is very variable and positivity is usually constant for Inhibin, Melan-A, SF1, and CD 99. Ten percent of these tumors express immunostaining for chromogranin, synaptophysin, and cytokeratins. The expression of nuclear beta-catenin is absent in 100% of them.




References



  1. 1.

    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;9:177–92.


     

  2. 2.

    Haas GP, Pittaluga S, Gomella L, Travis WD, Sherins RJ, Doppman JL, Linehan WM, Robertson C. Clinically occult Leydig cell tumor presenting with gynecomastia. J Urol. 1989;142:1325–7.


     

  3. 3.

    Javier Navarro F, Cozar JM, Nistal M, Martínez-Piñeiro L, Moreno JA, Jiménez J, Cisneros J, de la Peña J, Martínez-Piñeiro JA. Leydig cell tumor: presentation of 3 new cases with a benign course. Arch Esp Urol. 1991;44:145–50.


     

  4. 4.

    Van Der Gucht A, Maged Z, Burruni R, Barras JL, Schaefer N. Testicular estrogen-secreting Leydig cell tumor in 18F-FDG PET/CT: an incidental detection in a patient treated by chemotherapy for hodgkin lymphoma. Clin Nucl Med. 2018;43:41–3.


     

  5. 5.

    Zeuschner P, Veith C, Linxweiler J, Stöckle M, Heinzelbecker J. Two years of gynecomastia caused by Leydig cell tumor. Case Rep Urol. 2018;2018:7202560.


     


Case 54. Leydig Cell Tumor with Infertility (Sertoli Cell-Only)


Clinical case. A 36-year-old patient of who presented with infertility (azoospermia). On physical exploration, the presence of a slightly increased right testicle size was evident. The ultrasound showed a 1.3-cm in diameter hypoechoic nodule in the upper pole. Serum tumor markers were negative.


Pathological findings. The testicle measures 4.8 × 4 × 4 cm. The sectioned section showed a 1.5-cm in diameter poorly defined nodule in an upper pole, grayish yellow, without areas of necrosis or hemorrhage. Histologically, it is constituted by a proliferation in sheets of cells that show a great uniformity in terms of shape and size. They are cells with spherical nuclei, peripheral nucleolus, and eosinophilic cytoplasm. No mitosis is observed. Peripherally, the tumor cells infiltrate the intertubular interstitium. In the thickness of this infiltration, several seminiferous tubules similar to those of the peripheral parenchyma are recognized. Ultrastructurally, the cells show abundant lipid vacuoles and poor development of the smooth endoplasmic reticulum. Immunohistochemically, they have a strong expression for calretinin. All the testicular parenchyma presents seminiferous tubules with a Sertoli cell-only pattern.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figt_HTML.jpg

Fig. 1

Longitudinal section of the testicle. Poorly defined tumoral nodule in the upper pole of the testicle in contact with the rete testis. Peripherally, the tumor infiltrates the testicular parenchyma concentrically


../images/471462_1_En_3_Chapter/471462_1_En_3_Figu_HTML.png

Fig. 2

Proliferation in sheets of tumor cells in which their uniformity, the spherical nucleus, and eosinophilic cytoplasm stand out


../images/471462_1_En_3_Chapter/471462_1_En_3_Figv_HTML.png

Fig. 3

While growing, the tumor infiltrates among the seminiferous tubules that are included in it without showing atrophy


../images/471462_1_En_3_Chapter/471462_1_En_3_Figw_HTML.jpg

Fig. 4

Tumor cells show a slight anisocariosis. Most nuclei are spherical and have eosinophilic cytoplasm. Part of a seminiferous tubule is observed with dysgenetic Sertoli cell-only


../images/471462_1_En_3_Chapter/471462_1_En_3_Figx_HTML.jpg

Fig. 5

Part of two Leydig cells. One shows a spherical nucleus with peripheral nucleoli, and the other one a slightly folded nuclei. Both have many lipid vacuoles (electron microscopy)


../images/471462_1_En_3_Chapter/471462_1_En_3_Figy_HTML.png

Fig. 6

Strong immunoexpression for calretinin of the tumor cells that are surrounding a seminiferous tubule trapped by tumor growth


../images/471462_1_En_3_Chapter/471462_1_En_3_Figz_HTML.png

Fig. 7

The seminiferous tubules have a decreased diameter, slight thickening of the basement membrane and only contain Sertoli cells. The number of Sertoli cells per tubular section is high and their nuclei are elongated. Some tubules lack lumen (characteristic of the Sertoli cell-only syndrome with dysgenetic cells)


Comments. Infertility associated with Leydig cell tumors is usually secondary to a hormonal production by the tumor; when this corrected infertility is mostly reversible once the contralateral testicle is recovered. In 81.25% of the cases of the Leydig cell tumors, the peritumoral parenchyma presents an abnormal spermatogenesis; in 50% of the cases tubules with Sertoli cell-only pattern, and in 25% hyperplasia of the Leydig cells. Poor spermatogenesis can be explained by tumor compression or abnormal estrogenic or androgenic production by the tumor cells. The other two findings, tubules with only Sertoli cells and hyperplasia of Leydig cells, are similar to those seen in the peripheral parenchyma of germ cell tumors, where they are considered to be part of the testicular or dysgenesis syndrome. Taking into account these data, it could be inferred that this testicle shows a primary anomaly. It is unknown to what extent this anomaly may justify the development of some Leydig cell tumors. This case has the peculiarity of not being associated with endocrine alterations and showing a Sertoli cell-only syndrome. As the patient continued with repeated azoospermia months after the orchiectomy, it is likely that the contralateral testicle was also a carrier of the same primary anomaly.




References



  1. 1.

    Markou A, Vale J, Vadgama B, Walker M, Franks S. Testicular Leydig cell tumor presenting as primary infertility. Hormones (Athens). 2002;1:251–4.


     

  2. 2.

    Nistal M, Gonzalez-Peramato P, Regadera J, Serrano A, Tarin V, De Miguel MP. Primary testicular lesions are associated with testicular germ cell tumors of adult men. Am J Surg Pathol. 2006;30:1260–8.


     

  3. 3.

    Cajaiba MM, Reyes-Múgica M, Rios JC, Nistal M. Non-tumoural parenchyma in Leydig cell tumours: pathogenetic considerations. Int J Androl. 2008;31:331–6.


     

  4. 4.

    Sengupta S, Chatterjee U, Sarkar K, Chatterjee S, Kundu A. Leydig cell tumor: a report of two cases with unusual presentation. Indian J Pathol Microbiol. 2010;53:796–8.


     

  5. 5.

    Prasivoravong J, Barbotin AL, Derveaux A, Leroy C, Leroy X, Puech P, Mitchell V, Marcelli F, Rigot JM. Leydig cell tumor of the testis with azoospermia and elevated delta4 androstenedione: case report. Basic Clin Androl. 2016;26:14.eCollection 2016.


     

  6. 6.

    Hibi H, Yamashita K, Sumitomo M, Asada Y. Leydig cell tumor of the testis, presenting with azoospermia. Reprod Med Biol. 2017;16:392–5.


     


Case 55. Leydig Cell Tumor with Nodular and Microcystic Pattern


Clinical case. A 48-year-old patient who came to the urology office due to a several month long increase of his left testicle size. There was no gynecomastia and the testicular markers were negative.


Pathological findings. The testicle measures 5 × 4 × 4 cm. At the level of the lower pole, it showed a well-encapsulated yellowish tumor. In a large area of myxoid appearance, multiple yellowish nodules were prominent. Histologically, there is a proliferation of cells whose cytoplasm varies from eosinophilic to microvacuolated. The nuclei are spherical with a small nucleolus and the mitoses are very scarce. The cells, in zones, are arranged surrounding cystic spaces. In the myxoid zones, the cells are in small groups and show elongated cytoplasm in a loose and edematous stroma. Necrosis was not observed. Tumor infiltration was observed at the level of the tunica albuginea. The peritumoral parenchyma only shows signs of compression.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figaa_HTML.jpg

Fig. 1

Tumor in the lower pole of the testicle, apparently well encapsulated. It has solid areas and myxoid areas in equal proportion. The solid zone and the nodules of the myxoid areas are yellowish


../images/471462_1_En_3_Chapter/471462_1_En_3_Figab_HTML.png

Fig. 2

Proliferation in sheet of cells with little pleomorphism. Most of them show eosinophilic cytoplasm


../images/471462_1_En_3_Chapter/471462_1_En_3_Figac_HTML.jpg

Fig. 3

The tumor, even in the solid areas, shows myxoid zones and cystic formations. There are trapped seminiferous tubules inside the pseudocapsule


../images/471462_1_En_3_Chapter/471462_1_En_3_Figad_HTML.png

Fig. 4

The three tumor patterns, solid, cystic, and myxoid, are combined in different proportions. The cells that surround the cysts have eosinophilic cytoplasm and do not show vacuolation


../images/471462_1_En_3_Chapter/471462_1_En_3_Figae_HTML.png

Fig. 5

Marked xanthomization of the cytoplasm of tumor cells in some fields. The nuclei are small and eccentric. The tumor does not show mitosis


../images/471462_1_En_3_Chapter/471462_1_En_3_Figaf_HTML.png

Fig. 6

Transition between the most solid and cystic areas and the myxoid zones


../images/471462_1_En_3_Chapter/471462_1_En_3_Figag_HTML.png

Fig. 7

Leydig cells as they separate from the solid areas undergo deep morphological changes to become spindle cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figah_HTML.png

Fig. 8

Leydig cells of very elongated cytoplasm next to small groups of cells some with eosinophilic cytoplasm and others with microvacuolated cytoplasm


../images/471462_1_En_3_Chapter/471462_1_En_3_Figai_HTML.png

Fig. 9

Solid growth in contact with the albuginea. Several tumoral cell clusters are observed inside the vessels


Comments. Leydig cell tumors present a wide variety of histological patterns: solid, diffuse or nodular, pseudoglandular and trabecular. They rarely have a microcystic and myxoid pattern. In these cases, it can raise a differential diagnosis with several tumors. Seminomas, spermatocytic tumor, Sertoli cell tumor, granulosa tumors both juvenile and adult-type, and yolk sac tumor may have a microcystic pattern. Fortunately, in other areas all these tumors have histologically typical areas that allow them to be easily identified. Of all of the above, it is the yolk sac tumor the one that is histologically closest. The positivity of the cells of this tumor for AFP and glypican-3 and the negative expression for inhibin and calretinin facilitates the diagnosis. An important fact of this tumor is the infiltration of the lymphatic vessels of the albuginea. This worrying data advised a study of extension and strict surveillance of the patient.




References



  1. 1.

    Billings SD, Roth LM, Ulbright TM. Microcystic Leydig cell tumors mimicking yolk sac tumor: a report of four cases. Am J Surg Pathol. 1999; 23:546–51.


     

  2. 2.

    Loyd E, Boorjian S. A painless testicular mass in a 50-year-old man. Leydig cell tumor of the testis, microcystic variant. Arch Pathol Lab Med. 2006;130:e39–40.


     

  3. 3.

    Emerson RE, Ulbright TM. Morphological approach to tumours of the testis and paratestis. J Clin Pathol. 2007;60:866–80.


     

  4. 4.

    Young RH. Testicular tumors—some new and a few perennial problems. Arch Pathol Lab Med. 2008;132:548–64.


     


Case 56. Leydig Cell Tumor with Fatty and Osseous Metaplasia


Clinical case. A 36-year-old patient who had been studied for infertility for the last four years. Spermiogram revealed azoospermia in repeated analyses. Serum hormones showed an increase in serum estradiol and a decrease in FSH. On physical examination, a decrease in the size of the left testicle and an increase in the right one, that presents a nodule with a stony consistency, was detected. Right orchiectomy and contralateral biopsy were performed.


Pathological findings. The orchiectomy specimen shows a well-defined tumor, partially encapsulated, with small (1.3 cm in diameter) extracapsular tumor protrusions of. Microscopically, the tumor is composed of polygonal cells of eosinophilic, finely granular cytoplasm. The nuclei are round or oval with hardly any variation in size. Neither mitosis nor Reinke crystals are observed in the cytoplasm. Extensive areas of the tumor show groups of fat cells that in the periphery intermingle with the tumor cells. Irregularly distributed, several bone trabeculae stand out. The peritumoral parenchyma as well as the contralateral testicle biopsy shows tubules with marked hypospermatogenesis and Sertoli cell-only tubules.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figaj_HTML.jpg

Fig. 1

Nodular tumoration in the upper pole of the testicle, well delimited and partially encapsulated. Inside, a stellate eosinophilic area stands out


../images/471462_1_En_3_Chapter/471462_1_En_3_Figak_HTML.jpg

Fig. 2

Bone trabecula surrounded by tumor cells in the thickness of the fibrous capsule


../images/471462_1_En_3_Chapter/471462_1_En_3_Figal_HTML.jpg

Fig. 3

Proliferation in sheets of tumor cells in intimate contact with a bone trabecula


../images/471462_1_En_3_Chapter/471462_1_En_3_Figam_HTML.jpg

Fig. 4

The tumor cells trap seminiferous tubules inside the tumor. The trapped tubules lack germ cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figan_HTML.jpg

Fig. 5

Abundant adipocytes among tumor cells. The tumor cells have morphological characteristics similar to Leydig cells. Anisocytosis and anisocariosis is minimal. No mitosis is observed


../images/471462_1_En_3_Chapter/471462_1_En_3_Figao_HTML.png

Fig. 6

Some adipocyte clusters are aligned along the vessels


../images/471462_1_En_3_Chapter/471462_1_En_3_Figap_HTML.jpg

Fig. 7

Both tumor cells and Sertoli cells of the seminiferous tubules express inhibin


../images/471462_1_En_3_Chapter/471462_1_En_3_Figaq_HTML.png

Fig. 8

Mixed atrophy (seminiferous tubules with spermatogenesis next to others with Sertoli cell-only) in the contralateral testicular biopsy


Comments. Two facts are particularly important in this tumor. On the one hand, the clinical presentation: the patient sought consultation for infertility and not for testicular tumor. Infertility has been explained in these cases as secondary to the abnormal hormonal secretion of estrogens or androgens by Leydig tumor cells. In this case, in both testicles there is, focally, an added primary pathology, tubules with Sertoli cell-only, so the acquisition of fertility once the tumor is removed will be difficult. On the other hand, the coexistence of bone and adipose metaplasia, facts not previously observed until the publication of Santonja et al. in 1989. Bone metaplasia has only been observed in very few cases. In non-tumor pathology, it has been related to sequelae of ischemia or infection, facts not present in this case. Fatty metaplasia is common in undescended testes that are removed in the adulthood, in elderly patients, in tumors of the adrenogenital syndrome and in pediatric pathology, in the Proteus syndrome, the Cowden syndrome, and the Bannayan-Riley-Ruvalcaba syndrome. None of these situations occur in this patient, so both metaplasias are directly related to some activity of the tumor cells. These two histological findings have no prognostic value.




References



  1. 1.

    Minkowitz S, Soloway H, Soscia J. Ossifying interstitial cell tumor of the testes. J Urol. 1965;94:592–5.


     

  2. 2.

    Santonja C, Varona C, Burgos FJ, Nistal M. Leydig cell tumor of testis with adipose metaplasia. Appl Pathol. 1989;7:201–4.


     

  3. 3.

    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;26:1424–33.


     

  4. 4.

    Woodhouse J, Ferguson MM. Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J Radiol. 2006;79:801–3.


     


Case 57. Leydig Cell Tumor in Elderly Man


Clinical case. A 78-year-old patient who seeks consultation for voluminous left hydrocele. The testicle measured 2.8 × 2.6 × 2.5 cm.


Pathological findings. In the macroscopic figure, an atrophic testicle is shown longitudinally sectioned inside the vaginal sac that appears folded when the hydrocele is emptied. On the opposite side of the testicular mediastinum, the testicle presents an irregularly ovoid area, dark and 7 mm in diameter. It corresponds to a proliferation of Leydig cells that adopt a cord-like disposition associated to abundant and very congestive blood vessels. The cells have a marked anisocytosis and anisocariosis, frequent large nuclei with irregular contours, and a large nucleolus. No areas of necrosis or mitosis or vascular infiltration are observed. The tumor cells express immunostaining for CD56, calretinin, and androgen receptor.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figar_HTML.jpg

Fig. 1

Longitudinal section of the testicle surrounded by the folded parietal vaginal tunica that formed the voluminous hydrocele. In the testicle, under the albuginea, an ovoid, dark zone is observed which corresponds to the tumor


../images/471462_1_En_3_Chapter/471462_1_En_3_Figas_HTML.jpg

Fig. 2

Section of the tumor. It is well delimited, not encapsulated, peripherally surrounded by the tunica albuginea, showing very dilated veins in the tunica vasculosa


../images/471462_1_En_3_Chapter/471462_1_En_3_Figat_HTML.png

Fig. 3

Tumor cells adopt a cord-like growth, and the cords are separated by very congestive vessels


../images/471462_1_En_3_Chapter/471462_1_En_3_Figau_HTML.png

Fig. 4

Tumor cells are polyhedral, have a spherical nucleus, sometimes vacuolated, others hyperchromatic and a broad eosinophilic cytoplasm


../images/471462_1_En_3_Chapter/471462_1_En_3_Figav_HTML.jpg

Fig. 5

In the areas in which the growth is diffuse, the cellular pleomorphism is high with marked anisocariosis. Note the absence of mitosis


../images/471462_1_En_3_Chapter/471462_1_En_3_Figaw_HTML.jpg

Fig. 6

Some cells have monstrous nuclei of large size, irregular contours. Some nuclei are hyperchromatic, others show a huge central nucleolus


../images/471462_1_En_3_Chapter/471462_1_En_3_Figax_HTML.jpg

Fig. 7

Strong immunoexpression for calretinin in most tumoral Leydig cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figay_HTML.png

Fig. 8

Immunostaining for CD56 in an area of cord growth pattern of the tumor


../images/471462_1_En_3_Chapter/471462_1_En_3_Figaz_HTML.jpg

Fig. 9

Most tumor cells have expression for androgen receptor


Comments. This case has the following peculiarities: (a) It has been asymptomatic partly because of the hydrocele and partly because of its small size; (b) it concerns an atrophic testicle; (c) the advanced age of the patient: the peak of maximum incidence in adults is between 30 and 60 years; (d) the color of the tumor, that suggests more a vascular tumor or a melanoma metastasis than a Leydig cell tumor; (e) its small size, which raises the differential diagnosis with Leydig cells hyperplasia (in the hyperplasia respected tubules inside are observed), and (f) cellular pleomorphism, bizarre Leydig cells similar to those seen in some malignant tumors, that in this case probably represent only age changes.




Reference



  1. 1.

    Muheilan MM, Shomaf M, Tarawneh E, Murshidi MM, Al-Sayyed MR, Murshidi MM. Leydig cell tumor in grey zone: a case report. Int J Surg Case Rep. 2017;35:12–6.


     


Case 58. Bilateral Leydig Cell Tumor with Leydig Cell Hyperplasia


Clinical case. A 27-year-old patient with hypospadias, hypergonadotropic hypogonadism, and size increase of both testicles. He has a normal karyotype. Ultrasound examination revealed multiple hypoechoic lesions in both testes. The largest one, in the right testicle, measured 2 cm, and that of the left testicle measured 1.7 cm.


Pathological findings. Both testicles show similar images. A brown nodule measuring 1.8 cm in the right testicle and 1.6 cm in the left one. Both are well defined from the adjacent parenchyma. Histologically, they are formed by a proliferation in sheets of cells with a large eosinophilic cytoplasm, eccentric nuclei, one or two nucleoli without mitosis, and areas of necrosis. It is worth noting the practical absence of connective septa between the cells and those that are observed to contain vessels and are not collagenized. There is a Leydig cell hyperplasia in the parenchyma that adopts both a diffuse and nodular distribution. The seminiferous tubules show thickening of the wall and contain some spermatogonia and first-order spermatocytes.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figba_HTML.png

Fig. 1

Longitudinal section of the testicle and epididymis. Three nodules are observed in the testicular parenchyma, the two largest ones correspond to a tangential section of the Leydig cell tumor, the smallest to a Leydig cell hyperplasia


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbb_HTML.png

Fig. 2

Section of the testicular parenchyma with two nodular formations showing some seminiferous tubules trapped in the periphery. In the rest of the parenchyma, there is a diffuse Leydig cell hyperplasia


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbc_HTML.png

Fig. 3

Several nodules show seminiferous tubules inside in the parenchyma next to the Leydig cell tumor


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbd_HTML.jpg

Fig. 4

Tumor cells with sometimes fused spherical nuclei, peripheral nucleolus, and broad eosinophilic cytoplasm. Peripherally, there are multinucleated cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbe_HTML.png

Fig. 5

Nodular hyperplasia of Leydig cells in the vicinity of the tumor. Observe the presence of seminiferous tubules inside


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbf_HTML.png

Fig. 6

Proliferation of Leydig cells rejecting some seminiferous tubules. The latter have a thickened wall and only contain Sertoli cells, isolated spermatogonias and spermatocytes


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbg_HTML.png

Fig. 7

Atrophic seminiferous tubule inside a hyperplastic nodule of Leydig cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbh_HTML.png

Fig. 8

Intense immunoexpression for calretinin in all Leydig cells


Comments. The first diagnosis that should be considered before a bilateral testicular tumor that looks like a Leydig cell tumor is that we are in front of a patient with congenital adrenal hyperplasia and presents tumors of the adrenogenital syndrome. For this, as in this case, the mandatory laboratory studies have to be carried out. Having ruled out this diagnosis, we are facing a Leydig cell tumor in a somewhat special patient. Three data are interesting in this case: (a) bilaterality, only present in 3% of Leydig cell tumors, (b) association with Leydig cell hyperplasia, which is observed in less than 25% of Leydig cell tumors, and (c) the presence of hypospadias, a rare occurrence in these patients. Histologically, it is necessary to clearly differentiate a tumor from a hyperplasia, especially when it is nodular. The classic criteria of a hyperplasia are still valid: multiple lesion, not encapsulated, containing germline or atrophic tubules inside. Leydig cell hyperplasia has been described in multiple situations such as in the peripheral parenchyma in germ cell tumors, cryptorchidism, testicular atrophies of inflammatory etiology, and the Klinefelter syndrome. None of these are related to the present case. The presence of hypospadias does not discard a partial androgen insensitivity syndrome, neither does it rule out in this case a congenital pathology that could be related to a testicular dysgenesis. It is debated whether Leydig cell hyperplasia could represent, in some cases, a precursor lesion of Leydig cell tumors.




References



  1. 1.

    Nistal M, Santamaria L, Paniagua R. Quantitative and ultrastructural study of Leydig cells in Klinefelter’s syndrome. J Pathol. 1985;146:323–31.


     

  2. 2.

    Naughton CK, Nadler RB, Basler JW, Humphrey PA. Leydig cell hyperplasia. Br J Urol. 1998;81:282–9.


     

  3. 3.

    Colecchia M, Nistal M, Gonzalez-Peramato P, Carmignani L, Salvioni R, Nicolai N, Regadera J. Leydig cell tumor and hyperplasia: a review. Anal Quant Cytol Histol. 2007;29:139–47.


     

  4. 4.

    Cajaiba MM, Reyes-Múgica M, Rios JC, Nistal M. Non-tumoural parenchyma in Leydig cell tumours: pathogenetic considerations. Int J Androl. 2008;31:331–6.


     

  5. 5.

    Lakis NS, Lombardo KA, Mangray S, Netto GJ, Salles D, Matoso A. INSL3 expression in Leydig cell hyperplasia and Leydig cell tumors. Appl Immunohistochem Mol Morphol. 2019; 27:203–9.


     


Case 59. Malignant Leydig Cell Tumor


Clinical case. A 62-year-old patient seen in the urologist office due to discomfort and enlargement of the left testicle. The ultrasound showed a 6–8-cm in diameter hypoechoic tumor that takes most of the testicular parenchyma. Tumor markers were negative.


Pathological finding. A brown tumor formed by several coalescent nodules with hemorrhagic and necrotic areas that takes the entire testicular parenchyma. Histologically, it is formed by a proliferation of cells with a wide eosinophilic cytoplasm, which is arranged in sheets interrupted by fine connective septa. The cells have a high mitotic index. Focally, there is marked anisocytosis and anisocariosis. No Reinke crystals are observed. The tumor has areas of necrosis and infiltrates the adipose tissue of the paratesticular structures and the vessels of the spermatic cord. The cells strongly express calretinin and more weakly inhibin.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figbi_HTML.jpg

Fig. 1

Longitudinal section of the testicle. Nodular tumor that takes most of the testicle. It is blackish brown and shows hemorrhagic areas


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbj_HTML.jpg

Fig. 2

Proliferation in sheets of tumor cells crossed by fine septa without lymphoid infiltrates


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbk_HTML.jpg

Fig. 3

Cells of spherical nuclei with one or two nucleoli, abundant eosinophilic and granular cytoplasm. Presence of several mitoses


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbl_HTML.jpg

Fig. 4

Group of large bizarre cells. The nuclei are of varied shape and size (fusiform, reniform, and spherical)


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbm_HTML.jpg

Fig. 5

Tumor nodule with extensive necrosis


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbn_HTML.jpg

Fig. 6

The tumor proliferation index estimated with Ki67 staining is very high


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbo_HTML.jpg

Fig. 7

Infiltration of the paratesticular adipose tissue by the tumor


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbp_HTML.jpg

Fig. 8

Vascular infiltration of spermatic cord vessels


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbq_HTML.jpg

Fig. 9

Intense immunoexpression for calretinin in tumor cells


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbr_HTML.jpg

Fig. 10

Moderate immunoexpression for inhibin by the tumor cells in contrast with the intense immunostaining observed in the Sertoli cells of nearby seminiferous tubules


Comments. This case is a typical example of Leydig cell tumor of malignant behavior. It is admitted that only the presence of metastasis is the unequivocal sign of malignancy, but when Leydig cell tumors that metastasized have been reviewed, there are histological features that keep repeating: large size (>5 cm), endocrine changes, infiltration of margins, cellular pleomorphism, high mitotic index (>5 mitosis per high-power field), presence of necrosis and hemorrhage, and vascular infiltration. All these features are present in this case. Less than 10% of Leydig cell tumors have a malignant behavior. Lymph nodes, lung, liver, kidney, and bones are the most frequent sites of metastasis. Malignant tumors are frequently aneuploid and have an increased MIB1 index.




References



  1. 1.

    Heer R, Jackson MJ, El-Sherif A, Thomas DJ. Twenty-nine Leydig cell tumors: histological features, outcomes and implications for management. Int J Urol. 2010;17:886–9.


     

  2. 2.

    Valeri RM, Kotakidou R, Michalakis K, Andreadis C, Kousi-Koliakou K, Destouni C. Malignant Leydig-cell tumor of the testis diagnosed by fine-needle aspiration using ThinPrep technique. Diagn Cytopathol. 2011;39:368–72.


     

  3. 3.

    Geminiani JJ, Marshall SD, Ho TS, Brandes SB. Testicular Leydig cell tumor with metachronous lesions: outcomes after metastasis resection and cryoablation. Case Rep Urol. 2015;2015:748495.


     

  4. 4.

    Hendry J, Fraser S, White J, Rajan P, Hendry DS. Retroperitoneal lymph node dissection (RPLND) for malignant phenotype Leydig cell tumours of the testis: a 10-year experience. Springerplus. 2015;4:20. doi: 10.1186/s40064-014-0781-x. eCollection 2015.


     

3.2 Sertoli Cell Tumors



Case 60. Bilateral Sertoli Cell Adenomas with Seminoma in Complete Androgen Insensitivity Syndrome (CAIS)


Clinical case. A 65-year-old woman who consulted for abdominal tumors. Two voluminous masses of 12 cm (right) and 8 cm (left) in diameter could be seen in the laparotomy at the anatomical area of the ovaries. There was absence of both uterus and Fallopian tubes. The karyotype performed after the histological study was 46, XY. The patient was diagnosed with CAIS.


Pathological findings. When sectioning, the right gonad shows two different areas: the largest one, in the form of a crescent, is whitish and has a firm consistency, and the smallest one is rhomboidal, grayish and with a softer consistency. The left gonad looks similar to the crescent of the right gonad. Macroscopically, neither testicle nor epididymis is recognized. Histologically, the crescent of the right gonad and the entire left gonad are formed by a proliferation of solid tubules, not anastomosed, smaller than 70 μms. The tubules contain 2–10 cells per cross-section. The cells are cubic with a spherical nucleus, euchromatic with a small nucleolus. The cytoplasm is pale or slightly eosinophilic. The cells are supported by a thick basement membrane with no peritubular myoid cells. The thickness of the membrane is inversely proportional to the number of Sertoli cells. The intertubular space lacks Leydig cells. No mitosis is observed. The cells show immunoexpression for inhibin and WT1. The rhomboidal area of the right gonad was consistent with a seminoma.

../images/471462_1_En_3_Chapter/471462_1_En_3_Figbs_HTML.jpg

Fig. 1

Cross-section of the right gonad. It shows two different parts, the whitish one corresponds to a Sertoli cell adenoma. The gray area is a seminoma


../images/471462_1_En_3_Chapter/471462_1_En_3_Figbt_HTML.jpg

Fig. 2

Cross-section of the left gonad. The whitish surface shows small myxoid areas. No necrosis or hemorrhage is observed

Only gold members can continue reading. Log In or Register to continue

Oct 1, 2020 | Posted by in UROLOGY | Comments Off on Cord-Stromal Tumors
Premium Wordpress Themes by UFO Themes