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Small cell carcinoma of hypercalcemic type (SCCOHT) is a rare gynaecological neoplasm, originating mostly in the ovaries. Cervical origin of this very aggressive malignancy with unknown histogenesis is an extremely rare condition, without published management recommendations. Alterations in
Small cell carcinoma of the ovary (SCCO) is a very lethal malignancy. It contains two separate subtypes: the pulmonary type (SCCOPT), and hypercalcemic type (SCCOHT) [
SCCOHT is one of the most frequent malignant undifferentiated ovarian tumors in women younger than 40 years. It is a rare and highly lethal tumor that typically affects young women. Many women are diagnosed at early stage. However, the aggressive behaviour of SCCOHT leads to a significantly bad prognosis, while most women die within 1 year after the diagnosis is established. The prognosis is bad even for very early stage SCCOHT.
SCCOHT was first described in 1982 in a series of 11 patients with concurrent SCCO and hypercalcemia [
Familial SCCOHT cases may be more often bilateral [
A NCDB study (National Cancer DataBase) showed a high frequency of elevated CA125 (84% of cases) [
SCCOHT is well described in the miscellaneous ovarian tumors chapter in the recent WHO Classification of Female Genital Tumours (2020). Grossly, the tumor is usually unilateral, large, solid, and tan to white to grey. Foci of haemorrhage, cystic degeneration, and necrosis are common. Microscopically, the tumor is composed of monomorphic cells, arranged mostly in solid and, less commonly in follicular, trabecular, or nested growth pattern. The follicle-like spaces may contain eosinophilic or basophilic secretions. In most cases, the predominant tumor population consists of cells with round, ovoid, or occasionally spindled hyperchromatic nuclei with coarsely clumped chromatin and small nucleoli and with scant cytoplasm (so-called “small blue round cell” appearance). Mitotic activity is typically brisk and proliferation index Ki67 is regularly high. In about half of the tumors, larger cells with eccentric vesicular nuclei with prominent nucleoli and with abundant eosinophilic cytoplasm (so-called rhabdoid appearance) are present. If significantly predominant, a “large cell variant” of the tumor may be considered. In up to 15% cases, a minor mucinous component either in the form of benign glands or cysts, or rarely as malignant signet-ring cells is present. The stroma of the tumor is usually minimal, it may be, however, myxoid or edematous in occasional cases [
Recently, loss of SMARCA4 (a.k.a. BRG-1) expression, due to germline or somatic mutation of
Differential diagnosis depends on the proper localization of the tumor and includes, in principle, any poorly differentiated malignant tumor. Regarding malignancies of the uterine cervix, particularly poorly differentiated adenocarcinoma, adenosquamous or squamous cell carcinoma, malignant melanoma, small cell neuroendocrine carcinoma, SMARCA4-deficient undifferentiated uterine sarcoma, dedifferentiated endometrial carcinoma, non-Hodgkin malignant lymphomas, high-grade leiomyosarcoma and rhabdomyosarcoma, Ewing sarcoma, and germ cell tumors (e.g., embryonal carcinoma and yolk sac tumor) must be considered. As regards more common ovarian localization, particularly the juvenile variant of granulosa cell tumor needs to be distinguished [
As regards ovarian carcinoma, e.g.,
SCCOHT has typically a low mutation load with low PD-L1 (Programmed Death Ligand-1) expression, which makes this cancer less suitable for immune checkpoint blockade treatment. However, the response of SCCOHT to modern immunotherapy has to be studied, with some positive response already reported [
Next generation sequencing (NGS) technologies as Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) can distinguish driver and passenger mutations or non-pathogenic normal gene polymorphisms in ovarian carcinomas [
More than a hundred of pathogenic
In all mentioned studies, immunohistochemical SMARCA4 (a.k.a. BRG1) protein expression was lost in 82–95% of SMARCA4 altered tumors, confirming inactivating mutations of SMARCA4 gene with defective protein production. For comparison, only 0.4% of other primary ovarian tumors have negative SMARCA4 protein expression.
Other SCCOHT tumors with intact SMARCA4 protein expression may carry mutations in other SWI/SNF complex subunits, e.g., inactivating SMARCB1 (alias INI1), or ARID1A mutations [
To maintain the chromatin remodeling activity of the SWI/SNF complex in human, three core subunits (INI1/SMARCB1, BAF155/SMARCC1, and BAF170/SMARCC2) and two helicases/ATPases (BRM/SMARCA2 and BRG1/SMARCA4) are essential [
The mammalian SWI/SNF complex functions as a tumor suppressor, and the subunits of the mammalian complex (encoded by
Surgical resection of the primary tumor with expert gynecologic pathology review is widely recommended by recent management guidelines [
Patients older than 40 years have a worse survival than younger ones, but there is no significant outcome difference between patients with and without germline
No prospective randomized phase III studies have been conducted to date in SCCOHT. With dose-intensive chemotherapy approach, a 3-year survival rate of 49% was reported among SCCOHT patients [
Adjuvant systemic treatment of SCCOHT is not standardized and achieves only a modest improvement of survival. The standard chemotherapy for ovarian carcinoma (paclitaxel/carboplatin or BEP–bleomycin/etoposide/cisplatin) is applied in most SCCOHT patients, with no clearly proven benefit [
On the other hand, some
Multi-modality intensive treatment approaches combining surgery, high-dose multiagent chemotherapy (with eventual stem cell transplantation), and postoperative radiotherapy may be an adequate treatment option for most SCCOHT patients [
Several agents such as bortezomib, pazopanib, or PARP inhibitors were described as possible treatment options for SCCOHT [
SCCOHT displays notable genomic stability and does not seem to acquire additional mutations after exposure to chemotherapy [
The available literature about radiotherapy in SCCOHT consists of smaller case series and single case reports. Some series suggest that postoperative radiotherapy may play an important role in the primary treatment of SCCOHT [
An 18-year-old female, virgo intacta, came to a gynaecologist for metrorrhagia. During the examination, a tumor of the cervix was found. Immediate biopsy was performed, and the patient was referred to the onco-gynaecological centre. Magnetic resonance imaging (MRI) of the pelvis revealed a tumor measuring 80 × 90 × 80 mm, growing from the cervical region,
Baseline MRI of the uterine cervix SCCOHT. The cervical tumor grows atypically more around the uterus, than infiltrating it. Expansive tumor growth with pressing to the bladder or rectum, with no clear infiltration into adjacent organs.
During explorative laparotomy, the removal of lymphadenopathy with histologically confirmed metastases of hypercalcemic small cell carcinoma was successful. However, radical hysterectomy without residual disease was impossible, unless the patient underwent anterior pelvic exenteration. The patient was immediately indicated for chemotherapy via our multidisciplinary team. In the absence of any treatment recommendations, first-line cisplatin plus etoposide combined chemotherapy was selected, with regular pelvic MRI before each subsequent cycle to monitor the treatment response. After 2 cycles of chemotherapy, progression of the disease in the uterus was found, with infiltration of bilateral parametria, the bladder wall and anterior rectal wall infiltration. Distant dissemination on whole-body CT was not clearly demonstrated, except for non-specific small lesions of both lungs up to 5 mm.
Due to gynaecological bleeding and micturition problems, the patient underwent extended-field pelvic radiotherapy with retroperitoneal lymph-nodes up to 45 Gy in 25 fractions, with a subsequent boost to the tumor, uterus and vagina up to a total dose of 59.4 Gy in 33 fractions. The pattern of tumor growth outside the uterus was not suitable for intracavitary brachytherapy. The patient managed radiotherapy without complications with clinical relief from both bleeding and urinary symptoms. The partial regression of both the tumor and lymphadenopathy was confirmed by MRI (
MRI confirming a partial tumor response 1 month after completion of radiotherapy at a dose of 59.4 Gy in 33 fractions. The treatment response was obvious, however incomplete.
Three months after radiotherapy, 7 months from the initial diagnosis, the patient was admitted to the hospital for general deterioration, breathlessness, fever, loss of appetite, and pain. Immediate CT of the head ruled out brain metastases. Although partial regression of the pelvic tumor was confirmed on the whole-body CT scan, there was massive systemic progression of the disease with mediastinal and neck lymphadenopathy, multiple metastatic lesions of the lungs and pleura with bilateral pleural effusions, multiple liver metastases (largest 52 × 36 mm), omental involvement with soft tissue masses (largest 72 × 56 mm), and ascites (
CT scan confirming rapid tumor dissemination with omental, liver, lung, and pleural metastases, with ascites and bilateral pleural effusion.
In the present case, the diagnosis of hypercalcemic small cell carcinoma (large cell subtype was based on the microscopic appearance of the tumor in hematoxylin and eosin staining and the result of immunohistochemical examination).
Microscopically, the tumor was composed entirely of large cells with vesicular, less commonly hyperchromatic nuclei, frequently with prominent nucleoli, and with abundant eosinophilic cytoplasm, sometimes imparting a rhabdoid appearance (
SMARCA4-deficient carcinoma of uterine cervix resembling SCCOHT. The tumor consists of cells with enlarged vesicular nuclei with clearly visible nucleoli and abundant eosinophilic cytoplasm. It is so-called large cell, or rhabdoid, variant of this tumor (hematoxylin-eosin, original magnification 400x).
Immunohistochemically, the tumor cells showed diffuse or nearly diffuse expression of broad-spectrum cytokeratins (CK), CK18, PTEN, β-catenin (membranous), vimentin, and GATA3. Expression of MLH1, PMS2, MSH2, and MSH6 was retained in tumor cell nuclei, indicating the absence of microsatellite instability (MSI). There was focal expression of p16. Isolated tumor cells showed expression of PAX8, CD10, calretinin, and synaptophysin. Detection of CK5/6, CK7, CK19, CK20, EMA, p63, p40, ER, PR, CEA, chromogranin, CD56, WT1, SALL4, Oct3/4, CD30, glypican-3, inhibin, SOX10, melan A, HMB-45, and LCA gave negative results. The expression of PD-L1 was negative in the tumor. The most diagnostically beneficial finding was the complete loss of SMARCA4 (a.k.a. BRG-1) expression (
SMARCA4-deficient carcinoma of uterine cervix resembling SCCOHT. Tumor cells are negative for SMARCA4 expression. The brown staining of the nuclei of non-tumor fibroblasts and inflammatory cells can serve as a positive internal control. (immunohistochemistry, original magnification 400x).
HPV DNA detection and genotypization was performed by qualitative real-time PCR with the AmoyDx Human Papillomavirus Genotyping Detection Kit (Amoy Diagnostics, China). In a DNA extract of the tumor tissue, no HPV DNA was detected.
Both germline and somatic WES of the patient and the tumor was performed. Library for whole exome capture and sequencing was prepared from DNA extracted from patient´s blood and tumor using TruSeq Exome Kit according to the manufacturer´s instructions. Prepared library was loaded onto NextSeq 500/550 Mid Output Kit v2.5 (150 cycles) and sequenced on the NextSeq 500 instrument (all Illumina, CA, United States). Sequencing coverage for exomes was >20× at > 90% of captured regions.
The mutation burden of the tumor was low (4 mutations/Mb). Examination of both the germline and somatic exome revealed the following selected variants (
Germline and somatic gene variants found by the Whole Exome Sequencing (WES).
Variants detected by germline WES | ||||
---|---|---|---|---|
Gene | Variant c.DNA/protein | Zygosity | gnomAD variant frequency | ACMG variant classification |
|
c.3976G>T/p.E1326* | Heterozygous | - | Likely Pathogenic (class 4) |
|
c.4199C>G/p.T1400R | Heterozygous | - | Uncertain Significance (class 3) |
|
c.509_510del/p.R170fs | Heterozygous | 0.007% | Pathogenic (class 5) |
|
c.8350C>T/p.R2784W | Heterozygous | 0.0008% | Pathogenic (class 5) |
|
c.272C>T/p.A91V | Heterozygous | 4.62% | Uncertain Significance (class 3); a risk allele |
|
||||
|
|
|
|
|
|
c.586C>T/p.R196C | 7% | Uncertain Significance (class 3) |
gnomAD variant frequency–Non-Finnish European population.
VAF, Variant Allele Frequency (frequency of the variant in the tumor sample).
ACMG classification, The American College of Medical Genetics and Genomics classification.
There were no other variants of the genes encoding SWI/SNF complex found, including
As several germline likely pathogenic or pathogenic gene variants were detected by WES (
A heterozygous c.3976G>T/p.E1326* variant in the
The patient’s father (42 years, no malignancy) showed a heterozygous c.509_510delGA/p.R170fs variant in the
The patient’s brother (23 years old, no malignancy) showed a familial heterozygous
Here we report the very first published case of SMARCA4-deficient carcinoma of the uterine cervix resembling SCCOHT and our challenging diagnostic process and dismal treatment experience. The histological picture of the disease, as well as the severity of its behavior and insufficient response to treatment does not seem to differ from the experience we have with the ovarian type of the disease. It was an aggressive tumor that affected a very young woman, with an advanced stage at diagnosis, with a rapid progression and a typical severe course of the disease, with early dissemination to the liver, peritoneum, and lungs, which resulted in death within 8 months from the first symptoms.
The main uncertainity of this case study is whether the uterine cervix was the place of origin of such a rare histology. Uterine cervix is rarely the site of metastatic spread of other malignancies, but this cannot be excluded. On the other hand, vaginal metastases constitute the majority of vaginal malignancies, which mainly originate from the cervix, endometrium, or ovary, among other locations. Since the status of ovary/ovaries has never been examined histologically in our patient, we cannot exclude primary ovarian SCCOHT with cervical manifestation. There was no tumor mass present in the patient on ultrasound, CT, or MR imaging. Theoretically, the ovarian lesion can be subtle and may not be picked up by imaging. However, this possibility seems highly unlikely.
The patient was a virgin at diagnosis, excluding HPV associated tumorigenesis. Moreover, the detection of HPV DNA was negative in tumor tissue. Clinical manifestation was otherwise not atypical, instead of the primary tumor growing more around the uterus, than infiltrating it. It is crucial to distinguish SCCOHT of the uterine cervix from the much more common squamous cell carcinomas or adenocarcinomas, that is possible only after careful histopathological examination. The most diagnostic is the loss of SMARCA4 (rarely SMARCB2 or ARID1A) expression immunohistochemically.
However, the microscopic differential diagnosis is very broad and includes any poorly differentiated/high-grade malignant tumor of both the uterine cervix and the uterine corpus. Absence of HPV DNA excludes the diagnosis of both HPV-associated squamous cell carcinoma and HPV-associated adenocarcinoma. Moreover, markers of squamous differentiation, i.e., CK5/6, p63, and p40, were completely negative and the absence of CK7 and CEA expression would be unusual in cervical HPV-associated adenocarcinoma. Morphology of the tumor excludes the diagnosis of any of HPV-independent cervical adenocarcinomas, i.e., of gastric type, of clear cell type, and of mesonephric type. Large cell neuroendocrine carcinoma shows significant expression of CD56, chromogranin, and synaptophysin. In the present tumor, the expression of CD56 and chromogranin was completely negative, and synaptophysin was detected only in isolated tumor cells, making the diagnosis of large cell neuroendocrine carcinoma unlikely. Germ cell tumors should be also considered. However, the expression of SALL4 as well as of other markers (Oct3/4, CD30, glypican-3) was completely negative, arguing against this diagnosis. Absence of expression of LCA and of “melanoma” markers (SOX10, melan A, HMB-45) excludes the diagnosis of hematologic malignancy and malignant melanoma, respectively. As regards the uterine corpus, particularly dedifferentiated/undifferentiated endometrial carcinoma and recently described SMARCA4-deficient uterine sarcoma enter the differential diagnosis [
The overall mutation load of the tumor was typically low, as expected in SCCOHT. The most probable pathogenic variant associated with SCCOHT that was found in the patient was only the germline
The patient inherited a heterozygous mutation in the
Germline variants in
Effective treatment options for SCCOHT are lacking. The rarity of SCCOHT limits the design of randomized clinical trials. Available evidence suggests the benefit of multi-modality treatment with radical surgery, high-dose multiagent chemotherapy with eventual stem cell transplantation. Postoperative radiotherapy may be advocated, considering retrospective case series and otherwise high rates of tumor recurrence and progression. However, clear evidence for the standard use of adjuvant irradiation is lacking and when used, we advise for the careful implementation of IMRT techniques sparing as much as healthy tissue as possible. Palliative directed radiotherapy may provide some treatment response with no proven curative potential. In our patient, a dose of 59.4 Gy in 33 fractions lead to a partial, incomplete response. Therefore, we strictly do not recommend definitive radiotherapy of SMARCA4-deficient carcinoma of the uterine cervix resembling SCCOHT with curative potential, as otherwise standardized in the treatment of advanced squamous cell carcinoma or adenocarcinoma.
Overall response of SCCOHT to standard chemotherapy regimens is poor, with rapid progression of the disease during or shortly after chemotherapy. In our patient, there was an early progression of the disease during platinum-based chemotherapy. Combined cisplatin/etoposide chemotherapy is a standard of care in lung small cell carcinoma. However, due to our experience, we do not recommend combined cisplatin plus etoposide as an effective treatment of cervical SCCOHT.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
The study involving human participant was reviewed and approved by Ethics Committee University Hospital Hradec Kralove. The patient provided written informed consent to participate in this study.
IS: patient treatment, data preparation, manuscript preparation; JL: pathological evaluation, manuscript preparation; HV: pathological and molecular evaluation, NGS evaluation, manuscript preparation; LM: conception and design of the work; interpretation of data; FH: interpretation of data, manuscript preparation; MŠ: genetic evaluation, manuscript preparation; MV: manuscript preparation, research, interpretation of data.
Supported by the programme PROGRES Q40/6, PROGRES Q40/11 and by the project BBMRI-CZ LM2018125.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.