Diagnosis and treatment of neuroendocrine tumors in the cervix

Cervical neuroendocrine cancer accounted for less than 2% of all invasive cervical cancers, divided into low-level (class and atypical) and high-level (small and large cells) neuroendocrine cancer.
increasing data suggest that cervical neuroendocrine cancer may be associated with human papillomavirus infection (HPV), especially HPV18, and that most cervical neuroendocrine cancer p16 immunoglobation stains are positive.
and CD56 are the most sensitive immune grouping markers for cervical neuroendocrine cancer.
although there are no exact associated gene mutations, PIC3CA, KRAS, and TP53 are the most common gene mutations in neuroendocrine tumors.
cervical neuroendocrine cancer is a highly invasive tumor that is prone to lymph nodes and distant metastasis.
age, lymph node metastasis, smoking, small cell neuroendocrine cancer and tumor size were independent prognostic factors.
, the five-year survival rate for cervical neuroendocrine cancer was 36%, with an average total survival rate of 22-25 months.
current treatment for cervical neuroendocrine cancer is usually based on the treatment of small cell lung cancer and on the basis of limited retrospective research.
treatments are mostly comprehensive, including surgery, chemotherapy and systemic chemotherapy.
most commonly used chemotherapy treatment is a combination of cisplatin and etoposide.
in the case of relapsed diseases, the combined treatment of topological tycon, yew alcohol and beval monoantigen has demonstrated good results.
multi-center tumor registration study, such as neuroendocrine cervical tumor registration study (NECTUR), is a good way to evaluate tumor treatment patterns and efficacy.
（Salvo G, etal. Int J Gynecol Cancer 29:986-995) Background neuroendocrine tumors are a relatively rare disease of the female reproductive tract, and the cervix is one of the most common primary sites1.
Albores-Saavedra first described the tumor in 1972, which accounts for 1.4 percent of all invasive cervical cancer, and about 200 new cases are explicitly diagnosed each year in the United States.
The World Health Organization (WHO) in 2014 classified cervical neuroendocrine tumors as low-level (formerly known as atypical) and advanced neuroendocrine cancers (formerly known as small and large cell carcinomas), as seen in Table 1.
In cervical neuroendocrine cancer, small cell neuroendocrine cancer is the most common, accounting for about 80%, followed by large cell neuroendocrine cancer about 12%, other histological types such as undifferentiated neuroendocrine tumors about 8%.
The main mode of spread of cervical squamous and adenocarcinoma is local spread, but high-level neuroendocrine cancer is different from them, even if early clinical detection found that the lesions are confined to the cervix, it has a high incidence of lymphatic and blood-based metastasis.
These tumors often affect lymphatic blood vessels, closely related to HPV18 infection, the risk of lymph node metastasis increased when diagnosis, 40% of the clinical phase IB1 cervical neuroendocrine cancer pelvic lymph node pathology results were positive, while the clinical phase IB1 cervical squamous cancer lymph nodes positive rate of 10%-15%3,4%.
, patients with cervical neuroendocrine cancer were mostly diagnosed with advanced 5,6.
is also common for first diagnosis of pelvic metastasis, especially in the lungs and liver, and is often associated with a high risk of recurrence.
the medium total survival rate of patients with small cell neuroendocrine cancer was less than 2 years 5, 6, 9-11.
, 147 studies in the literature have reported a total of 3,538 cases of neuroendocrine cervical cancer, and only 9 studies have had more than 50 cases3.
is still lacking in prospective research, which also leads to limitations in the development and application of specific chemotherapy programmes, and the initial treatment is multi-mode, including surgery, radiotherapy and chemotherapy 1213.
registered for neuroendocrine cervical cancer at MD Anderson Cancer Center.
all neuroendocrine cervical cancer patients are treated by the same team of doctors.
purpose of this review is to summarize the latest and most relevant information about the disease and to provide diagnosis and treatment.
will also explore the specifics of the disease to help doctors around the world better treat the rare disease.
the relationship between cervical squamous cell carcinoma, adenocarcinoma and adenocarcinoma and human papillomavirus (HPV) has been well confirmed and explored.
the link between cervical neuroendocrine cancer and HPV has not yet been defined, but a growing body of research suggests there may be a link between them.
Alejo et al. discussed HPV DNA testing and genotype distribution of 49 cases of neuroendocrine tumors in the neck and their relationship to histology and immunogenic characteristics.
found that 86% of neuroendocrine tumors had HPV DNA.
98% of cases reported a single infection (1 HPV type).
HPV16 positive rate in neuroendocrine cancer was 55%, HPV18 was 41% and other types of HPV positive rate was 4%.
incidence of HPV18 in neuroendocrine cancer is four times higher than in other histology (41%).
authors, the higher HPV18 rates in neuroendocrine and adenocarcinoma suggest that HPV18 has a greater impact on adenocrine and neuroendocrine cells than other HPV types.
, they also found that neuroendocrine cancer combined with adenocellular lesions were more likely to develop lesions than combined squamous cell lesions.
neuroendocrine cancer showed significant lymph node metastasis, which is also a characteristic of HPV18 infection-related malignancies 17 almost all squamous cell carcinoma (97%) and half of adenocarcinomas showed p16 positive staining 18.
Alejo and others found that p16 positive staining is a special manifestation of neuroendocrine cancer.
p16 protein overexposed in 86% of neuroendocrine cancer cases.
all types of cancer, atypical cancer and large cell neuroendocrine cancer were p16 positive, and 79% of small cell carcinomas were p16 positive.
, 89% of cases observed consistent p16 and HPV test results.
kuji et al. assessed 37 cases of high-level neuroendocrine cancer and found that 72 percent had a high risk of HPV infection (HPV16 14 percent and HPV18 86 percent) 19.
Castle et al. published a meta-analysis of 32 cases of small cell neuroendocrine cancer and 9 studies containing 45 cases of large cell neuroendocrine tumors, and found that 85% of small cell carcinomas were HPV-positive (HPV16 and/or HPV 18:78%).
subgroup analysis of five studies, including 75 patients with small cell carcinoma, the positive rate of immunoglostification test p16 was 93% and the positive rate of HPV was 100%.
HPV positive rate for large cell neuroendocrine cancer (HPV16 and/or HPV 18,86%).
study is important to explore the possible relationship between cervical neuroendocrine cancer and human papillomavirus infection, as it is possible to prevent these cancers with the application of the human papillomavirus vaccine.
it also offers the possibility to use immunotherapy or therapeutic vaccines to treat women with such diseases.
immune histation dyeing is often used in the diagnosis of neuroendocrine tumors.
most commonly used neuroendocrine stains are chromosomal protein A, synaptic protein, CD56, and neuron-specific ene alcoholase.
for large cell neuroendocrine cancers, chromosomal protein A is the most specific marker that can help with a definitive diagnosis, in addition to HE chromosomal morphology.
the positive rate of small cell neuroendocrine tumors was between 33% and 100%.
in the latest systematic review published by Tempfer et al., the 13 most common immunoglostmarkers were synaptic protein (79 percent), neuron-specific oleolase (69 percent), chromium-like granules (66 percent) and CD56 (61 percent).
synactin and CD56 are the most sensitive neuroendocrine markers, but CD56 is not specific.
chromoglobin is the most specific neuroendocrine marker, but lack sensitivity, small cell neuroendocrine cancer positive rate of about 50%.
In Alejo et al., the positive rate of at least one immunostory chemical marker (chromosomal protein, CD56 and/or synaptic growth hormone) was 65%, with CD56 most common (62%), followed by chromium globulin (39%) and synaptic growth hormone (26%)16%.
same time, other researchers found that CD56 was the most sensitive marker of neuroendocrine differentiation (62 percent), followed by chromosomal protein A (39 percent) and synaptic protein (26 percent) 21,22.
of chromosomal globulin may be closely related to intermittent cytochrome immunoreactiveness, which is only visible under high-fold magnifying glasses.
small cell neuroendocrine cancer may only be locally positive (often intermittent cytotyte staining), or even broad-spectrum cell keratin negative.
as mentioned earlier, due to the presence of high-risk HPV infection, most cervical advanced neuroendocrine cancer p16 staining is diffuse positive 21.
insulin tumor-related protein 1 (INSM1) may be more specific to neuroendocrine tumors than chromosomal protein A or synaptic growth hormone23.
recent study, 37 advanced neuroendocrine cases were stained with neuroendocrine markers and INSM1.
in 86% of cases, both chromoglobulin A and synaptic growth hormone were expressed.
INSM1 was detected in 95% of cases, the INSM1 protein appears to be a useful new neuroendocrine marker that may be associated with the development of high-level neuroendocrine cancer.
In a pathology report that included 24 cases of neuroendocrine cervical cancer in large and small cells in patients, MD Anderson Cancer Center studied immunoglobic expression and prognosis of HER-2/neu, skin growth factor receptors (EGFR), endodertic growth factors (VEGF), epoxyase-2 (COX-2), estrogen receptors, and progesterone receptors.
23 (96%) expressed VEGF, 8 (33%) expressed EGFR, 10 (42%) expressed HER-2/neu, and 7 (29%) expressed COX-2.
there was no significant difference in the expression of these factors in large and small cell neuroendocrine cancer.
only HER-2/neu expressions were associated with survival rates, indicating that the survival rates of HER-2/neu expression negative patients were significantly lower than those of tumor-positive patients, at 14.2 months and 33 months (p-0.03) 24, respectively.
addition, immunoglostroming may help determine the origin of metastatic small cell carcinoma.
studies have shown that 33%-84% of small cell cervical cancers test positive for diffuse nucleopolyticity on thyroid transcription factor-1 (TTF-1) 21 25-27.
Liu et al. compared 23 cases of cervical small cell neuroendocrine cancer with 56 cases of pulmonary small cell carcinoma neuroendocrine markers, TTF-1, p53 and Ki-67.
expression of TTF-1 in small cell carcinoma tissue in the lungs was significantly higher than in cervical cancer tissue (P-0.003).
two tumors have similar morphological characteristics, they have different immune histological expressions.
the positive rates of CD56 and chromosomal protein A were similar, but the expression of synaptic protein in cervical small cell neuroendocrine cancer was significantly higher than that of small cell lung cancer (P-0.007).
immunogroup staining is important for the diagnosis of cervical neuroendocrine cancer, but it should be noted that when using standard markers, positive staining may be as low as 33%, and dyeing may only be positive at the lesions.
if the diagnosis is still unclear, new markers should be considered because they show higher positive rates, such as NMS-1 and VEGF.
detection of small cell cervical cancer is a rare tumor, and there is no definitive molecular mutation event.
study explores the opportunities for individualized treatment of such diseases, especially in the context of the current limited range of treatment options for relapsed diseases.
high-risk HPV may be involved in the early stages of many tumor occurrences, other molecular biology-driven events, development promoting the development of small cell carcinoma in the middle and late stages.
identification of carcinogenic drivers helps to better understand the evolution of neuroendocrine tumors.
in the latest systematic review, the most common mutations were p53 (26%), kras (12%), pik3ca (18%) and c-myc (53%).
more than 30% of cases found that the hybrid gene is missing 13.
44 patients with simple or mixed small cell cervical cancer were identified by Frumovitz et al.
patients were analyzed using a new generation of mutation hotspot sequences of 50 cancer-related genes.
35 mutations were identified in 24 patients (55%).
most patients (63%) had one mutation, 29% had two mutations, and 8% had three mutations.
in all 44 patients, the most common mutations were pic3ca (n=8;18%), kras (n=6,14%) and tp53 (n=5,11%).
no other mutations were found in specimens with a population greater than 7%.
21 (88%) of the 24 patients with the mutation had at least one mutation, and there is currently a class of biologics for the mutation.
although no common mutations have been found in patients with small cell cervical cancer, nearly half of patients have at least one gene mutation target that can be used for targeted therapy.
important for treating patients with relapsed diseases with limited options.
mutation analysis may help to select a phase I trial or even an "out-of-the-way" treatment