|MOLECULAR TUMOR BOARD
|Year : 2021 | Volume
| Issue : 1 | Page : 130-135
Rare case of Skene gland adenocarcinoma with RET-rearrangement
Suresh Kumar Bondili1, George Abraham1, Vanita Noronha1, Amit Joshi1, Vijay M Patil1, Nandini Menon1, Omshree Anil Shetty2, Anuradha Chougule2, Santosh Menon3, Pratik Chandrani2, Abhishek Mahajan4, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
2 Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
4 Department of Radiodiagnosis, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
|Date of Submission||11-Feb-2021|
|Date of Decision||28-Feb-2021|
|Date of Acceptance||06-Mar-2021|
|Date of Web Publication||26-Mar-2021|
Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Bondili SK, Abraham G, Noronha V, Joshi A, Patil VM, Menon N, Shetty OA, Chougule A, Menon S, Chandrani P, Mahajan A, Prabhash K. Rare case of Skene gland adenocarcinoma with RET-rearrangement. Cancer Res Stat Treat 2021;4:130-5
|How to cite this URL:|
Bondili SK, Abraham G, Noronha V, Joshi A, Patil VM, Menon N, Shetty OA, Chougule A, Menon S, Chandrani P, Mahajan A, Prabhash K. Rare case of Skene gland adenocarcinoma with RET-rearrangement. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Sep 27];4:130-5. Available from: https://www.crstonline.com/text.asp?2021/4/1/130/312100
| History and Examination|| |
A 57-year-old female patient with no comorbidities or family history of cancer presented with a 3-month history of vaginal mass and spotting. Past obstetric history revealed that she was married for 35 years, had 4 children by normal vaginal delivery, and was postmenopausal for 5 years. On per vaginal examination, a mass was palpated in the right paraurethral region involving the lower 2 cm of the introitus, and biopsies were taken from the external meatal mass and the endometrium.
| Radiology and Histopathology|| |
Magnetic resonance imaging (MRI) of the abdomen and pelvis done in May 2019 revealed an ill-defined hyperintense lesion of size 28 mm × 24 mm in the lower endometrial canal of the uterus with invasion of the myometrium and extension beyond the serosa and an enlarged node along the left internal iliac artery [Figure 1]. Contrast-enhanced computed tomography (CECT) scan of the thorax revealed multiple nodules of varying sizes in both the lobes of the lungs suggesting metastases [Figure 2]a. A biopsy revealed tumor cells in a ductal pattern with papillary and cribriform architecture. The tumor cells showed moderate nuclear atypia and moderately eosinophilic cytoplasm [Figure 3]. On immunohistochemistry, the tumor cells were found to be positive for estrogen receptor (ER), androgen receptor (AR), p16, alphamethyl acyl-CoA racemase (AMACR), CK7, CDX2, and vimentin, and negative for paired box gene 8 (PAX8), carcinoembryonic antigen, p40, and Wilms tumor protein 1 (WT1), favoring the diagnosis of an adenocarcinoma of Skene gland origin. The tumor cells were focally positive for CA125. The endometrial biopsy did not reveal any evidence of malignancy. The serum prostate-specific antigen (PSA) level was 0.005 ng/dl.
|Figure 1: (a and b) T2 axial MRI images of pelvis showing the Skene gland adenocarcinoma (ACRONYM: MRI-Magnetic resonance imaging)|
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|Figure 2: (a) Baseline CECT thorax in May 2019 showing multiple lung nodules, (B) CECT scan following six cycles of docetaxel and carboplatin in October 2019 showing partial response, (C) CECT scan in April 2020 showing new onset multiple lung nodules, (D) CECT scan in December 2020 showing stable disease following five cycles of gemcitabine and carboplatin chemotherapy (ACRONYM: CECT-Contrast enhanced computed tomography)|
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|Figure 3: Vaginal mass biopsy showing adenocarcinoma with ductal pattern and papillary and cribriform architecture (Hematoxylin and eosin, ×20)|
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| Treatment|| |
The patient was started on palliative chemotherapy with docetaxel and carboplatin in June 2019. Post three cycles of chemotherapy, she had symptomatic benefit in the form of a decrease in the size of the vaginal mass and reduced bleeding. The response CECT scan showed reduction in the size of the lung nodules with some nodules developing cavitation, suggestive of partial response. She received three more cycles of docetaxel and carboplatin, after which the response scan in October 2019 showed a maintained partial response [Figure 2]b. The patient tolerated chemotherapy well with no grade 3/4 toxicities and was kept under observation. In April 2020, she presented with an increasing frequency of non-productive cough. A CECT scan revealed an increase in the number and size of metastatic nodules scattered in the bilateral lung parenchyma with a stable mass in the lower third of the vagina and stable iliac adenopathy [Figure 2]c. Given the clinicoradiological progression, she was started on gemcitabine and carboplatin chemotherapy. Post the first cycle of chemotherapy, the patient had grade-3 febrile neutropenia, and the dose of chemotherapy was reduced to 75% from cycle two onward. The patient had stable disease on CECT post three cycles of chemotherapy. However, as she had prolonged grade-3 thrombocytopenia, after the 5th cycle, further chemotherapy was withheld, and she was kept under observation. Follow-up imaging in December 2020 revealed stable disease, and hence, she was continued on observation [Figure 2]d.
| Molecular Analysis (Next-Generation Sequencing)|| |
Next-generation sequencing (NGS) was performed at the time of initiation of second-line chemotherapy on the baseline periurethral mass biopsy sample using the AmpliSeq for Illumina Focus panel comprising 52 genes. The data were analyzed using ClinOme, a tool for NGS data analysis and clinical report generation. DNA and RNA libraries were prepared using the Ampliseq Focus library preparation kit and loaded on the Illumina MiSeq system for sequencing. Analysis of the raw NGS data using ClinOme revealed the presence of a TATA binding protein-rearranged during transfection (TBP-RET) fusion in this patient. The mean coverage was ×290 and read pairs per target were ×1691, with a Q30 (quality) value of 95%.
| Excerpts from The Discussion in The Molecular Tumor Board|| |
Skene gland adenocarcinoma is an extremely rare malignancy with very few cases reported in the literature. The Skene gland is analogous to the prostate gland in men. The molecular basis for the pathogenesis of Skene gland adenocarcinoma is not yet known. Recently, genetic characterization was attempted for the first time in a case of Skene gland adenocarcinoma which showed mutation and loss of heterozygosity of the phosphatase and tensin homolog (PTEN) gene. RET rearrangements occur in about 10–20% cases of sporadic papillary thyroid cancers, and 2–3% cases of non-small-cell lung cancer (NSCLC)., RET fusions have not been described in Skene gland adenocarcinoma before, and they are extremely uncommon in prostatic adenocarcinomas as well. The most common RET fusions in papillary thyroid cancer are CCCD6-RET and NCOA4-RET, and in NSCLC, the most common RET fusion is KIF5B-RET., Given the role of RET rearrangements in NSCLCs and thyroid cancers, it is likely to be the driver mutation in this patient. Interestingly, TBP is an uncommon fusion partner for the RET proto-oncogene, and its exact mechanism of tumorigenesis and sensitivity to RET inhibitors remains to be elucidated. The molecular tumor board recommended testing with fluorescence in situ hybridization for an orthogonal confirmation of the RET rearrangement. However, this could not be done as the tissue was depleted. Given the rarity of the disease and the absence of literature on the management of Skene gland adenocarcinoma, the molecular tumor board recommended the use of RET inhibitors for this patient at the time of disease progression.
| Literature Review on Skene Gland Adenocarcinoma|| |
Skene glands are periurethral glands in women that share histopathological and immunohistochemical similarities with the prostate gland in men. Female urethral adenocarcinoma can originate from more than one cell, including the glandular cells, ductal cells, or stromal cells of the Skene gland or other paraurethral glands. Female urethral adenocarcinomas can be classified as columnar/mucinous adenocarcinomas, clear cell carcinomas, and Skene gland adenocarcinomas., The average age at diagnosis for female urethral adenocarcinomas is 74.5 (range: 61–87) years. The tumor size ranges from 1 to 2 cm. The typical clinical presentation is a large mass in the urethral region with frequent urinary tract infections. Diagnosis is made using cystourethroscopy guided biopsy, and MRI is used to assess the local extent of the tumor.
Skene gland adenocarcinoma has histopathological features similar to those of the acinar prostatic adenocarcinoma with variable cribriform, fused, and poorly formed glands with a Gleason score of 4 + 4 = 8 in most of the reported cases. Immunohistochemical markers for Skene gland adenocarcinoma include PSA, P501S (also known as prostein), homeobox protein NK-3 Homolog A (NKX3.1), and AMACR. There are a few case reports of Skene gland adenocarcinomas with intestinal differentiation that are positive for cytokeratin 20 (CK20), caudal-related family of CDX homeobox genes (CDX2), and mucin 2 (MUC2) and negative for CK7. The origin of Skene gland adenocarcinoma from the paraurethral glands can be confirmed with the prostatic intraepithelial neoplasia 4 (PIN-4) cocktail involving cytokeratin, p63, and racemase. AMACR expression may also be present in gastrointestinal adenocarcinoma and clear cell adenocarcinoma of the urothelial tract. However, the morphology of Skene gland adenocarcinoma is similar to that of the conventional prostatic adenocarcinoma. In addition, PSA positivity has been reported in about only 50–80% of the cases of Skene gland adenocarcinoma. Hence, although PSA positivity favors the diagnosis of Skene gland adenocarcinoma, a negative PSA test would not rule out the diagnosis as long as the morphology of the tumor suggests Skene gland adenocarcinoma.
Given the rarity of this disease, there are no clear guidelines for the management of Skene gland adenocarcinoma. Surgical excision with or without adjuvant radiotherapy and chemotherapy is performed for localized disease., The role of palliative chemotherapy and androgen deprivation therapy (ADT) in Skene gland adenocarcinoma is not known. One case of localized Skene gland adenocarcinoma with a good PSA response to preoperative ADT has been described in the literature.
| RET Receptor|| |
The RET gene was discovered during the transfection of NIH/3T3 cell line with the human lymphoma DNA. RET is a cell membrane-associated receptor tyrosine kinase. Members of the glial cell line-derived neurotrophic factor family act as endogenous ligands for RET. The mechanism of action of the wild-type RET receptor as well as its aberrant activation are depicted in [Figure 4]. Germline gain-of-function mutations in the RET gene have been associated with familial medullary thyroid cancers and multiple endocrine neoplasia type 2A (medullary carcinomas of the thyroid gland, pheochromocytoma, and hyperparathyroidism) and 2B (medullary carcinomas of the thyroid gland, pheochromocytoma, marfanoid habitus, and mucosal neuromas).
|Figure 4: (a) Dimerization of the wild-type RET receptor protein upon ligand binding leading to phosphorylation of the tyrosine kinase domain and activation of the downstream signal transduction pathways. (b and c) RET rearrangement and activating mutations leading to ligand-independent constitutive activation of the tyrosine kinase domain and intracellular signaling pathways|
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| RET Alterations in NSCLC|| |
RET fusions or rearrangements involve the somatic juxtaposition of the 5'-sequences of other genes with the 3'-sequences of the RET gene. RET rearrangements occur in about 2–3% of all NSCLCs., RET alterations are mutually exclusive with other driver alterations such as those in the epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1 genes. They occur predominantly in younger patients, women, and non-smokers., The most common RET fusion partners are presented in [Table 1].
|Table 1: Commonly seen rearranged during transfection (RET) alterations in lung and papillary thyroid cancers|
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| RET Alterations in Thyroid Cancers|| |
RET rearrangements occur in about 10–20% of the sporadic papillary thyroid cancers (PTC). The most common RET fusions in PTC are CCDC6-RET and NCOA4-RET, comprising about 90% of the RET alterations. RET fusions have been found to be associated with an aggressive nature and advanced stage of the disease in some studies. RET fusions are seen in up to 50% of the cases of PTC and follicular carcinoma associated with radiation exposure. Unlike RET fusions, RET mutations are common in medullary thyroid cancers and are seen in about 40–60% of the sporadic cases and up to 98% of the familial cases.
| RET Fusions in Other Solid Tumors|| |
RET fusions have been described in epithelial ovarian tumors, salivary gland adenocarcinoma, pancreatic ductal adenocarcinoma, colorectal cancers, and several other malignancies.
| RET Inhibitors|| |
Non-selective RET inhibitors
Multi-kinase inhibitors with activity against the RET protein include vandetanib, cabozantinib, sunitinib, sorafenib, pazopanib, axitinib, lenvatinib, motesanib, imatinib, and ponatinib. The response rates for these multi-kinase inhibitors are summarized in [Table 2] and [Table 3].
|Table 2: Summary of non-selective rearranged during transfection (RET) inhibitors in non-small-cell cell lung cancer|
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|Table 3: Summary of non-selective rearranged during transfection (RET) inhibitors in medullary thyroid cancer|
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Selective RET inhibitors
Selective RET inhibitor such as selpercatinib (LOXO 292, LIBRETTO trial) and pralsetinib (BLU-667, ARROW trial) have recently been studied in Phase I/II trials [Table 4].,,, In previously platinum-treated patients with NSCLC harboring RET fusions, selpercatinib showed an objective response rate of 64% (95% CI: 54–73), with a median duration of response of 17.5 (95% CI: 12-not reached) months. In the treatment-naïve patients, the objective response rate was 85% (95% CI: 70–94), and 90% of the responses were ongoing at 6 months. The most common grade 3 toxicities were hypertension (14–21%), liver enzyme elevation (10–14%), hyponatremia (6–8%), lymphopenia (6%), and diarrhea (6%).
|Table 4: Summary of selective rearranged during transfection (RET) inhibitors in medullary thyroid cancer and non-small-cell lung cancers|
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| Conclusion|| |
With the recent increase in the availability of targeted drugs for various molecular aberrations, genetic characterization of the tumors should be pursued as much as possible, as it may help to select novel treatment strategies and improve the survival of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]