| disease | Cervical Cancer |
Cervical cancer occurs worldwide and is one of the most common cancers in the human body. It not only ranks first among cancers of the female reproductive organs but is also the most prevalent among various malignant tumors in women. However, its incidence shows significant regional variations. In China, the occurrence of cervical carcinoma exhibits a geographical distribution pattern where high-incidence areas often form contiguous clusters. Cities and counties with relatively high cervical carcinoma rates within provinces also frequently show interconnected patterns. The general trend is that rural areas have higher rates than urban areas, and mountainous regions have higher rates than plains. According to a retrospective survey across 29 provinces, municipalities, and autonomous regions, the mortality rate of cervical carcinoma in China ranks fourth among all cancer-related deaths and second among female cancers. The average age of onset for cervical carcinoma patients varies across countries and regions. In China, the majority of cases occur between the ages of 40 and 50, with another peak appearing between 60 and 70 years old. Cases before the age of 20 are rare.
bubble_chart Etiology
The exact cause of cervical cancer remains unclear. Extensive data from both domestic and international sources confirm that women who marry early, give birth early, have multiple pregnancies, or engage in disordered sexual activity have a higher incidence rate. Currently, it is also believed that cholesterol in smegma can be converted into carcinogenic substances by bacterial action, which is another significant contributing factor to cervical carcinoma.
bubble_chart Pathological Changes
Squamous cell carcinoma of the uterine cervix is the predominant type, accounting for approximately 90–95% of cases, while adenocarcinoma constitutes only 5–10%. However, there is no significant macroscopic difference between the two types, and both occur in the cervical vaginal portion or the endocervical canal.
(I) Gross Appearance Before progressing to invasive carcinoma, no specific abnormalities are visible to the naked eye, or it may resemble general cervical erosion. With the emergence of invasive carcinoma, the cervix may present the following four types:
1. Erosive Type: Around the external cervical os, there is a rough, granular area of erosion or an irregular ulcerated surface that bleeds easily upon contact.
3. Endophytic Type: Also called the infiltrative type. The cancerous tissue infiltrates deep into the cervical tissue, causing the cervix to become enlarged and firm, but the surface remains smooth or only exhibits superficial ulcers.
4. Ulcerative Type: As either the exophytic or endophytic type progresses further, the cancerous tissue undergoes necrosis and sloughing, forming ulcers. In severe cases, the entire cervix may be replaced by a large cavity. Due to frequent secondary infections, foul-smelling discharge is often present. Cervical cancer, particularly adenocarcinoma, can also grow into the endocervical canal, causing the cervix to enlarge into a barrel shape, which is another form of the endophytic type.
(II) Microscopic Examination
1. Atypical Hyperplasia: Atypical hyperplasia manifests as proliferation of basal cells, with not only hyperplasia but also disordered cell arrangement, nuclear enlargement, hyperchromasia, and uneven chromatin distribution, indicating nuclear atypia.
Atypical hyperplasia can be classified into mild, moderate, and grade III. ① Grade I atypical hyperplasia (dysplasia grade I): Epithelial cells are slightly disordered, with grade I cellular atypia, and atypical epithelium occupies the lower third of the epithelial layer. ② Grade II atypical hyperplasia (dysplasia grade II): Epithelial cells are markedly disordered, with obvious atypia, and atypical epithelium occupies the lower two-thirds of the epithelial layer. ③ Grade III atypical hyperplasia (dysplasia grade III): Almost the entire epithelium shows polarity disorder or loss, with significant cellular atypia that is difficult to distinguish from carcinoma in situ.
2. Carcinoma in Situ (CIS): Also known as intraepithelial carcinoma. The entire epithelial layer loses polarity, with markedly atypical cells, enlarged nuclei, hyperchromasia, uneven chromatin distribution, and mitotic figures. However, the lesion remains confined to the epithelial layer without penetrating the basement membrane or stromal invasion. Atypical cells may also extend into the cervical gland openings in the transformation zone, replacing the original columnar cells of the glands with multilayered atypical squamous cells, while the glandular basement membrane remains intact. This condition is termed cervical carcinoma in situ involving glands.
3. Microinvasive Carcinoma: On the basis of carcinoma in situ, occasional small clusters of cancer cells may be found penetrating the basement membrane, resembling teardrops invading the nearby stroma. The depth of invasion does not exceed 5 mm, the width does not exceed 7 mm, there is no fusion of cancerous foci, and no evidence of invasion into stromal vessels. Clinically, there are no distinctive features.
4. Invasive Squamous Cell Carcinoma: When cancer cells penetrate the epithelial basement membrane and invade the stroma to a depth exceeding 5 mm, it is termed invasive squamous cell carcinoma. Within the stroma, dendritic, cord-like, diffuse, or mass-like cancerous nests may appear.
Based on pathological sections, the degree of cancer cell differentiation can be classified into three grades: ① Grade I: Well-differentiated. The cancerous nests show a considerable amount of keratinization, with clearly visible keratin pearls. ② Grade II: Moderately differentiated (reaching the differentiation level of mid-cervical cells), with no obvious keratinization in the cancerous nests. ③ Grade III: Undifferentiated small cells (equivalent to the undifferentiated cells of the cervical basal layer).
5. Adenocarcinoma: Adenocarcinoma originates from the columnar epithelium that covers the surface of the cervical canal and the glands within the canal. Microscopically, glandular structures can be observed, and even papillary projections within the glandular lumens may be seen. The glandular epithelium proliferates into multiple layers, with short, atypical cells showing significant nuclear atypia and visible mitotic figures. When cancer cells fill the glandular lumens to the point where the original glandular structure is no longer identifiable, it is often difficult to distinguish adenocarcinoma from poorly differentiated squamous cell carcinoma. When adenocarcinoma and squamous cell carcinoma coexist, it is referred to as cervical adenosquamous carcinoma. Adenosquamous carcinoma is highly malignant, metastasizes early, and has a poor prognosis.
bubble_chart Clinical Manifestations
(1) Vaginal bleeding When the cancer invades the blood vessels in the stroma, bleeding begins. The earliest manifestation is slight bleeding or increased vaginal discharge after intercourse or bimanual examination in women of any age. Especially around menopause, the bleeding may be intermittent, irregular, and scant. In the advanced stage, bleeding increases and may even lead to life-threatening hemorrhage due to the erosion of larger blood vessels. Generally, exophytic cancers bleed earlier and more heavily, while endophytic cancers bleed later.
(2) Vaginal discharge This usually occurs after vaginal bleeding. Initially, the discharge is scant and odorless. As the cancerous tissue breaks down, a serous discharge may appear. In the advanced stage, necrosis and infection of the cancerous tissue can lead to copious foul-smelling purulent or rice-water-like leucorrhea.
(3) Pain This is a symptom of advanced cancer. When the parametrial tissue is significantly infiltrated and involves the pelvic wall, obturator nerve, or lumbosacral nerves, severe and persistent lumbosacral or sciatic pain may occur. If the pelvic lesions are extensive, obstruction of venous and lymphatic drainage may cause swelling and pain in the affected lower limb.
Based on medical history and clinical manifestations, especially in cases of contact bleeding, the possibility of cervical carcinoma should be considered first. A thorough general and gynecological examination should be performed, along with the following auxiliary tests:
(1) **Cervical smear cytology** is the primary method for detecting precancerous lesions and early-stage cervical carcinoma. However, attention must be paid to proper sampling and careful microscopic examination, as there is a 5%–10% false-negative rate. Therefore, results should be interpreted in conjunction with clinical findings, and regular screenings should be conducted using this method.
(2) **Iodine test**: The normal cervix or vaginal squamous epithelium contains abundant glycogen, which stains brown with iodine. In contrast, cervical columnar epithelium, cervical erosion, and abnormal squamous epithelial areas (including squamous metaplasia, dysplasia, carcinoma in situ, and invasive carcinoma) lack glycogen and thus do not stain. Clinically, after exposing the cervix with a vaginal speculum and wiping away surface mucus, iodine solution is applied to the cervix and fornix. Any abnormal iodine-negative areas can then be biopsied for pathological examination.
(3) **Cervical and endocervical biopsy**: If cervical smear cytology shows grade III–IV or higher but the cervical biopsy is negative, four-point biopsies should be taken at the 6, 9, 12, and 3 o'clock positions of the squamocolumnar junction. Alternatively, multiple tissue samples may be taken from iodine-negative areas or suspicious cancerous regions for histological examination. A small curette may also be used to scrape the endocervical canal, with the scrapings sent for pathological analysis.
(4) **Colposcopy**: While colposcopy cannot directly diagnose cancer, it assists in selecting biopsy sites for cervical tissue sampling. Statistics show that biopsies performed under colposcopic guidance achieve an accuracy rate of approximately 98% for early cervical carcinoma diagnosis. However, colposcopy cannot replace smear cytology or biopsy and cannot detect lesions within the endocervical canal.
(5) **Cervical conization**: If biopsy results are inconclusive regarding the presence of invasive carcinoma, cervical conization may be performed. However, diagnostic cervical conization is now rarely used. Once cervical carcinoma is confirmed, further tests such as chest X-rays, lymphangiography, cystoscopy, and proctoscopy may be conducted based on specific circumstances to determine the clinical staging of cervical carcinoma.
bubble_chart Treatment Measures
The management of cervical cancer is divided into atypical hyperplasia, carcinoma in situ, microinvasive carcinoma, and invasive carcinoma.
(I) Treatment Principles
1. Atypical hyperplasia: For biopsy-confirmed grade I atypical hyperplasia, initially treat as inflammation with follow-up smears every six months and repeat biopsy if necessary. Persistent lesions may continue to be monitored. For grade II atypical hyperplasia, laser, cryotherapy, or electrocautery is recommended. For grade III atypical hyperplasia, total hysterectomy is generally advised. If fertility is strongly desired, close follow-up after cone biopsy may be considered.
2. Carcinoma in situ: Total hysterectomy with preservation of bilateral ovaries is generally recommended. Some advocate removing 1–2 cm of the vagina. In recent years, laser therapy has been used domestically and internationally, but close follow-up is essential post-treatment.
3. Microinvasive carcinoma: Extended total hysterectomy with removal of 1–2 cm of vaginal tissue is generally recommended. Since lymph node metastasis is highly unlikely in microinvasive carcinoma, pelvic lymphadenectomy is unnecessary.
4. Invasive carcinoma: Treatment depends on clinical stage, age, overall health, and available resources. Common treatments include radiation, surgery, and chemotherapy. Generally, radiotherapy is suitable for all stages; surgical outcomes for stages Ib to IIa are comparable to radiotherapy. Cervical adenocarcinoma is less radiosensitive, so combined surgery and radiotherapy is preferred.
(II) Surgical Treatment Radical hysterectomy and pelvic lymphadenectomy are performed. The resection includes the entire uterus, bilateral adnexa, upper vagina, paravaginal tissue, and pelvic lymph nodes (cervical, obturator, internal iliac, external iliac, and lower common iliac lymph nodes). The surgery must be thorough, safe, strictly indicated, and aim to prevent complications.
(III) Surgical Complications and Management
1. Complications include intraoperative bleeding, postoperative pelvic infection, lymphocyst formation, urinary retention, urinary tract infection, and ureterovaginal fistula.
2. With advancements in surgical techniques, anesthesia, prophylactic antibiotics, and postoperative negative-pressure drainage, the incidence of these complications has significantly decreased.
(IV) Radiation Therapy The primary treatment for cervical carcinoma, applicable at all stages. The radiation field includes the cervix, affected vagina, uterine body, parametrial tissue, and pelvic lymph nodes. Combined intracavitary and external beam radiation is typically used. Intracavitary radiation targets the primary cervical lesion and adjacent areas (uterine body, upper vagina, and parametrial tissue, "Point A"). External beam radiation targets pelvic lymph node regions ("Point B"). Intracavitary sources (radium or 137Cs) focus on the primary lesion, while external sources (60Co) target metastatic sites, including pelvic lymph nodes. The typical dose is 60Gy. For early-stage cervical carcinoma, intracavitary radiation is often prioritized. For advanced stages, especially with large tumors, active bleeding, or infection, external beam radiation is preferred.
(V) Chemotherapy Currently, cervical cancer is largely resistant to most chemotherapeutic agents, with response rates below 15%. Advanced-stage patients may benefit from combined chemotherapy and radiotherapy. Agents like 5-fluorouracil and doxorubicin can be administered intravenously or locally.
After treatment, if the clinical symptoms and signs of a cancer patient disappear but cancer signs reappear after more than six months, it is called a recurrence. Cases where cancer is still detected within 3 to 6 months after treatment should be classified as uncured.
(1) Prognosis of recurrent cancer patients Among patients who relapse after radiotherapy, the highest number of deaths occurs within one year after treatment, accounting for about half of the deceased patients, meaning that more than half of the relapsed patients develop symptoms within one year after treatment. Approximately 88% of recurrent cases show symptoms within three years after treatment. Subsequently, the mortality rate gradually declines without a clear pattern. Generally, 93% of deaths occur within five years, while 5% of deaths due to recurrence occur between 5 to 10 years after treatment.
(2) Survival time after recurrence of cervical carcinoma varies depending on the site of recurrence. For example, patients with recurrence at the vaginal stump or local recurrence may have a shorter survival time. According to an analysis of 200 recurrent cases in a foreign hospital, 50% survived from half a month to one year, 32% survived from one to two years, and 18% survived for more than two years.
(3) Site of recurrence In cases of persistent uncured disease, recurrence always occurs at the primary site. The location of recurrent cancer is often difficult to determine. Regarding the recurrence sites of cervical carcinoma after radiotherapy, statistics from 426 cases show: 112 cases (26%) in the uterus or upper third of the vagina; 54 cases (6%) in the lower two-thirds of the vagina; 18 cases (43%) in the parametrium and pelvic wall; 68 cases (14%) at distant sites; and 34 cases (8%) with unknown sites.
(4) Clinical manifestations The main symptoms of recurrent cancer include pain in one lower limb, aching pain in the abdomen and pelvis, vaginal bleeding, and foul-smelling leucorrhea. Other manifestations vary depending on the recurrence site, such as cough, chest pain, hematuria, rectal bleeding, etc. In addition to the primary lesion, most patients may have palpable masses in the lower abdomen or pelvic wall, as well as lower limb edema.
(5) Diagnosis The above symptoms and signs can serve as general diagnostic criteria for recurrent cancer. For cervical carcinoma patients, pain in one lower limb or lower limb edema after treatment indicates recurrent cancer in the pelvis compressing nerves or obstructing lymphatic or venous return. Postoperative recurrent cases are easier to diagnose. However, unabsorbed lymphocysts or pelvic inflammatory masses can sometimes be confused with recurrence. Early local aspiration for cytological smears and pathological examination is necessary to confirm the diagnosis. Examination of other body parts is also important. Attention should be paid to possible metastasis in supraclavicular or inguinal lymph nodes. If enlarged and hardened lymph nodes are found, they should be excised for pathological examination. Chest X-rays and gastrointestinal barium meal examinations may also be necessary.
(6) Treatment Once diagnosed, the treatment for recurrent cases still involves surgery, chemotherapy, or radiotherapy. First, analyze whether the previous treatment was reasonable, appropriate, and thorough. Then, based on the patient's overall and local condition, choose a suitable single therapy or combination therapy. For advanced-stage cases, symptomatic treatment should be provided. Postoperative recurrent cases may opt for radiotherapy.
(7) Prevention Before initial treatment, a clear diagnosis should be made, and a reasonable and feasible treatment plan should be formulated and strictly followed. Regular follow-ups after treatment are essential. This way, even if recurrence occurs, it can be detected early and treated promptly.
Uterus cancer combined with pregnancy is relatively rare, accounting for 0.92% to 7.05% of total cervical carcinoma cases in domestic reports and 1.01% in foreign literature. Patients may seek medical attention due to threatened late abortion or prenatal bleeding. Vagina smear and biopsy can confirm the diagnosis. Early pregnant women with vagina bleeding should routinely undergo speculum examination of the cervix and cervical scraping cytology.
The impact of pregnancy on uterus cervical cancer: during pregnancy, increased blood supply and lymphatic flow in the pelvic region may promote cancer metastasis. Additionally, childbirth can lead to cancer spread, severe bleeding, and postpartum infection. During pregnancy, due to the influence of estrogen, the transitional zone cells of the cervix become hyperactive, resembling in situ cancer changes, but they still exhibit directional differentiation and maintain polarity. These changes can recover postpartum. However, pregnancy may also be complicated by in situ cancer, which does not recover postpartum and requires careful differentiation.
The treatment approach depends on the stage of cancer and the duration of pregnancy. For stage I and IIa cases combined with early pregnancy, radical surgery may be performed. Alternatively, radiation therapy can be administered first, followed by radical surgery after fetal death and natural expulsion, or continued radiation therapy. For early pregnancy, a cesarean section to remove the fetus can be performed along with seasonal epidemic radical surgery. For all stages of uterus cervical cancer combined with advanced stage or ongoing labor, cesarean section should be performed, followed by surgery or radiation therapy.
bubble_chart Metastasis and Spread
In recent years, extensive research has confirmed that atypical hyperplasia is a precancerous lesion, with atypical hyperplasia, carcinoma in situ, and invasive carcinoma forming a continuous spectrum of disease progression. Starting from early surface lesions such as atypical hyperplasia, if the causative factors persist, the condition will gradually progress to invasive carcinoma. Studies have also demonstrated that the vast majority of cervical carcinomas develop gradually rather than suddenly. Precancerous lesions often remain reversible for a considerable period before entering the superficial "carcinoma in situ" stage, which can persist for many years without clinical symptoms. During this stage, the condition can be detected through cytological scrapings of the cervix and cervical canal and confirmed via biopsy. In the precancerous stage, abnormal cells do not invade the stroma or metastasize. If detected and treated aggressively at this point, the chance of cure is very high. However, once cervical carcinoma progresses to invasive cancer, it develops rapidly. Without treatment, patients may die within 2 to 5 years.
