Adenoid cystic carcinoma of the Bartholin’s gland: Two case reports and review of literature

Abstract

BACKGROUND

Adenoid cystic carcinoma (ACC) of the Bartholin’s gland represents an exceptionally rare malignancy with limited documented cases in the medical literature. It typically manifests as a solid mass that clinically warrants suspicion for neoplastic processes.

CASE SUMMARY

This case series details two cases of primary ACC cases involving the Bartholin’s gland treated with radical surgical resection of the vaginal lesions. Notably, divergent therapeutic approaches resulted in contrasting prognoses: The patient receiving adjuvant radiotherapy following surgery maintained disease-free status with no locoregional recurrence or metastatic progression through 58 months of surveillance. Conversely, the non-radiated patient experienced disease recurrence within 18 months postoperatively.

CONCLUSION

Our findings suggest that postoperative radiation therapy may significantly decrease local recurrence rates in Bartholin’s gland ACC, potentially influencing long-term disease control. This comparative outcome analysis underscores the importance of integrating adjuvant radiotherapy integration into treatment protocols for this rare malignancy.

Key Words: Bartholin’s gland; Adenoid cystic carcinoma; Exenteration of vaginal mass; Radiation therapy; Case report

Core Tip: In two cases of primary adenoid cystic carcinoma (ACC) involving the Bartholin’s gland treated with radical surgical resection of vaginal lesions, different therapeutic approaches resulted in contrasting prognoses: The patient who received adjuvant radiotherapy after surgery remained disease-free with no locoregional recurrence or metastatic progression through 58 months of surveillance, whereas the untreated patient experienced disease recurrence within 18 months postoperatively. Postoperative radiotherapy may significantly reduce local recurrence rates in Bartholin’s gland ACC, potentially influencing long-term disease control.

INTRODUCTION

Bartholin’s gland carcinoma (BGC) is an exceptionally rare malignancy, constituting approximately 0.1%–5% of vulvar cancers and 0.001% of all gynecologic neoplasms[1]. Histological subtypes encompass squamous cell carcinoma, epithelioid-myoepithelial carcinoma, neuroendocrine carcinoma, Merkel cell carcinoma, and adenoid cystic carcinoma (ACC), which reflect the embryological origin of the gland’s from the urogenital sinus and its heterogeneous epithelial composition[2-4]. Among these variants, ACC is one of the rarest manifestations that arises in the greater vestibular glands (Bartholin’s glands) of the vulva. Due to the scarcity of ACC and the absence of prospective randomized controlled trials, standardized therapeutic protocols remain undefined[4]. This report describes the clinical management of two cases of ACC in female patients, supplemented by a comprehensive literature review to contextualize the diagnostic and therapeutic challenges.

CASE PRESENTATION

Chief complaints

Case 1: In April 2020, a 52-year-old Chinese multiparous woman (gravida 6, para 1) presented to our institution with a progressively enlarging mass in the right Bartholin’s gland region.

Case 2: A 46-year-old female presented to a local clinic with a 12-month history of a progressively enlarging, asymptomatic mass in the left posterior labium minus. The lesion had initially been misdiagnosed as a Bartholin gland cyst. Physical examination revealed a 3 cm irregularly marginated tumor near the left Bartholin’s gland, with intact vaginal mucosa and perineal skin. Bimanual and inguinal examinations showed no additional abnormalities. Tumor marker panels [e.g., cancer antigen 125 (CA-125), carcinoembryogenic antigen (CEA)] were within normal limits. Initial biopsy confirmed ACC, characterized by infiltrative nests of basaloid cells with cribriform architecture. The patient underwent partial vulvectomy under general anesthesia in November 2020. Histopathology confirmed a left Bartholin’s gland ACC with negative resection margins, a diagnosis of International Federation of Gynecology and Obstetrics (FIGO) Stage I vulvar carcinoma was established (T1N0M0). Adjuvant therapy was deferred postoperatively.

History of present illness

Case 1: Her medical history included a Bartholin’s cyst managed conservatively with local heat therapy a decade prior, without prior incision, drainage, or catheterization. The current lesion had grown from approximately 1 cm to 2 cm in diameter over 2-3 months, accompanied by persistent discomfort during sitting. She reported no additional symptoms, denied a history of sexually transmitted infections, and had a recent normal cervical Pap smear.

Case 2: 18 months after the initial treatment, the patient presented to our institution with a new left vulvar mass.

History of past illness

Case 1: She reported no history of hypertension or any other medical conditions.

Case 2: She reported no history of hypertension or any other medical conditions.

Personal and family history

Case 1: No personal or family history was available.

Case 2: No personal or family history was available.

Physical examination

Case 1: Digital examination revealed unremarkable external and internal genitalia, with a firm, immobile 2.5 cm mass localized to the right Bartholin’s gland area. Vaginal mucosa and perineal skin appeared intact, and no nodularity or extension was noted on rectovaginal palpation.

Case 2: Gynecologic examination identified a 3 cm × 3 cm firm, tender lesion in the left vestibular gland region.

Laboratory examinations

Case 1: Admission laboratory studies, including complete blood count and renal/hepatic function panels, were within normal limits. Histological analysis of the biopsy specimen revealed carcinoma with myoepithelial differentiation, characterized by neoplastic cells forming irregular papillary and tubular structures. Immunohistochemistry confirmed the myoepithelial lineage, with strong positivity for p63 and smooth muscle actin (SMA) in the peripheral cell layers of the tubular formations (Figure 1).

Figure 1 Contrast-enhanced pelvic computed tomography imaging and pathological images of case 1. A: Pelvic Computed tomography with IV contrast revealed right-side asymmetry in the vulvar region, described as a 1.8 cm × 1.5 cm rounded, uneven reinforcement area with blurred margins; B: Pathological images of hematoxylin and eosin-stained samples showing carcinoma with myoepithelial components. Neoplastic cells with mildly enlarged nuclei were noted, and these cells formed irregular papillary or tubular structure (hematoxylin and eosin × 100); C: P63; D: CK7 revealed diffusely positive staining (EnVision × 100).

Case 2: Tumor marker panels (e.g., CA-125, CEA) were within normal limits. Initial biopsy confirmed ACC, characterized by infiltrative nests of basaloid cells with cribriform architecture.

Imaging examinations

Case 1: Contrast-enhanced pelvic computed tomography (CT) demonstrated a 1.8 cm × 1.5 cm heterogeneously enhancing lesion with ill-defined margins in the right vulvar region, distinct from adjacent structures (urethra, anus, and vaginal wall). No lymphadenopathy or distant metastasis was observed (Figure 1).

Case 2: Pelvic magnetic resonance imaging (MRI; in April 2022) demonstrated a 3 cm × 4 cm × 3 cm × 3 cm heterogeneous soft tissue mass in the left posterolateral vaginal introitus and anteromedial infiltration of the vaginal wall without midline crossing (Figure 2). A-repeat biopsy confirmed ACC recurrence.

Figure 2 Pelvic magnetic resonance imaging and pathological images of case 2. A: Enhanced nuclear magnetic resonance revealed left-side asymmetry in the vulvar region, described as a 3 cm × 3 cm unrounded, uneven reinforcement area with blurred margins; B: Pathological images of hematoxylin and eosin-stained samples showing carcinoma with myoepithelial components. Neoplastic cells with mildly enlarged nuclei were noted, and these cells formed irregular papillary or tubular structure (hematoxylin and eosin × 20).

FINAL DIAGNOSIS

Case 1: The preoperative diagnosis was FIGO Stage II vulvar carcinoma (T2N0M0). The patient underwent radical surgical excision of the mass (Figure 3), with final pathology confirming negative resection margins.

Figure 3 Surgical specimen and pathological images of case 1. A: Surgical specimen from the vaginal mass; B: Pathological images of hematoxylin and eosin stained samples revealing adenoid cystic carcinoma.

Case 2: The diagnosis suggests a recurrence of the tumor.

TREATMENT

Case 1: Adjuvant intensity-modulated radiation therapy (IMRT) was administered, targeting the right inguinal region (45 Gy in 25 fractions, 1.8 Gy/fraction) and tumor bed (55 Gy in 25 fractions, 2.2 Gy/fraction) (Figure 4).

Figure 4 Treatment of case 1 External radiotherapy treatment: The dose was 45 Gy divided into 25 fractions of 1.8 Gy over the right inguinal region and 55 Gy divided into 25 fractions of 2.2 Gy over the tumor bed. A: Transverse image of radiotherapy; B: Coronal image of radiotherapy; C: Sagittal image of radiotherapy.

Case 2: Wide local excision of the left vulva was performed, with final pathology confirming ACC (Figure 2). Immunohistochemical profiling revealed: Ductal epithelium: CEA (+), epithelial membrane antigen (+). Myoepithelial cells: p53 (+), p63 (+), SMA (+), calponin (+), CD117 (+); S-100 (-). Proliferative index: The Ki-67 positivity rate was approximately 10%. The surgical margins were tumor-free. The patient underwent adjuvant treatment, which included external pelvic radiotherapy at a dose of 50.4 Gy divided into 28 fractions of 1.8 Gy over the left inguinal region. The tumor bed received a dose of 56 Gy divided into 28 fractions of 2.0 Gy, delivered by a technique of IMRT with concurrent weekly 40 mg/m² cisplatin chemotherapy. Treatment tolerance was excellent, with only Grade 2 dermatitis and dysuria per Radiation Therapy Oncology Group (RTOG) criteria (Figure 5).

Figure 5 Treatment of case 2 external radiotherapy treatment: The dose was 50.4 Gy divided into 28 fractions of 1.8 Gy over the inguinal regions and 56 Gy divided into 28 fractions of 2.0 Gy over the tumor bed. A: Transverse image of radiotherapy; B: Coronal image of radiotherapy; C: Sagittal image of radiotherapy.

OUTCOME AND FOLLOW-UP

Case 1: Treatment tolerance was favorable, with only grade 2 dermatitis and dysuria per RTOG criteria. At 58 months of follow-up, the patient remains disease-free, with no evidence of local recurrence or metastatic progression (Figure 6).

Figure 6 Follow-up of case 1. A: Images of Pelvic Computed tomography with IV contrast when followed-up 58 months; B: Images of liquid-based cytology testing of the vaginal when followed-up 58 months.

Case 2: At the 38-month post-treatment surveillance, clinical and radiographic evaluations (MRI) showed no evidence of locoregional recurrence (Figure 7). The patient remains on a structured monitoring protocol.

Figure 7 Follow-up of case 2. A: Image of enhanced nuclear magnetic resonance when followed-up 38 months; B: Images of liquid-based cytology testing of the vaginal when followed-up 38 months.

DISCUSSION

ACC is a rare malignancy that occurs most frequently in the head and neck salivary glands. Clinically, it exhibits paradoxical behavior; it is slow-growing, yet locally aggressive, with a propensity for perineural invasion and late metastases. First described in 1853 by Robin and Laboulbène as “tumeur hétéradénique” and later classified as an adenocarcinoma by Foote and Frazell in 1953[5], ACC rarely manifests in the Bartholin’s glands (greater vestibular glands) of the vulva, a presentation termed BGC. BGC predominantly affects postmenopausal women with a median age of 53 years[6]. Epidemiological studies have reported a 5-year progression-free survival rate of 47% and an overall survival rate of 71%, highlighting its indolent but persistent clinical course[7]. Diagnosis is often delayed because of nonspecific symptoms (e.g., painless vulvar masses) that mimic benign Bartholin’s cysts, highlighting the need for heightened clinical suspicion in women over 40 years of age presenting with vulvar lesions.

The most common complaints associated with ACC of Bartholin’s gland are burning pain, palpable masses, and swelling, which can mimic a benign condition. Consequently, initial misdiagnosis or delayed diagnosis may occur in up to 50% of patients[8]. In the case of this malignancy manifesting in older, sexually inactive women, the diagnosis can be delayed, often resulting in the malignancy being detected at an advanced stage. By this time, urinary and rectal symptoms persist for an extended duration.

The underlying mechanisms driving the development and progression of ACC remain incompletely understood. Although certain squamous subtype ACCs have shown a potential link to human papillomavirus (HPV) infection, notably HPV-16, as observed in cervical cancer cases[9], the role of HPV in ACC appears to be context-dependent. Miller et al[10] revealed a low prevalence (11%) of HPV involvement in sinonasal ACCs, suggesting a limited association with this anatomical subtype[10]. Notably, pure ACCs originating in the bartholin gland have been uniformly negative for high-risk HPV in multiple studies[11,12], a finding further reinforced by Nakamura et al[13] Through the analysis of two cases lacking p16 overexpression, a surrogate marker for HPV oncogenic activity, their work provided molecular evidence supporting the hypothesis that HPV does not contribute to the pathogenesis of Bartholin gland ACCs[13].

Molecular insights into salivary gland ACC revealed characteristic genetic alterations that affect key oncogenic pathways. Recent studies have identified recurrent mutations in chromatin regulators, including PIK3CA, ATM, and TSC1, in these tumors[14]. Togashi et al[15] detected that MYB or MY BL1 Locus rearrangements have been identified in nearly all ACCs examined, suggesting that these rearrangements may serve as effective diagnostic markers for ACCs[15]. Recently, gain-of-function mutations in NOTCH1 have been associated with poor outcomes in patients diagnosed with ACC[16]. Pure ACCs from the Bartholin gland parallel other anatomical sites, featuring characteristic MYB-NFIB and MYBL1-NFIB fusion oncoproteins that underscore shared pathogenesis mechanisms[12]. These recurrent translocations have demonstrated diagnostic utility, with MYB/MYBL1 rearrangement analysis emerging as a valuable adjunct tool for confirming AdCC-BG diagnosis[17]. Diagnostic confirmation of Bartholin gland carcinomas requires stringent clinicopathological correlation. Histopathological assessment must demonstrate: (1) Architectural continuity with the Bartholin gland anatomy; (2) Transition zones between normal glandular tissue and neoplastic elements; and (3) Exclusion of secondary malignancies through a comprehensive workup[12]. The ACC comprises epithelial and myoepithelial cells, which can manifest as a variety of tubular and cribriform structures with various solid components. The cribriform pattern, the most typical and recognizable architectural form, is characterized by nests of tumor cells interrupted by sharply punched spaces filled with basophilic basement membrane material[4]. A distinctive feature of the tubular pattern is the haphazard proliferation of tubular structures, which are frequently lined with two layers of tumor cells[12]. Furthermore, tumor cells surrounding pseudocysts exhibit immunoreactivity for SMA, p63, and S-100, suggesting myoepithelial differentiation. The lumen of the pseudocyst demonstrates intense immunoreactivity for markers such as CK8/18, AE1/AE3, and cKIT/CD117, indicating a myoepithelial lineage[4]. This integrated diagnostic approach, which combines molecular genetics, histomorphology, and immunophenotyping, enhances the diagnostic precision for these rare malignancies.

The management of ACC, particularly at rare sites such as the Bartholin gland, remains poorly standardized because of the rarity of the disease and the absence of robust prospective trials[18]. Current strategies prioritize surgical resection as the cornerstone of treatment, with procedural selection guided by tumor characteristics and patient-specific factors. The surgical approach encompasses wide local excisions, hemivulvectomy, simple vulvectomy, and radical vulvectomy, with or without inguinal and/or femoral lymphadenectomy, which is determined on a case-by-case basis, considering factors such as patient age, reproductive status, comorbidities, and the presence of pregnancy. The European Society of Gynecological Oncology guideline recommends surgical excision margins of at least 1 cm. Surgical excision aims to achieve tumor-free margins that decrease the likelihood of local recurrence. Hemivulvectomy is recommended for lesions measuring less than 2 cm, whereas radical total vulvectomy and inguinofemoral lymph node dissection are the preferred surgical approaches for larger lesions[4]. One study revealed that 30% of patients in the radical vulvectomy group had positive resection margins compared with 48% in the simple excision group[19]. However, the role of lymph node dissection in ACC remains controversial. The prevailing opinion among experts in the field is that lymphadenectomy should not be routinely recommended unless there is clinical or radiological suspicion of lymph node involvement, as this tumor often metastasizes to distant organs before involving locoregional lymph nodes[2].

Because of the absence of prospective trials, a consensus regarding the efficacy of radiation therapy remains elusive. ACC is characterized by its propensity for frequent and often silent distant metastases, likely attributable to its proclivity for extensive perineural invasion compounded by delayed diagnosis[20]. Distant metastasis of ACC is rare, with the most prevalent sites being the lungs, followed by the liver and, in rare instances, the bone[21]. To date, guidelines for postoperative chemotherapy in BACC have not been established. In the event of distant metastasis, chemotherapeutic alternatives, such as chlorambucil-adriamycin, methotrexate-dactinomycin, cyclophosphamide-adriamycin-cisplatin, or cyclophosphamide, can be used[19-24]. Budd et al[25] reported complete remission of metastatic ACC of the salivary gland using a combination of intravenous 5-fluorouracil 500 mg/m² and Adriamycin 30 mg/m² every 4 weeks, mitomycin C on the first day and every 8 weeks at a dose of 10 mg/m²[2], and a combination of cyclophosphamide 750 mg/m², cisplatin 60 mg/m², and doxorubicin 40 mg/m², all administered intravenously on day 1 every 3 weeks, continuing for a maximum of six cycles[22].

Several reports have emerged that support the notion that adjuvant radiotherapy confers benefits to patients diagnosed with breast cancer with positive surgical margins. A review by Hsu et al[22] reported that among 16 cases of surgical margin positivity treated with adjuvant radiotherapy, ten patients did not experience local recurrence. In contrast, six patients developed distant metastasis[6]. This finding suggests a beneficial role of adjuvant radiotherapy in reducing local recurrence. Copeland et al[7] reported nine (25%) recurrences (six local, two distant, and one local and distant), and it is noteworthy that local failure occurred in one of 14 patients (7%) who received adjuvant irradiation compared with six of 22 (27%) who did not[8,23]. Alsan et al[24] reported that radiation therapy decreased local recurrence, especially in patients with positive margins. Positive margins exhibited a 35% recurrence risk compared to a 10% recurrence risk observed in negative margins, indicating that radiotherapy can effectively manage local recurrence[21]. This finding suggests a beneficial role for adjuvant radiotherapy, at least in reducing local recurrence.

As previously indicated in our reports, the initial patient who received radiotherapy demonstrated a positive outcome at the subsequent follow-up. Conversely, patients who did not undergo radiotherapy experienced rapid recurrence. Notably, radiotherapy has been observed to reduce the likelihood of local tumor recurrence; radiotherapy was administered to 21/77 patients, and the recurrence rate was statistically higher in the group without radiotherapy (P = 0.010). Adjuvant radiotherapy has been reported to be beneficial in cases of surgical margin positivity[2,22]. Alsan et al[24] reported that ERT reduced recurrence rates regardless of the surgical margin status. Postoperative adjuvant radiation therapy using a combination of photon and electron beams typically delivers 45-50 Gy to the target volume, which includes the vulvar and inguinofemoral lymph nodes. In cases where complete tumor resection with free margins is achieved, radiotherapy is focused on the locoregional lymph node territories in the event of lymph node metastasis[19]. An additional boost of 10–15 Gy to the primary lesion in the vulva is recommended in cases with positive margins, and brachytherapy is one of the best ways to increase the dose to the residual tumor in contact with the urethra or vagina[24]. Acute and late radiation-related morbidity is a significant concern in the management of vulvar carcinomas, and novel treatment strategies, particularly those that combine radiotherapy and chemotherapy, should incorporate advanced radiation techniques, such as intensity-modulated radiation therapy, to minimize the occurrence of severe complications. Denise et al. demonstrated that patients exhibited a favorable response to bimodality treatment, with a dose delivery of up to 24 GyE C12 plus 50 GyE photons, resulting in a substantial enhancement in local control and overall survival. C12 therapy followed by photon IMRT provides a treatment alternative for patients with pelvic ACC, particularly those with locally advanced disease[25,26]. Thibault et al[27] reported using a CT-based HDR-ISBT boost in five patients with BGC in a separate study. All five patients received high-dose-rate interstitial brachytherapy (HDR-ISBT) as a boost (median dose, 30 Gy) after EBRT (median dose, 45 Gy). A complete response was observed in all patients, and no local recurrence was observed. All patients remained alive and disease-free (median follow-up, 78 months; range, 8-93). These findings suggest that HDR-ISBT boost after EBRT offers excellent long-term local control in patients with BGC[26]. Varela et al[17] recommended that radiotherapy or chemoradiotherapy should be the first choice for the treatment of Bartholin’s gland cancer because of its lower morbidity and better preservation of normal function. In their report, ten patients were treated with primary radiation or chemoradiation, and only four patients developed recurrence (three of them had stage I disease; only one patient had advanced-stage disease). The most common adverse effects of radiation therapy are desquamation, dermatitis, and bowel symptoms (including diarrhea, constipation, and temporary incontinence), which are successfully treated with conservative methods[27].

CONCLUSION

Our findings suggest that postoperative radiation therapy may significantly decrease the local recurrence rates in Bartholin’s gland ACC, potentially influencing long-term disease control. This comparative outcome analysis underscores the importance of integrating adjuvant radiotherapy into treatment protocols for this rare malignancy. Given the limited number of cases presented, the possibility of cancer should be considered in any female older than 40 years of age with a lesion near the Bartholin’s glands, and the optimal management of ACC of the Bartholin’s gland should be tailored to each patient. Because recurrence may occur over a long period, long-term follow-up is required for such patients.