but they contain crystalloids of Reinke in their cytoplasm.

The
presence of crystalloid is specific and of diagnostic value.

Leydig cell tumors HILUS CELL TUMORS The hilus cell tumors arise from preexist-
ing normal Leydig cells of the hilus. There is a sharply delin-
not classified as eated junction between the basophilic ovarian stroma and the
eosinophilic collagenous stroma of the hilus. In the hilar zone,
Sertoli-Leydig group the hilar Leydig cells can be found normally in 80-85% of the
postpubertal ovaries, usually in association with non-myeli-
nated nerve fibers. Similar Leydig cells associated with nerve
ÉVA MAGYAR, M.D., NÓRA KISFALUDY, M.D. are present in the hilus and capsule of the testis. It is assumed
that the ovarian hilar cells and the testicular ones are identi-
Department of Pathology, National Medical Center, Budapest
cal (1). Ovarian hilar Leydig cell tumors usually develop in
association with hilus cell hyperplasia.
ABSTRACT Leydig cell tumors belong to the small group of ova-
rian steroid tumors, which are hormone-producing, and derived The hilus cell tumors are encountered predominantly in post-
from specific stromal cells. They are divided into subtypes menopausal women (average age 58 years) and cause hir-
according to their cell origin as follows: 1. stromal luteomas, 2. sutism and/or virilization in 75% of the cases (2). The andro-
Leydig cell tumors, and 3. steroid tumors not otherwise specified. genic manifestations are milder than those associated with
The Leydig cell tumors have two forms: 1. the hilus cell tumors, Sertoli-Leydig cell androblastomas, and their onset is less
which arise from preexisting normal Leydig cells of the hilus, and abrupt. The tumor secretes testosterone, which is not a 17-keto-
2. the stromal Leydig cell tumors, which take their origin in the steroid, thus the urinary 17-ketosteroid levels are typical ly nor-
cortex or subcortical region in the ovary from ovarian stromal mal or only slightly elevated. Occasionally, estrogenic activity
cells that have differentiated into Leydig cells. The Leydig cell may be observed (3).
tumors are rare and benign. In spit of this, the pathologists should
identify them, and their diagnosis using is possible with high accu- Almost all of these tumors are unilateral, rarely bilateral, and
racy using a simple HE stained slides of good quality. present as nodules in the mesovarium (4-5). The tumor size
ranges between 1 and 15 cm in diameter but, in the vast ma-
Key words Leydig cell tumors, ovary, stromal cells, jority of the cases, they are less than 5 cm with a mean value
of 2.4 cm (2, 6).

INTRODUCTION Leydig cell tumors belong to the small group of The tumors are reddish-brown, orange or yellow in colour,
ovarian steroid tumors. They are hormone-producing and well-circumscribed, and fleshy. Haemorrhagic mottling is
derived from specific stromal cells. Morphologically, their common. They are generally benign, malignant course is ex-
endocrine-like structure is characteristic, formed of large,
polyhedral cells resembling luteal, adrenocortical, and Leydig
cells. The group is divided into subtypes according to their cell
origin as follows: 1. stromal luteomas, 2. Leydig cell tumors,
and 3. steroid tumors not otherwise specified.

The Leydig cells may originate in the hilus of the ovary or

within the ovarian stroma. The tumors arising from the previ-
ous site is called hilus cell tumors, while the latter are the stro-
mal-Leydig cell tumors or non-hilar-type Leydig cell tumors.
Leydig cells of different origin show the features of lipid cells,

Address correspondence to:

Éva Magyar, M.D.

Department of Pathology
National Medical Center
Szabolcs Hospital,
1135 Budapest, Szabolcs u. 33-35. Hungary Figure 1. Hilus cell tumor. The polyhedral and rounded cells with abundant, somewhat
Phone (36 1) 3500305 Fax (36 1) vacuoled cytoplasm resemble lutein cells. Some of the centrally placed, round nuclei are
E-mail: [email protected]
hyperchromatic (arrows).

164 CME Journal of Gynecologic Oncology 2002; 7:16 4–166

 Chapter 23

reported cases are under 10 in number (14-16). Like hilus cell

tumors, they also occur in postmenopausal patients, are unilat-
eral and due to the significant production of androgens it is fre-
quently associated with symptoms of virilization. One single
case is known when a non-hilar Leydig cell tumor occured in a
young person aged 15 years and this was associated with preg-
nancy (12). These tumors are usually small, average from 2 to
5 cm in greatest dimension, frequently multinodular and lobu-
lated. Like the clinical signs, the pathological features are also
similar to those of the hilus cell tumors, except for their loca-
tion. On microscopical examination, nests of Leydig cells are
generally admixed with ovoid and spindle shaped cells, which
show the appearances of stromal hyperthecosis or thecoma.
Presence of detectable crystalloid of Reinke is required for
Figure 2. The Leydig cells aggregated in nests, their nuclei cluster. In the center, nucleus- identification of the Leydig cells of stromal origin.
free eosinophilic mass of cytoplasm is seen.
The diagnostic value, rather the necessity of the presence of
the crystals in the Leydig cell tumors has to be discussed.
ceptionally rare (7). According to the literature, the malig- There is confusion whether it is permissible to diagnose Leydig
nant variation has no special histologic features to indicate cell neoplasms in the absence of the crystals or not. In case of
their aggressive nature (8). hilus cell tumors, the neoplastic cells arise in the collagenous
connective tissue of the mesovarium. The location is charac-
The microscopy is characteristic (Figures 1, 2, 3, 4). The tumor teristic and it allows not insisting on finding crystalloids. The
cells are polyhedral or rounded and uniform with abundant attitude differs fundamentally when the tumor occurs in the
granular, eosinophilic cytoplasm. Small cytoplasmic lipid vac - ovarian stroma, when the nests of supposed Leydig cells are
uoles are common, as well as lipochrom pigment. The nuclei intermingled with thecoma-like stromal elements. In such
are large and round, often hyperchromatic, occasionally cases, the presence of detectable crystalloids is an absolute
bizarre, containing small nucleoli. Cytoplasmic pseudoinclu- requirement for the diagnosis of Leydig cell neoplasm.
sions into the nucleus may be found. Mitotic figures are rare.
Reinke crystalloids, as homogenous eosinophilic rods, are DIFFERENCIAL DIAGNOSIS The differential diagnosis of the
present by definition in varying number and size in the cyto- Leydig cell tumors includes ovarian neoplasms containing
plasm or in the nucleus, but it is rather difficult or even im- Leydig cells or luteinized stromal cells.
possible to find them. The crystals consist of globular proteins
(9) and may dissolved out in routine sections. In the cases 1. Sertoli-Leydig cell androblastoma occasionally exhibits
when they are present, they are very unevenly distributed and predominance of Leydig cell component. Prolonged search is
are completely absent from hilar cells in many adult ovaries.
The detailed chemical nature of the crystalloids and their rela-
tionship to the endocrine activity of the cells has not yet been
explained. The fact that, except in cases of precocious puber-
ty, these crystals do not appear until puberty suggests a close
relationship to the endocrine activity of the cells (10-11).

Within the tumor, the Leydig cells are arranged into nests and
cords, their nuclei are often aggregated or pooled. Fibrinoid
necrosis of the walls of moderate-large intraneoplastic blood
vessels, without inflammatory cell infiltration, is a characte-
ristic feature. This pattern is highly suggestive of hilus cell
tumors even in the absence of crystalloids of Reinke (6).

THE STROMAL-LEYDIG CELL TUMORS The stromal-Leydig cell

tumors take their origin in the cortex or subcortical region in
the ovary from ovarian stromal cells, which have differentiated Figure 3. Typical eosinophilic Reinke crystal (arrows) is presented. Moderate variation in
into Leydig cells (12-13). They are very rare benign tumors, the nuclear size and prominent nucleoli are evident in the surrounding Leydig cells.

CME Journal of Gynecologic Oncology 2002; 7:164 –166 165

Leydig cell tumors not classified as Sertoli-Leydig group

originating from Leydig cells represent one third only, one

has to know their diagnostic criteria. It is noteworthy that in
the era of sophisticated and expensive histopathological
methods including immunhistochemistry, this rare and benign
tumor can be diagnosed with high accuracy using a simple HE
stained slides of good quality.

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166 CME Journal of Gynecologic Oncology 2002; 7:16 4–166