Keywords
phyllodes - complete androgen insensitivity syndrome - testis
Androgen insensitivity syndrome (AIS) is a disorder resulting from complete or partial
resistance to the biological actions of androgens in an XY karyotype causing a female
phenotype with normal testis determination and production of age-appropriate androgen
concentrations.[1] Partial AIS (PAIS) has phenotype of varying degrees of masculinization which could
even be mild intensity such as gynecomastia or infertility in healthy men. They may
present with ambiguous genitalia, microphallus, severe hypospadias, and bifid scrotum
that may contain gonads.[2] Complete AIS (CAIS) on the other hand has a complete female phenotype with testis
and male equivalent androgen levels. They present with normal pubertal growth spurt
and breast development with history of primary amenorrhea.
AIS has been associated with gonadal malignancies, namely germ cell tumors. These
are more commonly seen in PAIS with a 6 to 15% incidence or higher if the testis are
present intra-abdominally.[1] Other tumors such as breast tumors are uncommon and are related to excessive hormone
administration.[2]
Phyllodes tumor is considered a rare tumor found in females. Although the exact etiology
for the tumor is not certain, it has a familial association and is associated with
syndromes such as Li–Fraumeni. The patients present with age ranging between 9 and
93 years.[3] There have not been any documented cases of phyllodes in association with AIS till
date. This is a case report of a 60-year-old patient with CAIS presenting with bilateral
phyllodes tumor of the breasts.
Case Report
A 60-year-old female presented with a bilateral breast lump since 3 years. The two
lumps grew in size with the left breast lump being larger than the right and both
involving the entire breast with a wound over the upper and outer aspect of the left
breast. On further enquiry, patient gave history of amenorrhea since childhood and
did not bare any children.
On examination, she was found to have a lump in both breasts which involved all four
quadrants. The left breast lump was larger and involved the skin. Both lumps were
firm and bosselated with dilated superficial veins. An ulcer of 2 × 2 cm was present
in the upper and outer quadrant of the left breast which was healthy. Central group
of lymph nodes were palpable in the left axilla which were firm with restricted mobility.
Right side lump was not attached to the underlying chest wall with no dilated veins
and no axillary lymph node involvement.
She was found to have bilateral swellings in the inguinal region which she claimed
to have since childhood. The swellings were both 10 × 6 cm in size and directed inferomedially
([Fig. 1]). They were firm, mobile, and increased in size on coughing.
Fig. 1 Anterior profile of the clinical presentation with bilateral breasts lumps (right
more than left) and bilateral inguinal masses.
Perineal examination showed feminine characteristics with a clitoris and labia minora
and majora. Vaginal vault prolapse was visible. On per vaginal examination the cervix
and uterus were not palpable. Per rectal examination was unremarkable.
Ultrasound (USG) of the breasts showed ill-defined solid masses with cystic spaces
involving all quadrants in the left side and the upper outer and inner quadrants of
the right breast. A left axillary lesion was also present. Internal vascularity was
seen with no evidence of calcifications within suggestive of sarcomatous changes likely
phyllodes. USG abdomen and pelvis showed agenesis of the uterus with right and left
inguinal masses with few cystic areas and microcalcifications.
Core needle biopsy of bilateral breast lumps was taken. Right breast biopsy showed
fragments of stromal tissue with scanty foci of papillary lesions and no evidence
of malignancy. Left breast biopsy showed fragments of stromal tissue with scanty foci
of papillary lesion. On immunohistochemistry, the left breast biopsy tissue showed
the myoepithelial cells highlighted within and around the lesion with p40 and calponin.
This was suspicious for papillary neoplasm.
Magnetic resonance imaging (MRI) of the pelvis was done to further investigate the
herniated mass. It showed bilateral inguinal heterogeneous structures measuring 3.2 × 5.2 cm
on the right and 4.3 × 2.6 cm on the left. The lesion showed heterogeneous hyperintensity
on T2-weighted image (T2W1), isointense on T1WI, and heterogeneous postcontrast enhancement
([Fig. 2]). There was mild fluid surrounding both the masses. The findings were suggestive
of bilateral testis with malignant transformation. There were also structures resembling
epididymis and spermatic cords. Bilateral patent processus vaginalis was visualized
through which herniation of inguinal masses with small bowel was visible. There was
a presence of vagina with an absence of Mullerian duct structures and ovaries. Posterior
urethrocele and anorectal descent below the level of pubococcygeal line was seen in
neutral position. Bilateral lobulated breast masses (left > right) were visible with
left breast mass being more heterogeneous and with indistinct fat planes with the
left chest wall.
Fig. 2 T1- and T2-weighted magnetic resonance imaging (MRI) transverse section of pelvis
showing bilateral testis. White arrow showing the right testis, white arrow head showing
the right epididymis, and the black arrow with white outline showing the left testis.
A positron emission tomography with computed tomography scan was done which showed
massive metabolically active mildly lobulated mass lesion in the left breast parenchyma
(with deep component showing high grade metabolically activity) representing a neoplastic
pathology which favored sarcomatoid pathology. A similar multilobulated heterogeneous
mass lesion in the right breast showed low-grade metabolic activity. Herniation was
seen in bilateral labia with bowel loops and omental fat as its contents. There was
no active disease elsewhere.
Karyotyping was done which showed 46XY disorder of sex differentiation ([Fig. 3]). Chromosome analysis revealed genetic sex complement to be that of male with no
evidence of any structural or numerical abnormality. Hence, there was discordance
between the chromosomal, gonadal, and phenotypic sex.
Fig. 3 Peripheral venous blood karyotyping showing 46XY disorder of sex differentiation.
Hormone study was done which showed a follicular-stimulating hormone (FSH) of 6.86
mIU/mL, testosterone of 5.27 ng/mL (correlating to male), anti-Mullerian hormone of
2.395 ng/mL, serum dehydroepiandrosterone sulfate (DHEA SO4) of 184.2 (correlating
to male), and luteinizing hormone (LH) of 4.967 mIU/mL. Tumor markers showed an alpha-fetoprotein
value of 1.55 IU/mL, CA-125 of 39.91 U/mL, CEA of 3.39 ng/mL, and beta-human chorionic
gonadotropin (beta-HCG) of 4.43 mIU/mL (raised for males).
The overall clinico-radiological features were suggestive of a CAIS with female phenotype
(breast tissue formation with lump) and male genotype (presence of testis, epididymis,
and spermatic cords). Further investigations also confirmed the presence of raised
male hormones with a raised beta-HCG tumor marker.
The operative decision was taken to do a left modified radical mastectomy (MRM) due
to the aggressive nature and involvement of the left axillary lymph nodes, suggestive
of a malignant variety of phyllodes. This was planned alongside a right wide local
excision along with a bilateral gonadectomy and hernia repair.
Intraoperatively, the breast masses were seen to be highly vascular. Left MRM and
right side wide local excision was done. Closure was done with simple polyamide sutures
with drains placed bilaterally. Bilateral gonads were also dissected and seen to rest
in the inguinal canals from where they were carefully dissected out and a high inguinal
ligation of the cord with vessels was done. Bilateral hernioplasty was done.
Grossly, the right breast mass was 11 × 10 × 5 cm, lobulated, and firm. It was well
encapsulated. On cutting open it was seen to be grayish white and lobulated with no
areas of necrosis or hemorrhage. The left breast mass with axilla measured 32 × 19 × 11 cm
with the tumor reaching up to the skin. It was lobulated with a variegated appearance
with solid, firm to hard areas, with areas of hemorrhage and areas of myxoid changes.
Twelve lymph nodes were excised with the largest lymph node being 2 × 2 × 1 cm in
size.
The right gonad consisted of a testis of 7 × 6 × 4 cm with a spermatic cord of 7 cm.
It was encapsulated, smooth, and consisted of congested vessels. On cut section there
were multiple yellowish white nodules with areas of fibrosis and no necrosis or hemorrhage
identified. The left gonad consisted of a testis measuring 6 × 4 × 2.5 cm and a spermatic
cord of 8 cm. It was encapsulated and smooth with congested blood vessels. Cut section
showed multiple yellowish white nodules with areas of fibrosis and no necrosis or
hemorrhage.
Microscopic examination of the right breast tissue was suggestive of benign phyllodes
tumor with free margins ([Fig. 4]). Left breast tissue and lymph nodes were suggestive of malignant phyllodes tumor
with fibrosarcomatous, osseous, and chondroid areas seen along with muscle invasion
([Fig. 5]). Margins of the specimen were free of tumor. Bilateral gonads showed Leydig cell
hyperplasia with Reinke crystals and wit bilateral spermatic cord free of tumor.
Fig. 4 Low power view of the right breast showing benign phyllodes with overgrown stroma
and sparse epithelial elements.
Fig. 5 Low power view of the left breast showing malignant phyllodes with muscle invasion.
Patient was discharged on postoperative day 8 after all subcutaneous drains were removed
with a healthy suture line ([Fig. 6]). After suture removal, patient was advised to undergo adjuvant radiotherapy in
view of malignant phyllodes of the left breast. Follow-up of 9 months has shown the
patient to be symptom and disease free.
Fig. 6 Anterior profile of the postoperative presentation prior to discharge.
Discussion
AIS is a 46XY disorder of sexual development caused by inactivation of or deletion
in the X-linked androgen receptor (AR) gene.[4] This leads to decrease or abolishment of the androgenic effects on target tissues
depending on the degree of responsiveness of the genitals to external androgens. It
is caused by a mutation of the AR gene at Xq11Y12.[5] AIS is traditionally divided into three general phenotypical subgroups: CAIS with
female genitalia; PAIS with predominantly female, male, or ambiguous genitalia; and
mild AIS with male genitalia.[6]
Development of estrogen-dependent secondary sexual characteristics occurs as the result
of excess aromatization of androgens.[1] They could present with breast development, amenorrhea, lack of axillary and pubic
hair, absence of uterus and fallopian tubes, gonads in the abdomen, inguinal region
or labia, and have a taller physique. All these features were present in the present
case. Inguinal hernias are seen with AIS with 80 to 90% of those with CAIS[5] as in the present case. Endocrine features in AIS show an endocrine profile of a
hormone-resistant state with testosterone normal/slightly higher range, LH elevated,
and FSH and inhibin normal. Excess testosterone produced is peripherally aromatized
to estrogen which, together with LH-induced direct secretion of testicular estrogen,
results in serum estradiol concentrations higher than those noted in men and boys
but lower than those reported in women without CAIS.[1]
AIS has been seen to have an increased risk of testicular tumors. Rarely, they present
in the prepubertal age group. Studies have suggested an increased tumor risk of greater
than 30% in late adulthood if gonadectomy is not done.[7] As the case in the present study was 60 years of age, there was a high chance of
testicular tumor. Germ cell tumors are most commonly seen in these patients. Few cases
of tumors of nongerminal origin such as Leydig cell tumor, Sertoli cell tumor, sarcoma,
and lymphoma have been reported.[8] Present case showed Leydig cell hyperplasia of bilateral gonads; however, there
was no evidence of malignancy. Testicular neoplasia is avoided by gonadectomy in such
cases once puberty is attained.
Phyllodes tumors are rare primary breast malignancies which are commonly seen between
the ages of 40 to 50 years and are mostly seen in female individuals. Few cases of
phyllodes in males have been reported with those who have gynecomastia.[3] There have been no reports in the past of AIS with phyllodes. With this being the
first reported case of phyllodes in a case of AIS, it is safe to consider the finding
of phyllodes in the present case to be due to the presence of bilateral breast development.
Phyllodes present clinically with a breast lump with irregular borders and rapid progression.
Radiological examination can be done with USG and mammography. There is no clear indicator
of malignancy observed on either USG or mammography as they have features similar
to fibroadenoma on mammography and ultrasonography. Although MRI is considered to
be extremely sensitive for the detection of breast cancer, it is still difficult to
differentiate phyllodes from other breast tumor types.[3] Hence, the mainstay diagnosis is by histopathological examination of a biopsy sample
which was done through core needle biopsy in the present study.
Phyllodes are subclassified histologically as benign, borderline, or malignant.[9] The grading is based on the evaluation of criteria such as the stromal component:
nuclear pleomorphism, mitotic rate, overgrowth, cellularity, and aspects of tumor
margins. In the present study, the histology of the right breast tumor showed exaggerated
intracanalicular growth pattern with leaf-like projections extending into dilated
lumina with an intact basement membrane. There was also no evidence of abnormal mitosis,
ductal carcinoma in situ, apocrine metaplasia, necrosis, or malignancy in the tissue.
Hence, the right breast tissue was labeled as benign phyllodes. The left breast mass
tissue in the present study showed spindle cells arranged in various patterns with
areas of calcification, necrosis, and hyalinization. The tumor also showed infiltrating
borders with heterogeneous differentiation along with 10 to 12 mitotic figures/high-power
field. These features suggested the histological diagnosis of malignant phyllodes.
Surgery is the mainstay treatment for phyllodes. Breast conservation surgery is attempted
with a wide local excision of the tumor to prevent any local recurrences. The margin
of resection of the tumor has been arguable but recent studies show that there is
no direct relationship between local recurrence rate and the width of negative margins.[10]
[11] After consulting with the previous studies a decision was taken to do a wide local
excision with breast conservation surgery for the right breast. Due to the aggressive
nature and extent of the left breast tumor with the malignant grading, the decision
for a MRM was done. Wound closure was done with simple polyamide sutures bilaterally
with drains for adequate approximation and to prevent seroma accumulation.
Adjuvant radiotherapy, although controversial, has proven to give positive results
in various studies. Adjuvant chemotherapy, however, lacks the evidence of providing
benefits in reducing local recurrences or improvement in disease-free or overall survival
or death. Endocrine therapy has not been shown to be effective in phyllodes as well.
This led to the decision of further oncological assessment and the initiation of adjuvant
radiotherapy in this study. Follow-up of 9 months showed her to be disease and symptom
free.
Conclusion
CAIS is a syndrome of gonadal dysgenesis which can present with gonadal herniation
in the inguinal region. Gonads in CAIS could present uncommonly with conditions such
as Leydig cell hyperplasia as in the present case. Due to the presence of breast development,
there is a possibility of the development of breast tumors such as phyllodes which
are not usually seen in genotypic males. After adequate evaluation and planning, excision
of the tumor can be done safely in these patients. Regular follow-up would be mandatory
to look out for possible recurrences as is done in female patients with phyllodes
tumor. Overall survival can be improved with strategic treatment planning, surgery,
and postoperative surveillance.
