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280 Case report
Vlaams Diergeneeskundig Tijdschrift, 2010, 79 Estrogen-induced pancytopenia due to a Sertoli cell tumor in a
cryptorchid Beauceron
Oestrogeengeïnduceerde pancytopenie door een sertoliceltumor bij een 1 H. De Bosschere, 2 C. Deprest
1 Medisch Labo Bruyland – Afdeling Diergeneeskunde, Meiweg 1, B-8500 Kortrijk, Belgium2 Dierenartsenpraktijk Deprest, Verlovestraat 4, B-8755 Ruiselede, Belgium ABSTRACT
The present report describes the clinical history, radiography, ultrasonography, hematology, bone marrow
sample, and histology of a case of estrogen-induced pancytopenia due to neoplastic change of cryptorchid
testes. The anemia gradually improved after castration, several blood transfusions and treatment with
nandrolondecanoate.
Dit is een beschrijving van de voorgeschiedenis, radiografie, echografie, hematologie, beenmergpunctie en histologie van een oestrogeengeïnduceerde pancytopenie ten gevolge van een tumorale ontaarding van cryptorchetestikels. Deze anemie verbeterde geleidelijk na castratie, verscheidene bloedtransfusies en nandrolondecanoaat.
trophy or perianal adenoma, or when it is produced by Pancytopenia is a medical condition in which there a testicular tumor or ovarian granulose cell tumor (Son- is a reduction in the numbers of red and white blood cells tas et al., 2009). The response of the bone marrow to and of platelets due to damage to stem cells or to the estrogens varies from one dog to another, because some bone marrow microenvironment leading to bone mar- dogs may have fatal bone marrow suppression, where- row failure. The frequently used term ‘aplastic anemia’ as others have only mild to moderate damage (Crafts, is confusing since all cell lines are affected, and not only the red blood cells. Bone marrow damage may be caused Clinical signs relate to thrombocytopenia (petechial by infections, drugs, toxins, neoplasia, myelodysplasia, hemorrhages, melena, etc.), neutropenia (pyrexia and bone marrow necrosis, osteosclerosis, myelofibrosis or sepsis) and anemia (lethargy and pallor).
immune-mediated mechanisms, or it may be idiopath- The present case report describes the successful treat- ic (Harvey, 1997; Tilley and Smith, 2004; Villiers and ment of a paraneoplastic syndrome of estrogen-induced Blackwood, 2005). In the acute form of the disease, the pancytopenia due to a Sertoli cell tumor in cryp- destruction of progenitor and dividing cells leads to leu- copenia/neutropenia within 5 days and to thrombocy-topenia within 8-10 days. Anemia develops more gradually due to the long red blood cell lifespan. Bonemarrow aspiration reveals a mix of necrotic lysing cells, Case history
macrophages and stromal cells. Depending on the cause,the bone marrow may recover and be repopulated, usu- A 9-year-old bilateral cryptorchid male Beauceron ally within 3 weeks after the original marrow injury, or was presented in poor general condition. The owner was the disease may progress to the chronic form. In the aware of the possible risks of cryptorchidy, but refused chronic form, the stem cell damage is irreversible and to castrate the dog. During the examination, the dog did the red marrow is replaced by fat, leading to neutropenia, not show any obvious signs of feminizing syndrome, thrombocytopenia and moderate to severe anemia such as gynecomastia or alopecia. However, based on the anamnesis of approximately one year prior to the Estrogen-induced pancytopenia is only observed in time of presentation, the dog had then been making cop- dogs and ferrets (Crafts, 1948; Kociba and Caputo, 1981). The dog is very susceptible to the myelotoxic ef- anamnesis, however, there was no report of abnormal fects of estrogen when estrogen is administered in fe- sexual behavior. Clinical examination revealed high fever male dogs for urinary incontinence, mismating, estrus (40.5°C) and increased heart beat (150 bpm). The dog induction or pseudopregnancy, when it is administered had a lick granuloma on the hind leg and a large bite in male dogs for the management of prostatic hyper- wound in the neck. The dog was treated conservative- Vlaams Diergeneeskundig Tijdschrift, 2010, 79 Table 1. Results of blood analysis of a 9-year-old bilateral cryptorchid Beauceron.
Hematology
References
17-beta-estradiol
ly with antibiotics and nonsteroidal anti-inflammatory incision from the umbilicus to the pubis. Both neoplastic drugs (NSAIDS). Nine days later there was only slight testicles were double ligated with Vicryl 2/0, transect improvement in the dog’s condition. The dog was ane- and removed. The abdomen was closed using a standard mic and showed syncope after jumping. Physical ex- procedure. Both testicles were histopathologically ex- amination showed a temperature of 39.3°C, a systolic heart murmur grade 2/6 left apex due to the anemic sta-tus of the patient, and weak femoral pulses. Other ex- Histopathology of the testes
aminations such as blood analysis, radiography and ul-trasonography were carried out.
The size of the testes was respectively, 3.5 cm in di- ameter and 11 cm by 7 cm (Figure 3). Hematoxilin eosin Blood examination
(HE) sections of the enlarged testis revealed a prolif-eration of Sertoli cells, spread over numerous tubuli, in- The results of the hematology and follow-up analy- termixed with a trabecular collagenous network. The ses are summarized in Table 1. Initially, there was a mod- neoplastic cells formed tubules of elongated cells in a erate nonregenerative normocytic slightly hypochromic parallel arrangement, with a large round to ovoid nu- anemia, leucepenia/neutropenia and severe thrombo- cleus and a large amount of vacuolated or dense cytopenia. The 17-beta-estradiol concentration was eosinophilic cytoplasm. The tumor consisted of well markedly increased at 149.2 pg/ml (normal values 13-55 pg/ml).
Radiography
The x-ray of the thorax showed a normal heart with a VHS (vertebral heart score) < 10.5 and a slightly di-minished lung vessel pattern. The x-ray of the abdomenshowed an enlarged spleen with a caudal well circum-scribed mass. The intestines were pushed dorsally andlaterally by this mass situated on the midventral aspectof the caudal abdomen (Figure 1). Ultrasonography
On the ultrasonographic examination of the abdomen, the mass noticed on the x-ray consisted of two mass-es, both showing echogenic zones. The larger of the two Figure 1. The X-ray with the dog in right lateral recum-
masses was approximately 7 cm by 6 cm, while the oth- bency shows an enlarged spleen (yellow arrow) and a
well –circumscribed soft-tissue abdominal mass on the
er mass was smaller (Figure 2). These masses were sus- caudal midventral abdomen (red arrow) approximately
pected to be neoplastic transformations of the cryptorchid twice the size of the kidneys. The intestines seem to be
testes. Both testes were removed via a ventral midline displaced dorsally and laterally of this mass.
Vlaams Diergeneeskundig Tijdschrift, 2010, 79 Figure 4. Neoplastic proliferation of Sertoli cells (X),
spread over numerous tubuli, intermixed with a dense
Figure 2. On ultrasonography, the mass observed on X-
trabecular collagenous network (Y). The neoplastic cells
ray appears to be well circumscribed with irregular hy-
formed tubules lined by multiple layers of elongated cells
poechoic zones (yellow arrow), suggestive of fluid. The
in a parallel arrangement, with a large round to ovoid
testicular parenchyma is mixed hypoechoic.
nucleus and a large amount of eosinophilic cytoplasm.
The cells are arranged perpendicularly to the basement
membrane. HE staining - Bar = 100µm.
Figure 3. The left testicle changed into the largest tumor
and measured 11 cm by 7 cm, the right testicle tumor
measured 3.5 cm in diameter.
formed tubules that were lined by multiple layers of neo-plastic Sertoli cells. These Sertoli cells were arranged Figure 5. The bone marrow showed severe lack of ery-
perpendicularly to the basement membrane (Figure 4).
throid, myeloid and megakaryocytic cell types. There
The contralateral smaller atrophic testis showed severe were numerous mature erythrocytes, a moderate num-
ber of neutrophils (arrowheads) and a moderate num-
fibrosis with a small number of tubular sections.
ber of large mononuclear cells (arrows). Presence of fat
After surgery the anemia became worse (Table 1).
(F). Modified Wright stain - Bar = 50 µm
Due to the nonregenerative nature of the anemia, a bonemarrow aspiration was carried out for evaluation.
Treatment
Bone marrow cytology
A diagnosis of estrogen-induced pancytopenia due to a Sertoli cell tumor in a cryptorchid testis was made.
The bone marrow a showed severe lack of erythroid, After castration, the dog received 4 consecutive blood myeloid and megakaryocytic cell types. There were nu- transfusions of 350 ml, each time at an interval of 4 to merous mature erythrocytes, a low number of neutrophils 6 days. The 2nd and 4th blood transfusions were followed with some band neutrophils, and a low number of large by injections of Deca-Durabolin (200 mg IM - nan- mononuclear cells (Figure 5). Small amounts of fat tis- drolondecanoate). Over time, the anemia gradually sue were also observed on the slides. These findings are changed into a slightly regenerative macrocytic consistent with estrogen-induced myelotoxicity.
hypochromic anemia, and thrombocytopenia. Fourmonths after the start of the treatment, the complete Vlaams Diergeneeskundig Tijdschrift, 2010, 79 blood count was almost within reference levels (Table infections, and stimulation of the remaining bone mar- row (Hall, 1992). Untreated cases of estrogen inducedmyelotoxicity always have an unfavorable prognosis.
Death occurs from complications of hemorrhage and in-fection.
Sertoli cell tumors of the testes arise from the sup- However, in chronic cases, the stem cell damage may porting cells within the seminiferous tubuli. This is a be irreversible and the red marrow is replaced by fat, common neoplasia in dogs, especially in dogs with cryp- leading to neutropenia, thrombocytopenia and moder- torchid testicles. Almost 50% of all canine Sertoli cell ate to severe anemia (Villiers and Blackwood, 2005). tumors arise in cryptorchid testes and the incidence of The use of lithium appeared to be successful in in- Sertoli cell tumors is more than 20 times higher in cryp- ducing regeneration of the bone marrow in dogs (Hall, torchid than in scrotal testes (Hayes and Pendergrass, 1992). In humans, various drugs have been used suc- 1976). Approximately 20 to 30% of dogs with Sertoli cessfully to treat aplastic anemia: corticosteroids, an- cell tumor manifest signs of hyperestrogenism, char- drogens, lithium carbonate and cyclophosphamide.
acterized by any combination of feminization, gy- Bone marrow transplantation is also another possibil- necomastia, atrophy of the contralateral testicle (as in ity in humans (Kjeldsberg et al., 1989).
the present case), squamous metaplasia within the In the present case, Deca-Durabolin (nandrolonde- prostate gland (often with accompanying suppurative canoate) was used. This drug is an anabolic steroid and prostatitis), alopecia and bone marrow atrophy (as in the is useful in treating certain types of anemia, such as present case) (McEntee, 1990). It has not been proven aplastic anemia and anemia due to chronic kidney fail- that estrogen is solely responsible for all these mani- ure. In certain cases where the bone marrow has festations. Serum estrogen concentrations are not in- stopped producing new erythrocytes, administration of creased in some dogs with apparent hyperestrogenism anabolic steroids will stimulate this system again and associated with testicular Sertoli cell tumor (Grooten- bring the numbers of these cells back to normal levels.
huis et al., 1990). However, in the present case the es- They also are known to stimulate the production of white trogen concentration was markedly increased. Estrogen- blood cells and platelets, though to a lesser degree. In induced production of myelopoiesis-inhibitory factor by summary, the present dog showed a severe estrogen- thymic stromal cells has been described (Grootenhuis induced pancytopenia due to neoplastic transformation et al., 1990; Farris and Benjamin, 1993). The bone mar- of cryptorchid testes (paraneoplastic syndrome), which row suppressive effects accompanying Sertoli cell tu- gradually improved to almost within reference ranges mors, also known as aplastic anemia, can be so severe after castration, blood transfusions and administration as to cause anemia, leukopenia and thrombocytopenia. Aplastic anemia is characterized as a nonregenera- tive anemia with normal erythrocytic indices, neu- tropenia, and thrombocytopenia, and it suggests amultipotential stem cell disorder. Cytologic evaluation We would like to thank the staff of Medisch Labo of the bone marrow of the present case confirmed bone Bruyland and Labo Pathologie Yperman for their as- marrow aplasia. Neutropenia from decreased cellular production usually has a minimal left shift (due to anincreased demand for neutrophils and/or depletion of the bone marrow storage reserves of mature neu-trophils). Crafts R. C. (1948). The effects of estrogens on the bone mar- Differential diagnosis of nonregenerative anemia in- row of adult female dogs. Blood 3, 276–285.
cludes: infections (canine parvovirus, Ehrlichia canis), Farris G. M., Benjamin S. A. (1993). Inhibition of drugs (estrogens, meloxicam, griseofulvin, chemother- myelopoiesis by serum from dogs exposed to estrogen.
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gen induced effects may disappear after removal of the Hayes H. M., Pendergrass T., W. (1976). Canine testicular tu- underlying cause of the myelotoxicity, i.e. castration in mors: epidemiologic features of 410 dogs. International the present case. Treatment also includes: correction of Journal of Cancer 18, 482–487.
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