Vulvar rhabdomyosarcoma

　　First, Etiology

　　Vulvar rhabdomyosarcoma is a tumor derived from primitive mesenchyme and significantly tends to differentiate into myogenic tumors.

　　Second, Pathogenesis

　　In alveolar RMS, common structural chromosomal abnormalities such as t(2,13)(q35,q14) and t(1,13)(p36,q14) exist. This rearrangement forms the PAX3/AX7-FKHR fusion gene on chromosome 13. PAX3-FKHR can affect cell growth, cell differentiation, and apoptosis. Downregulating the wild-type PAX3 or PAX3-FKHR by the antisense oligonucleotide pathway can induce apoptosis in RMS cells. This apoptosis pathway is non-p53 dependent and is achieved by regulating the transcriptional activity of the anti-apoptotic protein BCL-XL (Margue 2000). However, Zhao et al. (2001) believe that the occurrence of RMS is not due to the acquisition of the function of the PAX3-FKHR fusion gene, but rather due to the loss of differentiation function of FKHR.

　　在70％～100％的胚胎型RMS中可见到11pl5.5的等位基因丢失即杂合性缺失，通过串联重复序列PCR分析，Barr等(1997)发现是由于微卫星的不稳定性导致了等位丢失。11p15.5的等位基因丢失可使该位点的印迹基因扰乱，这些印迹基因是指源自双亲的两个等位基因中一方不表达或者很少表达的基因。当处于印迹状态的基因重新表达而呈双等位基因表达时称为印迹缺失。目前研究较多的是H19(一种非可读框架RNA)和IGF2(Ⅱ型胰岛素样生长因子)这一对反向印迹基因。Barr(1997)等认为胚胎型RMS的发生是由于11p15.5上一个公认的母系表达的肿瘤抑制基因如H19的功能丢失，而父系表达的生长促进基因如IGF2的表达增加所致。在体内，IGF2和PAX3-FKHR互相抑制彼此的肌源性分化而导致未分化。未分化的肌母细胞具有了IGF2所赋予的迁徙能力，这种作用同时被PAX3-FKHR所增强，通过尚不知道的分子事件导致腺泡型RMS的发生。胚胎型RMS亦可在IGF2和PAX3-FKHR过度表达的情况下进一步发展为腺泡型RMS。

　　1. Pathology

　　(1) Gross morphology: presenting different macroscopic appearances according to the content of tumor cells, collagen, and mucinous stroma, and often accompanied by secondary changes such as hemorrhage, necrosis, cystic change, and ulcer formation.

　　(2) Microscopic examination: scattered typical myoblasts in the embryo-type with unequal amounts, tumor cells are small and poorly differentiated, mostly round or oval, a few cells are fusiform, strip-like, or tadpole-like, cells show significant heterogeneity and nuclear hyperchromatism, abundant cytoplasm, and eosinophilia. Tumor cells tend to be distributed around blood vessels, with loose arrangement of cells and a large amount of mucinous stroma, with little collagen. The grape cluster type is a variant of the embryo type, mostly occurring in the submucosal layer, protruding to the surface to form polypoid or grape-like mucinous masses. There is usually a dense circular or short fusiform tumor cell area under the dermis, known as the 'cambium layer'. The acinar type is formed by irregularly aggregated low-differentiated round or oval tumor cells, surrounded by dense, hyalinized fibrous septa, with the cells in the middle area losing adhesion to form irregular acinar cavities, often with dilated blood vessels in the septa, and multinucleated giant cells are common. There are also solid adenomatous tumors that are difficult to differentiate from the embryo type and require cytogenetic examination. Under the electron microscope, parallelly arranged thick and thin myofilaments, primitive myofibrils, and Z band material can be seen in the cytoplasm.

　　(3) Special staining and immunohistochemistry: The typical RMS can be proven by the presence of striations under light microscopy by phosphotungstic acid-hematoxylin staining. There are various immunohistochemical markers with different specificity and sensitivity. Common muscle protein markers include intermediate filament proteins such as vimentin, desmin, and nestin; cytoplasmic proteins such as myoglobin, creatine kinase isoenzymes (CK-MM, CK-BB); contractile proteins such as myosin, which constitutes the thick myofilaments, and actin, which constitutes the thin myofilaments; regulatory proteins such as troponin, troponin T, and titin; as well as nuclear proteins MyoDl and myogenin, etc. Among them, the skeletal muscle-specific indicators include myoglobin, titin, fast skeletal muscle myosin, MyoDl, and myogenin. Although myoglobin is a unique oxygen-binding protein of skeletal muscle, it is only expressed in highly differentiated myoblasts, with a low positive rate. The positive expression rate of titin in RMS varies with the degree of differentiation, ranging from 10.0% to 95.0%, and titin is strongly positively expressed in spindle cell-type RMS. Because most RMS have poor differentiation, MyoDl and myogenin, which have high specificity and sensitivity among the many muscle protein markers for auxiliary diagnosis of RMS, have received increasing attention in recent years. Especially for long-term formalin-fixed specimens, MyoDl has higher sensitivity than vimentin and desmin, but because antigen hot repair can increase the non-specific cytoplasmic staining of MyoD1 and myogenin, the positive staining standard of MyoDl and myogenin must be strictly located in the nucleus. Chen et al. (1998) found that MyoDl and myogenin show strong diffuse expression in acinar-type RMS, while they show unevenly low-level expression in embryonal RMS, and MyoDl and myogenin can quickly, simply, and accurately differentiate the two types of RMS.

　　2. The main pathological types mainly include the following:

　　(1) Traditional classification: Proposed by Horn and Enterline in 1985, it is divided into 4 types based on gross and cellular morphology: embryonal, grape cluster, acinar, and pleomorphic. This method is adopted by IRS and WHO. However, it cannot classify undifferentiated small cell sarcoma, and it cannot determine the type when the tissue is scarce.

　　(2) Cellular histological classification: Also known as Palmer classification, it is divided into mixed type, single round cell type, and regressive developmental type according to the shape of the nucleus rather than the cytoplasmic differentiation.

　　(3) International Society of Pediatric Oncology (SIOP) classification: It is divided into embryonal, acinar, pleomorphic RMS, and embryonal sarcoma types based on cell differentiation and rich cell density. Among them, the embryonal RMS is further divided into 5 subtypes based on the degree of differentiation, the presence or absence of grape clusters, and the dense or loose texture.

　　(4) National Cancer Institute (NCI) classification: It is also divided into embryonal, acinar, and pleomorphic types. However, a solid acinar type is proposed, and the embryonal type is further divided into smooth muscle tumor-like, grape cluster, and pleomorphic.

　　(5) International Classification of Rhabdomyosarcoma (ICR): A new pathological classification method proposed in 1995 with high homology and the ability to reflect prognosis, which has been in use until now. It is divided into good prognosis types including capillary and spindle cell types, moderate prognosis type, i.e., embryonal type, poor prognosis type including acinar RMS and undifferentiated sarcoma, and currently unestimatable prognosis type including RMS with striated features.

　　It is commonly manifested as swelling or progressively enlarged masses in the vulva, with local pain, which may appear polypoid or cauliflower-like. Initially, the mass is small, located under the skin, and may have no symptoms. As the mass gradually increases, it invades the skin to form ulcers, with irregular vaginal bleeding and discharge. Pain may occur with infection. At the same time, there may be systemic symptoms such as decreased appetite and weight loss.

　　It is commonly manifested as swelling or progressively enlarged masses in the vulva, with local pain, which may appear polypoid or cauliflower-like. Initially, the mass is small, located under the skin, and may have no symptoms. As the mass gradually increases, it invades the skin to form ulcers, with irregular vaginal bleeding and discharge. Pain may occur with infection. At the same time, there may be systemic symptoms such as decreased appetite and weight loss. Patients often seek medical attention due to the mass, bleeding, and pain. Some cases may show no change in the mass for several years and then rapidly increase.

　　Clinical staging:

　　First, IRS surgical pathological grouping

　　The grouping system formulated by the International Society of Paediatric Oncology (IRS) is widely adopted

　　Stage I: tumor confined, completely resected, with no regional lymph node involvement

　　Stage I a: tumor confined to the primary muscle and organ

　　Stage I b: tumor infiltration beyond the primary muscle and organ, such as through the fascial layer

　　Stage II: tumor confined, completely resected grossly

　　Stage IIa: complete gross resection of the primary tumor, but microscopic residual disease at the resection margin, without regional lymph node metastasis

　　Stage IIb: tumor confined, completely resected, with regional lymph node metastasis

　　Stage IIc: complete gross resection of the primary tumor, but microscopic residual disease at the resection margin, with regional lymph node metastasis

　　Stage III: incomplete resection or biopsy, with gross residual disease

　　Stage IV: distant metastasis at diagnosis

　　Second, IRS preoperative TNM staging system

　　Due to surgery, chemotherapy, and radiotherapy, the status of their roles in the treatment of rhabdomyosarcoma is gradually changing, and preoperative treatment can lead to changes in surgical pathological grouping. Therefore, in 1997, the International Society of Paediatric Oncology (IRS) proposed a preoperative TNM staging system, which determines the stage based on the location, size, status of local lymph nodes, and distant metastasis of the primary tumor. In this preoperative staging system, genitourinary rhabdomyosarcoma is considered to be in a favorable location, regardless of the size of the tumor and the status of local lymph nodes. It is classified as stage I when there is no distant metastasis and stage IV when there is distant metastasis. Since the TNM staging system does not well reflect the prognosis, it still needs to be further improved.

　　Third, the SIOP TNM staging system

　　Established by the International Society of Pediatric Oncology (SIOP).

　　1. Preoperative TNM staging:

　　Stage I: Tumor confined to primary tissue or organ, no regional lymph node metastasis.

　　Stage II: Tumor invades one or more surrounding tissues or organs, no regional lymph node metastasis.

　　Stage III: Distant metastasis.

　　2. Postoperative staging:

　　pT1: Tumor confined to primary organ, completely resected, negative margin.

　　pT2: Tumor invades surrounding tissue or organ, completely resected, negative margin.

　　pT3: Tumor not completely resected.

　　pT3a: Residual disease visible under the microscope.

　　pT3b: Gross residual disease or only biopsy performed.

　　Early detection, timely treatment, and good follow-up. Prognosis: Mortality has decreased significantly. The 5-year survival rate is about 25%. Most recurrences occur within 1 to 2 years after treatment, and more than 80% of the复发者 will eventually have lung metastasis. Ariza reported a case of a 14-year-old vulvar rhabdomyosarcoma patient who was cured after chemotherapy and radiotherapy and gave birth to a healthy baby after more than 10 years. Epidemiology: Age distribution is wide, with an average age of onset of 12 years among patients aged 8 months to 44 years. About 60% of patients are over 10 years old, and 40% are over 15 years old.

　　1. Tissue and cell pathological examination.

　　2. Cytogenetic and molecular biological indicators

　　RMS tumor markers include nicotinic acetylcholine receptor (AchR) γ subunit, sialylated neural cell adhesion molecule (PSA-NCAM), insulin-like growth factor II (IGF2), etc. When diagnosing RMS using PCR methods, AchR mRNA is more sensitive and specific than MyoDl and myogenin, especially using α/γAchR.

　　In alveolar RMS, cytogenetic methods can detect common chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), but with poor sensitivity. Now, fluorescence in situ hybridization technology (FISH) combined with RT-PCR is mostly used to detect the specific PAX3/PAX7-FKHR fusion gene formed on chromosome 13 due to chromosomal translocation, which is visible in 54% to 87% of alveolar RMS, while PAX3-FKHR is visible in 8% to 15% of alveolar RMS. The PAX3/PAX7-FKHR fusion gene not only aids in the diagnosis of alveolar RMS but also, as reported by Athale et al. (2001), detecting PAX3/PAX7-FKHR in bone marrow or other body fluids by RT-PCR can identify metastatic lesions with a sensitivity of 100%, significantly better than traditional morphological methods. In addition, the use of PCR combined with restriction enzyme fragment length polymorphism analysis to detect heterozygous deletions at 11p15.5 can help in the diagnosis and differential diagnosis of embryonal RMS.

　　3. X-ray films, vaginal ultrasound, abdominal ultrasound, CT, magnetic resonance imaging, and hysteroscopy.

　　One: Dietetic recipes for external genital rhabdomyosarcoma

　　1. Sarsaparilla and egg: 2 eggs, 60 grams of brown sugar, 60 grams of sarsaparilla. Boil sarsaparilla to obtain a concentrated decoction, add the beaten eggs and brown sugar, and boil until done. Eat the eggs and drink the soup. Take once a day, for 6 days as one course. It has the effects of clearing heat, detoxifying, drying dampness, and healing sores, and can be used for the prevention and treatment of vulvar ulcers.

　　2. Gentian root and egg: 10 grams of gentian root, 3 eggs, 30 milliliters of honey. Decoct the gentian root and discard the dregs, beat the eggs into omelets, add honey, and eat on an empty stomach once a day, for 5 days as one course. It has the effects of clearing heat, removing dampness, and healing sores.

　　3. Chinese cabbage and mung bean sprout drink: 1 root of Chinese cabbage, 30 grams of mung bean sprouts. Clean the root of the Chinese cabbage and slice it, then clean the mung bean sprouts and put them in a pot with an appropriate amount of water, boil for 15 minutes, remove the dregs and take the juice, and drink it as tea at any time. It has the effects of clearing heat and removing dampness, and can be used for the treatment of vulvar ulcers.

　　4. Rock sugar winter melon soup: 30 grams of winter melon seeds, 30 grams of rock sugar. Clean the winter melon seeds, grind them into coarse powder, add rock sugar, pour a bowl of boiling water, put them in a clay pot, and simmer over low heat. Take two doses a day, for several days. It has the effects of clearing heat, removing dampness, and stopping leukorrhea, and can be used for the treatment of vaginal itching.

　　5. Cockscomb and pork tripe: 1 pork tripe, 30 grams of cocklebur seeds, and 10 grams of fructus psoraleae. Clean the pork tripe, add water and the latter two herbs for decoction, and discard the medicine while eating the tripe. It has the effects of补肾祛风止痒 (tonifying the kidney, dispelling wind, and relieving itching). It is used for the prevention and treatment of atrophic white lesions of the external genitalia.

　　6. Goji berry congee: 20 grams of goji berries, an appropriate amount of rice. Boil and eat as congee.

　　Two: What is good for the body when eating external genital rhabdomyosarcoma

　　1. It is recommended to eat more foods that have the effects of preventing external genital tumors and leukoplakia, such as sesame seeds, almonds, wheat, barley, cucumbers, black-bone chickens, cuttlefish, green snakes, pork pancreas, chrysanthemums, black plums, peaches, lichees, Portulaca oleracea, chicken blood, eels, abalones, crabs, horseshoe crabs, sardines, clams, and tortoises.

　　2. For pain, eat horseshoe crab, red, lobsters, sea snails, sea cucumber, tiger fish, beets, mung beans, radish, chicken blood.

　　3. For itching, eat amaranth, cabbage, mustard, taro, kelp, purple kelp, chicken blood, snake meat, pangolin.

　　4. To enhance physical fitness and prevent metastasis, eat silver ear, black fungus, mushrooms, truffles, chicken gizzards, sea cucumber, Job's tears, walnuts, crabs, monitor lizards, needlefish, etc.

　　5. After vulvar rhabdomyosarcoma surgery, it may consume Qi and injure blood, so it is advisable to eat more Qi-tonifying and blood-nourishing foods, such as jujube, longan, mung beans, glutinous rice, lychee, mushrooms, carrots, quail eggs, lotus root powder, beans, etc.

　　6. Radiotherapy after vulvar rhabdomyosarcoma surgery: It may consume Yin and fluid, so it is advisable to eat more nourishing Yin and fluid products, such as spinach, green vegetables, lotus root, radish, watermelon, banana, grapes, sea cucumber, sugarcane, lily, etc.

　　7. Chemotherapy after vulvar rhabdomyosarcoma surgery: It may damage both Qi and blood, so it is advisable to often eat foods that tonify Qi and blood, such as black fungus, mushrooms, walnuts, mulberries, Job's tears congee, jujube, longan, sea cucumber, etc.

　　3. Foods to avoid for vulvar rhabdomyosarcoma:

　　1. Avoid stimulants such as coffee.

　　2. Avoid spicy and刺激性 foods such as scallions, garlic, ginger, and cinnamon.

　　3. Avoid smoking and drinking.

　　4. Avoid greasy, fried, moldy, and salted foods.

　　5. Avoid foods such as rooster, goose, and other stimulants.

　　Prevention:

　　Regular physical examinations, early prevention and treatment, and attention to follow-up. There are currently no effective traditional Chinese medicine treatment methods and traditional Chinese medicine for the treatment of vulvar rhabdomyosarcoma.

　　The main method of Western medicine for treating vulvar rhabdomyosarcoma is surgery, and adjuvant anticancer chemotherapy or radiotherapy can be expected to improve the efficacy.

　　1. Surgery

　　Patients with vulvar embryonal or grape cluster types can receive chemotherapy first after excision or incisional biopsy, and the scope of surgery can be decided according to the response to chemotherapy. For patients with complete response to chemotherapy, there is no need for local surgery. However, all cases of rhabdomyosarcoma with acinar types have early lymphatic and hematogenous metastases, and radical vulvectomy and inguinal lymph node dissection should be performed regardless of the stage of the disease. If the inguinal lymph nodes are positive, pelvic lymph node dissection should be performed.

　　2. Radiotherapy

　　There is no need for radiotherapy for patients with stage I embryonal or grape cluster types. If there is no residual disease in the vulva after induction chemotherapy and reoperation, even for patients with stage IV embryonal or grape cluster types, radiotherapy is not necessary. However, for patients with acinar or undifferentiated types, even in stage I, radiotherapy should be performed, because the 10-year disease relapse-free survival rate of the radiotherapy group is significantly higher than that of the non-radiotherapy group. As for the timing of radiotherapy, Arndt et al. (2001) pointed out that for patients with stage II vulvar embryonal RMS, radiotherapy should start in the third week of chemotherapy, and it is better to start in the ninth week for stage III patients. The dose of radiotherapy is determined according to the response to chemotherapy. For acinar and other types with microscopic or gross residual disease, ±48Gy is used, while for embryonal types, if the volume decreases by more than 2/3 after chemotherapy, the dose is ±32Gy.

　　3. Chemotherapy

　　In the past, chemotherapy was in an auxiliary position, used to eliminate residual lesions after surgery. Now, preoperative chemotherapy with multiple drugs is adopted. For sarcomas with late stages and active nuclear division, the combination of radical surgery before and after chemotherapy can improve the prognosis.

　　1. Currently, commonly used anti-cancer chemotherapy regimens for the treatment of soft tissue sarcoma include:

　　(1) VAC regimen: Vincristine (vincristine) 1.5mg/, intravenous injection, days 1, 8; Actinomycin or Actinomycin D (Actinomycin) 400-600??g/, intravenous injection, days 1-4; Cyclophosphamide (cyclophosphamide) 300mg/, intravenous injection, days 1, 4, 8. Repeat every 3-4 weeks, but depending on the recovery of bone marrow function. There are reports that this regimen can extend the survival period of pelvic sarcoma by 4-5 times (Rivard, 1975).

　　(2) ADIC regimen: Doxorubicin (Adriamycin) 60mg/?, intravenous infusion, day 1; Dacarbazine (Methisazone) (DTIC) 250mg/, intravenous infusion, days 1-5. Efficacy rate 42% (Beretta, 1983).

　　(3) CYVADIC regimen: Cyclophosphamide 500mg/?, intravenous infusion, day 2; Vincristine 1.5mg/, intravenous injection, days 1, 8; Dacarbazine (Methisazone) 250mg/, intravenous infusion, day 2. Course interval of 4 weeks. Efficacy rate 47%.

　　2. For patients with localized malignant lymphoma, surgery should be performed first, followed by chemotherapy, with commonly used regimens including:

　　(1) COP regimen: Cyclophosphamide 800mg, intravenous injection, days 1 and 15; Vincristine 1.4mg, intravenous injection, day 1; Prednisone (Prednisone) 100mg, oral, days 1-5. Repeat one course every 3 weeks. Efficacy rate over 80% (Pan Qichao, 1989).

　　(2) CHOP regimen: Cyclophosphamide 750mg. Intravenous infusion, day 1; Doxorubicin (Adriamycin) 50mg, intravenous infusion, day 1; Vincristine 1.4mg, intravenous injection, day 1; Prednisone (Prednisone) 100mg, oral, days 1-5. Repeat one course every 3 weeks, with an efficacy rate of over 90%.

　　4. Radiotherapy

　　It was previously believed that radiotherapy was ineffective for vulvar sarcoma, however, adjuvant radiotherapy after radical surgery for soft tissue sarcoma is beneficial, can reduce the local recurrence rate after surgery, and can also achieve recent cure when combined with chemotherapy.