Keywords
adenoid cystic carcinoma - Bartholin gland - gynecology - oncology - vulvar neoplasms
Palavras-chave
carcinoma adenoide cístico - glândula de Bartholin - ginecologia - oncologia - neoplasias
vulvares
Introduction
Primary adenoid cystic carcinoma (ACC) of the Bartholin gland is a rare tumor first
described in 1859.[1] It corresponds to approximately 0.001% of all gynecological malignancies and to
2% to 7% of vulvar malignant tumors. Tumors of the Bartholin glands may have different
histological forms, but approximately 80% consist of squamous-cell carcinomas and
adenocarcinomas.[2]
[3]
[4] The diagnosis of Bartholin gland cancer is usually late, because it has a nonspecific
clinical presentation and differential diagnosis with Bartholin gland cyst and Bartolinitis.
As a consequence, it is often discovered at an advanced stage, with a risk of lymph
node (inguinal and pelvic) or general (pulmonary and bone) metastases.[4]
The present article is the report of a rare case of ACC with high-grade transformation
(HGT-ACC), which has only been reported in carcinomas in other regions, such as the
head and neck. To our knowledge, this is the first reported case of HGT-ACC of the
Bartholin gland.
Case Report
A 77-year-old woman, nulliparous, postmenopausal but not undergoing hormonal therapy,
with a history of infertility and resection of an ovarian cyst in 1966. In October
2016, the patient presented a non-ulcerated vulvar lesion of 5 cm in diameter on the
topography of the right Bartholin gland, with apparent deep-layer infiltration without
associated inguinal lymph node enlargement. Magnetic resonance imaging (MRI) and positron
emission tomography-computed tomography (PET-CT) were performed, which showed a tumor
measuring 4.0 × 2.7 × 3.8 cm on the topography of the right Bartholin gland topography,
involving the distal third of the right labia majora of the vulva, the lower third
of the vagina, and the distal urethra, with vulvar uptake with a standardized uptake
value (SUV) of 11.22, without metastatic disease, lymph node involvement, or invasion
of the mesorectal fascia and pelvic floor musculature. A biopsy of the lesion revealed
a high-grade undifferentiated carcinoma in a limited material with no recognizable
morphology of ACC.
Tumor resection was performed under general anesthesia and spinal anesthesia. In the
perioperative period, tumor invasion of the right ischioanal fossa was evidenced,
with involvement of the levator ani muscle, extending up to the bladder, but without
bladder invasion. Extended local excision of the tumor was performed with macroscopically
free margins, without lymphadenectomy. At the end of the procedure, no gross macroscopic
lesions were observed ([Fig. 1]). The intraoperative analysis of a frozen section showed tumor-free surgical margins.
We used the V-Y advancement flap from the medial thigh for vulvar reconstruction.
Upon macroscopic inspection of the resected specimen, we established that the lesion
was a solid mass measuring 5.0 × 4.0 × 3.0 cm, showing ulcerated tumor lesion measuring
4.0 × 3.5 cm, and distant 0.2 cm from the lowest margin.
Fig. 1. Surgical specimen (A) and immediate postoperative view of the reconstructed vulva with a V-Y island flap
(B).
The microscopic analysis of the histopathological examination revealed a primary ACC
of the Bartholin gland, with areas of high-grade morphology, extensive perineural
invasion, and presence of angiolymphatic emboli ([Fig. 2]). The areas with conventional ACC had a morphological aspect ranging from tubular
and cribriform areas to solid areas, and some transition areas composed of well-differentiated
components with HGT were observed ([Fig. 2E]). The high-grade components were predominantly composed of solid architecture (71%)
and highly atypical pleomorphic nuclei with a high number of mitoses. The immunohistochemical
study with p53 showed a diffuse and strong positive reaction in HGT areas, and some
tubular and cribriform areas also stained positively for p53 ([Fig. 3]). In both the well-differentiated component and the HGT-ACC, P63 positivity was
observed. The deep and circumferential margins of the surgical piece had no signs
of neoplasia.
Fig. 2. Microscopic features of the case herein reported. Histologic evaluation of primary
adenoid cystic carcinoma of the Bartholin gland, with areas of high-grade morphology
and extensive perineural invasion (hematoxylin-eosin, magnification ×100). (A) Area with well-differentiated tumor component; (B,C,D) areas with high-grade transformation; (E) transition area composed of well-differentiated components with high-grade transformation.
Fig. 3. Immunohistochemical evaluation of primary adenoid cystic carcinoma of the Bartholin
gland, with areas of high-grade morphology (magnification ×100). (A) Difuse positivity of p53; (B) p53 positivity in the well-differentiated component; (C) Immunostaining for p63 in the well-differentiated component; (D) p63 in the high-grade component; (E) pan cytokeratin AE1/AE.
The patient received adjuvant treatment with external pelvic radiotherapy. Intensity-modulated
radiation therapy (IMRT) was indicated and the dose was 45 Gy divided into 25 fractions
of 1.8 Gy over the right inguinal region and the tumor bed. In addition, another boost
of 14.4Gy was performed, divided into 8 fractions of 1.8Gy, reaching a total dose
of 59.4Gy in the tumor bed, including the urethra. The patient presented good tolerance
to the treatment, evolving only to dermatitis and moderate dysuria (according to the
scale of the Radiation Therapy Oncology Group [RTOG]), and remained in clinical follow-up
for 24 months, with no signs of relapse.
After the follow-up period, the patient remained asymptomatic, but presented signs
of recurrence of the disease on PET-CT, with the presence of surgical-site hypermetabolism
(SUV: 3.81) and bilateral pulmonary nodules (SUV: 3.35). Cisplatin and 5-fluorouracil
(5-FU) chemotherapy was initiated. However, the patient died during treatment due
to disease progression. Death occurred 36 months after the diagnosis.
Discussion
Slow growth, high rate of local recurrence, perineural invasion, and usual late onset
of distant metastases are known characteristics of ACC.[5]
[6] It is found mainly in the glandular tissues of the head and neck, especially in
the salivary glands. However, in other tissues, such as in the breast and uterine
cervix, ACC can also be detected, and displays the same behavior as salivary gland
carcinoma.[5]
[7] Histologically, ACCs are characterized by three different growth patterns: tubular,
cribriform, and solid growth. The number of solid segments seems to be the most important
prognostic factor for adverse events.[8] A study[9] on ACC in the salivary glands showed that distant metastases occurred in 73% of
the patients with a solid growth pattern, compared to 17% of cases with tubular growth
pattern, and 8% with cribriform growth pattern. In the case herein reported, we observed
percentages of distribution of growth patterns similar to those reported in the literature,
with a predominance of the solid pattern.
A rare phenomenon not reported in the traditional ACC classification is the undifferentiation
or HGT. The first description of this phenomenon in a case of ACC was made in 1999.[10] High-grade transformation is defined as the abrupt change of a well-differentiated
tumor into undifferentiated morphology that does not have the original histological
characteristics, making high-grade morphological areas usually well demarcated. However,
in some cases, it is possible to identify a transition zone for a more typical morphology
with cribriform and tubular areas, with frequent perineural invasion.[8] Although not easily identified, some transition areas, composed of well-differentiated
components with HGT, were observed in the microscopic analysis of the tumor of the
case herein reported ([Fig. 2E]).
The histological features present in HGT areas are thickening or irregularity of the
nuclear membranes, prominent central nucleoli, necrosis, and microcalcifications.
In addition, some features are considered major criteria, such as increase in nuclear
size, confluent solid nodules, incomplete and focally absent luminal cell layers,
increased Ki-67 labeling, fibrocellular desmoplastic stroma, micropapillary, squamous
areas, and overexpression of p53.[11] In the present case, although the electron microscopic findings of such tumors revealed
that the nuclear membranes were not thickened, such findings appear on hematoxylin-eosin
(H&E) staining.
With the use of immunohistochemistry, specific tumor characteristics can be observed
to distinguish well-differentiated areas of ACC from HGT-ACC. The p63 tumor marker,
a myoepithelial marker, is present in well-differentiated ACC and absent or focally
absent in HGT- ACC.[11]
[12] In the case herein reported, p63 positivity was observed in both the well-differentiated
component and the HGT-ACC. Another marker that can be used for this identification
is Ki-67, most expressed in areas with HGT.[12] In addition to these, some studies have shown that p53 genes have increased expression
in the high-grade component, although other studies show that this marker may also
have increased expression in well-differentiated ACC.[8]
[10]
[11]
[12] There is evidence that overexpression of the p53 gene in well-differentiated ACC
is accompanied by a worse prognosis. Thus, changes in the p53 gene may be associated
with the appearance of undifferentiated tumor cells, characterizing a marker of poor
prognosis.[13]
[14] In the case herein reported, a diffuse positivity was observed for p53 in the well-differentiated
component, which may have contributed to the poor outcome.
To differentiate between HGT-ACC and solid ACC, in addition to the immunohistochemical
characteristics, some cellular characteristics can be evaluated. Nuclear increase,
irregularities and necrosis of chromatin appear to be more pronounced in HGT-ACC.
In addition, confluent sheets, fibrocellular desmoplastic stroma, necrosis, and high
mitotic activity are also found in HGT-ACC. In cases in which the transition from
well-differentiated ACC to HGT-ACC is not as abrupt as described in most cases, some
characteristics can be found in both HGT-ACC and solid ACC, such as pleomorphism,
mitotic activity, and focal necrosis.[12] In the present case, the microscopic analysis of the histopathological examination
of tumor recurrence identified solid areas with pleomorphic areas with high mitotic
index.
HGT-ACC is a variant of ACC with a more aggressive behavior, with a high probability
for the development of recurrences and metastases.[11]
[15] A study[11] on subjects with head and neck HGT-ACC showed that approximately 57% of these patients
developed lymph node metastases, compared to 5% to 25% of those with well-differentiated
ACC. In addition, this study[11] indicated that 81% of the patients reported in the literature with HGT-ACC had recurrence
of the disease. Of these 81%, 56.3% presented local recurrence, 57.9% presented lymph
node metastasis, and 47.1% were diagnosed with distant metastases.[11] The most common site of metastasis is the lung.[2] The patient described in the present study presented both local recurrence and distant
metastasis at the most common site.
Since ACC is a rare tumor and there are no prospective and randomized controlled trials
on it, the treatment is not consensual,[4] but surgical resection is the preferred treatment. It can be performed with wide
local excisions, hemivulvectomy, simple vulvectomy, and radical vulvectomy with and
without inguinal and/or femoral lymphadenectomy. In patients with deep local infiltration,
positive incisional margin or recurrence, adjuvant radiotherapy or chemotherapy can
be performed.[2]
[3] The patient herein described underwent extended local excision of the tumor followed
by adjuvant radiotherapy as the primary treatment, and chemotherapy after tumor recurrence.
Considering the lack of consensus on treatment recommendations for Bartholin gland
carcinomas and negative PET-CT for lymph node involvement, we chose not to perform
lymphadenectomy. When we compare our case to a series of cases of Bartholin gland
carcinomas described in the literature,[7] we observe coincident recurrence sites (the vulva and lung). However, the patient
in the case herein presented was older when compared to the average age observed in
the literature (72 years against 57 years), and the follow-up was shorter in our case
(36 months against 41.9 months) than in in the case series mentioned.[7] This shorter follow-up was due to the patient's death.
Conclusion
We reported a case of a 77-year-old woman with a primary ACC of the Bartholin gland,
with areas of high-grade morphology, extensive perineural invasion, and presence of
angiolymphatic emboli. To our knowledge, this is the first case of HGT reported in
ACC of the Bartholin gland. Our patient was treated with extended local excision of
the tumor, with free margins, followed by adjuvant radiotherapy. After 24 months of
follow-up, the patient presented distant metastases, and the outcome was death, despite
the chemotherapy received, reinforcing the aggressiveness of the tumor and probably
of the HGT. A rare tumor, ACC of the Bartholin gland has no established diagnostic
methods or defined treatment standards. Further research is needed to improve the
understanding of the incidence and prognosis of HGT-ACC in gynecological tumors, including
those of the Bartholin glands.
