Pediatric Oncologic Pathology
Moderators: Dr. Tony Bourne and Dr. Denis Benjamin
Case 2 -
Multicystic Ovaries Due to Hypothyroidism
Ronald Jaffe, MB. BCh
A 9-year-old girl presented with a 2-year history of abdominal pain, increasing abdominal girth and
fatigue. The physical examination was unremarkable, Tanner stage 0, but she had palpable abdominal
masses. A CT scan revealed cystic masses arising from the pelvis to the level of the umbilicus,
multiloculated, multicystic and ovarian in origin. The cysts were decompressed laparoscopically and the
cyst wall biopsied. The cytology was benign and the cysts were diagnosed as "luteinized follicular
cysts", with the note that since they were large and bilateral, a non-ovarian endocrine effect was
possible. Within 2 months, the ovarian cysts recurred, larger than before and were removed
laparoscopically. The cysts were signed out as "multiple luteinized cysts with a prominent granulosa
cell layer", but an expert consultation was sought because of the clinical concern around their rapid
re-growth. The consultant diagnosed "multicystic juvenile granulosa cell tumors", the in-house diagnosis
was revised accordingly. The slide is from this procedure. A bilateral salpingo-oophorectomy was done,
4 months after first presentation. The diagnosis was "cystic ovaries with multicystic granulosa cell
tumor", with a note that suggested that the granulosa cell tumors were on the background of
(non-neoplastic) cystic ovaries and that no extra-ovarian spread was present. The consultant confirmed
his original diagnosis and agreed that there were also benign cysts. She was treated with Cisplatin,
VP-16 and Bleomycin for 6 months and one year later, is well without evidence of disease.
Case 2 - Slide 1
At the time of her first chemotherapy administration, clinical hypothyroidism was suspected. The
free T4 was 0.23 ng/dl (0.81-2.06) TSH 2003 uIU/mL (0.700-5.700) prolactin 87.1 ng/mL/ (1.2-11.4)
Inhibin A 175.3 (high) Inhibin B 37 (less than 30 pg/mL). She was begun on Synthroid and improved
clinically and her pituitary and thyroid tests normalized.
Multiple ovarian cysts due to hypothyroidism are described extensively in the literature
the major textbooks are silent on the subject, except for Blaustein. Since the advent of pelvic
sonography, more cases have been described suggesting that the condition of cystic ovaries is common in
hypothyroidism . The cysts can be massive, and the presentation can be as ovarian masses, torsion,
delayed or more commonly precocious puberty and vaginal bleeding. Because the hypothyroidism is commonly
the condition under observation, and because the ovarian cysts regress rapidly and completely with
thyroid replacement therapy, there are few descriptions of the histopathology of the cysts
Gross descriptions reveal multiple cysts that contain clear yellow fluid. The descriptions include
"cystic cavities lined by a single layer of ovoid cells...with no evidence of luteinization"  and Van
Voorhis et al  describe the finding in an adult who underwent unilateral salpingo-oophorectomy to
remove a necrotic ovary following torsion as "Multiple (hemorrhagic) luteinized follicular cysts were
The ovarian resection in this instance revealed numerous follicular cysts that had a compact granulosa
cell component, 2-3 cell layers thick over a slightly luteinized theca interna. Other cysts had
prominent granulosa cell proliferation that had an "immature" appearance with pleomorphism, slightly prominent nucleoli and brisk apoptotic and mitotic activity, sometimes several
within a single high-power field. The peripheral granulosa cell layer revealed prominent luteinization.
Inhibin A and CD99 staining was intense on these elements confirming their granulosa cell nature
Although these were interpreted as bilateral juvenile granulosa cell tumors at the time, in
light of the documentation of hypothyroidism it is overwhelmingly likely that these represent the ovarian
cysts of hypothyroidism.
The pathophysiology is not clear. Van Wyk  described "hormonal overlap" in that TSH, GH, FSH and
LH have common alpha chains and it is their β-chains that confer specificity of action. Some
cross-reaction of the very high TSH could produce FSH and LH-like activity responsible for the luteinized
ovarian cysts . In some of the cases reported, however, FSH levels have been very high. There may,
therefore, be some action of thyroid releasing hormone on pituitary cells to stimulate gonadotropin
release, FSH and LH. An enlarged pituitary gland or even pituitary adenomas are described in
hypothyroidism, some of these also with ovarian cysts
An animal model of hypothyroid rats
suggests yet another mechanism in that there is increased sensitivity to FSH because of an increase in
the number of ovarian FSH receptors . Combinations of pituitary and local ovarian effects are
likely, given the histopathology. More recent functional data from administration of LH and FSH to women
have shown that selective LH rise in the late follicular phase favors Inhibin A secretion from more
mature follicles while FSH and E 
in the early follicular phase results in Inhibin B secretion .
From this data we can infer that there was indeed FSH and LH effect on the hypothyroid induced cysts.
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