Cervical malignancy with cachexia is an immune system tumor of lymph nodes and extranodal lymphoid tissues, originating from the malignant transformation of lymphocytes or histiocytes. In China, although cervical malignancy with cachexia is relatively rare, the number of new cases has been increasing annually, with at least over 25,000 cases each year. In contrast, the incidence in Western countries such as Europe, America, and Australia can be as high as 11 to 18 per 100,000, slightly exceeding the total incidence of all types of leukemia. In the United States, at least 30,000 new cases are diagnosed each year. In China, the mortality rate of cervical malignancy with cachexia is 1.5 per 100,000, ranking 11th to 13th among all malignant tumor deaths, similar to leukemia. Moreover, cervical malignancy with cachexia in China exhibits some unique characteristics: ① Higher incidence and mortality rates are observed in the central coastal regions; ② The peak age of onset is around 40 years, showing a single peak curve similar to Japan, unlike the bimodal curve seen in Europe and America; ③ The proportion of Hodgkin's disease is lower than in Europe and America but shows an increasing trend; ④ Among non-Hodgkin lymphomas, the follicular type is rare, with the diffuse type accounting for the vast majority; ⑤ Data from the past decade indicate that T-cell lymphomas in China account for 34%, similar to Japan and significantly higher than in Europe and America.

bubble_chart Etiology

The exact cause of cervical malignancy with cachexia remains incompletely understood. However, the following related factors have been identified: ①EB virus infection; ②Immunodeficiency is a high-risk factor; ③Ionizing radiation may also contribute to the development of this disease; ④Genetic factors have also been reported to be associated with the disease cause. Occasionally, significant familial clustering can be observed.

Cervical malignancy with cachexia is pathologically classified into two major categories: Hodgkin's disease and non-Hodgkin's disease, which can be further subdivided into different types based on tumor cell size, morphology, and distribution patterns.

(I) Hodgkin's Disease (HD) HD is a special type of cervical malignancy with cachexia. Histological diagnosis primarily relies on identifying characteristic Reed-Sternberg (R-S) cells against a polymorphic inflammatory infiltrate background. In 1965, the Rye International Conference classified HD into four types:

1. Lymphocyte-predominant (LP) HD: Predominantly characterized by proliferation of small to medium-sized lymphocytes, sometimes with predominant histiocytic proliferation. Typical R-S cells are difficult to find, but numerous L-H cells are often present.

2. Nodular sclerosis (NS) HD: Characterized by broad collagen fiber bundles with birefringence, dividing lymphoid tissue containing lacunar-type R-S cells into nodules of varying sizes. Typical R-S cells are rare.

3. Mixed cellularity (MC) HD: Abundant typical R-S cells and H cells, with markedly polymorphic inflammatory cells, accompanied by vascular proliferation and fibrosis.

4. Lymphocyte-depleted (LD) HD: In addition to typical R-S cells, many polymorphic R-S cells (reticular cell type) or diffuse non-birefringent fibrous tissue proliferation may be present, with a significant reduction in reactive inflammatory cells.

(II) Non-Hodgkin's Lymphoma (NHL) In 1985, during the Chengdu Conference in China, a working classification was formulated based on the characteristics of domestic NHL and referencing the international working classification, as shown in Table 29-l.

bubble_chart Clinical Manifestations

(1) The main symptom or sign of cervical malignancy with cachexia is painless enlargement of superficial lymph nodes. Hodgkin's disease usually involves cervical or supraclavicular lymph nodes, while in NHL, besides the involvement of lymph nodes above and below the diaphragm, careful clinical examination may reveal invasion of other lymphoid tissue sites such as epitrochlear, orbital lymph nodes, and Waldeyer's ring.

(2) Symptoms such as fever, night sweating, or weight loss may occur.

(3) Pruritus is more common in Hodgkin's disease than in NHL and is usually resistant to antihistamine treatment.

(4) Occasionally, patients with Hodgkin's disease experience pain after drinking alcohol, with the pain localized to the affected area.

(5) Besides lymph node enlargement, physical examination may also reveal splenomegaly. Patients with splenomegaly often have concomitant hepatomegaly. Advanced-stage patients may develop superior vena cava obstruction due to mediastinal lymph node enlargement.

bubble_chart Diagnosis

(1) Detailed inquiry about the

medical history, including initial symptoms, the time of lymph node enlargement and subsequent growth rate, presence of systemic symptoms such as fever, night sweating, skin itching, weight loss, etc. For non-Hodgkin's lymphoma, inquire about any digestive tract symptoms.

(2) Sign

1. Check for enlargement of superficial lymph nodes throughout the body, and whether the skin and appendages are involved. Pay attention to possible involvement of the Waldeyer's ring, breasts, testes, etc.

2. Other signs such as venous or lymphatic reflux obstruction, tracheal compression, superior vena cava syndrome, etc.

1. Routine blood tests, including hemoglobin, white blood cell count and differential, platelet count, erythrocyte sedimentation rate, etc.

2. Blood chemistry tests, including urea nitrogen, non-protein nitrogen, creatinine, alkaline phosphatase, total protein, albumin, globulin, transaminases, and transpeptidases.

3. Serum immunoglobulin tests.

4. Routine urine tests.

5. Iliac bone marrow smear or biopsy.

6. Radiological examinations: Chest X-rays (frontal and lateral views) and lymphangiography of both lower limbs.

7. Pathological examinations: Lymph node biopsy, skin biopsy, and liver biopsy if necessary.

8. Cellular immunity tests: E rosette formation, lymphocyte transformation, macrophage tests, skin tests, etc.

9. Abdominal ultrasound or CT scan, MRI, and gastrointestinal barium meal examination.

10. Exploratory laparotomy should only be performed in selected cases, especially for non-Hodgkin's lymphoma, where caution is particularly advised.

bubble_chart Treatment Measures

(I) Treatment Principles

1. Principles for the Treatment of Hodgkin's Disease

(1) Stages IA and IIA: Primarily treated with radiotherapy. If there is a large mediastinal mass, a combination of chemotherapy and radiotherapy should be used. For the lymphocyte-depleted histological type, total nodal irradiation is applied.

(2) Stage IIB: Generally treated with total nodal irradiation, but chemotherapy alone may also be used.

(3) Stage III1A: Treated with radiotherapy alone.

(4) Stage III2A: Treated with a combination of radiotherapy and chemotherapy.

(5) Stage III _B : Treated with chemotherapy alone or chemotherapy plus radiotherapy.

(6) Stage IV: Treated with chemotherapy alone.

2. Principles for the Treatment of Non-Hodgkin's Lymphoma

(1) Low-grade malignancy: ① Stages I and II: Mostly treated with radiotherapy, but chemotherapy after radiotherapy does not prevent recurrence years later. ② Stages III and IV: Mostly treated with chemotherapy.

(2) Grade II malignancy: Stage I patients may be treated with radiotherapy alone. For Stage II and above, chemotherapy regimens based on doxorubicin are used.

(3) High-grade malignancy: Lymphoblastic lymphoma is treated with leukemia-like regimens.

3. Surgery as a treatment for cervical malignancy with cachexia has very limited indications and low cure rates, often requiring adjuvant radiotherapy or chemotherapy.

(II) Surgical Treatment

1. Surgical Treatment for Gastrointestinal Cervical Malignancy with Cachexia

Primary gastrointestinal cervical malignancy with cachexia should emphasize surgical treatment. It can clarify the lesion site, remove diseased tissue, and formulate a treatment plan. The resection rate for lymphoma is higher than that for carcinoma. Gastric lymphoma may undergo subtotal gastrectomy, while total gastrectomy should be used cautiously. For intestinal lymphoma, the affected segment and corresponding mesentery can be resected. For unresectable tumors, silver clips may be placed during surgery to facilitate postoperative radiotherapy.

2. Surgical Treatment for Urogenital Cervical Malignancy with Cachexia

Primary cervical malignancy with cachexia in organs such as the kidney, bladder, testis, ovary, and uterus should be surgically removed early, followed by radiotherapy or chemotherapy.

3. Surgical Treatment for Splenic Cervical Malignancy with Cachexia

Primary splenic cervical malignancy with cachexia is rare. Preoperative differentiation from other splenic tumors is difficult, and postoperative pathology confirms the diagnosis. For Stage I–II cases, the 5-year survival rate with surgery alone is 40%, which can increase to 60% with adjuvant chemotherapy or radiotherapy.

(III) Chemotherapy

1. Chemotherapy for Hodgkin's Disease

Over the past 20 years, significant progress has been made in the drug treatment of Hodgkin's disease, primarily due to improvements in treatment strategies and the availability of more effective combination chemotherapy regimens. Currently, the cure rate for Stages III–IV Hodgkin's disease exceeds 50% in most research institutions. The efficacy of single Yaodui for Hodgkin's disease generally ranges from 40–70%. Notably, some drugs alone can achieve complete remission, such as HN2 (13%), CTX (12%), PCB (methylhydrazine, 38%), VCR (36%), and VLB (Madagascar periwinkle alkaloid, 30%), but the efficacy rarely lasts beyond six months.

Combination chemotherapy is mainly applicable to cases of stages IB, IIB, III2A, III_B, IV, and those with large mediastinal masses. The most widely used regimen is mechlorethamine (M), vincristine (O), procarbazine (P), and prednisone (P), abbreviated as the MOPP regimen. To achieve optimal therapeutic effects, the drugs must be administered in full doses and on schedule. Although most patients achieve complete remission after 2 to 3 cycles of treatment, a total of 6 cycles is usually administered. After complete remission is achieved, an additional 2 cycles of treatment should be administered regardless. Recent studies have shown that the most effective combination chemotherapy regimen is adriamycin (A), bleomycin (B), vinblastine (V), and dacarbazine (D), abbreviated as the ABVD regimen, which follows the same principles as MOPP. The complete remission rate for this regimen is 75%, and it has no cross-resistance with the MOPP regimen. For cases that do not respond to MOPP, the ABVD regimen can achieve remission in 75–80% of patients. Commonly used combination chemotherapy regimens are listed in Tables 29-2 and 29-3.

Table 29-2 MOPP Regimen

Treatment for 2 weeks, rest for 2 weeks, at least 6 cycles.

Table 29-3 ABVD Regimen

2. Chemotherapy for Non-Hodgkin’s Lymphoma

Currently, there is no well-established first-line chemotherapy regimen for NHL. Due to the complexity of NHL’s histological types and significant individual differences among patients, factors such as tumor malignancy, site of onset, and the patient’s general condition (e.g., age, presence of systemic symptoms, and bone marrow function) should all be considered when selecting a treatment regimen.

(1) Treatment of low-grade cervical malignancy with cachexia: This type of lymph tumor disease has a mild condition and a prolonged course, so a gentler chemotherapy regimen should be selected. For stage III and IV low-grade cervical malignancy with cachexia, a multi-drug combination regimen can be chosen. Especially for newly diagnosed patients, it is essential to strive for complete or partial remission while avoiding unnecessary treatment to prevent or reduce long-term toxicity or bone marrow suppression. Commonly used chemotherapy regimens include COP, COPP, and CHOP.

Table 29-4 CHOP Regimen

Note: Rest for 2 weeks before repeating the regimen, with each cycle lasting 3 weeks.

Table 29-5 COPP Regimen

(2) Treatment of grade II cervical malignancy with cachexia: It can account for 60% of NHL. In Western countries, most cases are of B-cell origin, but about 20% may be of T-cell origin. These patients are sometimes referred to as "peripheral T-cell lymphomas." Most scholars believe that the important factors affecting the prognosis of progressive NHL include the patient's general condition, whether the tumor exceeds 10 cm, involvement of multiple extranodal organs, B symptoms, etc. Age is also a factor influencing prognosis, possibly related to tolerance to treatment. There is relatively consistent agreement on the treatment of grade II malignant non-Hodgkin's lymphoma. Available treatment options include COP, COPP or MOPP, CHOP, etc. The overall complete remission rate is generally between 50-80%. For diffuse histiocytic types, CHOP, COMA, or COMLA regimens show better efficacy.

Table 29-6 COMLA Regimen (Sweet, 1980)

Note: Ara-C is cytarabine, CF is calcium folinate.

(3) Treatment of advanced cervical malignancy with cachexia: This group of patients is particularly challenging to treat. Chemotherapy shows better efficacy in pediatric patients, with response rates reaching 85–95%, but relapse often occurs within one year. Immunoblastic lymphoma is a subtype with poor prognosis, predominantly affecting children and young adults, with a median age of 24.5 years and a male-to-female ratio as high as 2.5–5:1. Lymphoblastic lymphoma has a high mediastinal involvement rate of 42%, and approximately 50% eventually progress to leukemia. Current treatment often adopts regimens similar to those for acute leukemia, including aggressive induction therapy, consolidation therapy, early central nervous system prophylaxis, and long-term maintenance therapy.

Small non-cleaved cell lymphoma can be either Burkitt's lymphoma or non-Burkitt's lymphoma. Small non-cleaved cell lymphoma in adults is rarer than diffuse large cell lymphoma, and the preferred chemotherapy regimens are COM and COMP.

(IV) Radiotherapy

1. Radiotherapy for Hodgkin's Disease

The principles of radiotherapy depend not only on staging but also on factors such as lesion location, pathology, and age. For example, in stage IA patients with lesions in the right upper neck, where infra-diaphragmatic involvement is less likely, mantle field irradiation alone may suffice. If the lesion is in the left neck, where infra-diaphragmatic involvement is more common, the irradiation field should include at least the para-aortic and splenic regions in addition to the mantle field. In stages IB and IIB, if the pathology is mixed cellularity or lymphocyte-depleted, chemotherapy is recommended after total lymphoid irradiation. For patients younger than 10 or older than 60 years, due to poor radiation tolerance, the irradiation field should generally be limited to local areas.

(1) Radical tumor dose: The radical tumor dose adopted by Shanghai Medical University Cancer Hospital is 45Gy/6 weeks; for larger tumors with slow regression, the local dose can be increased to around 50Gy.

(2) Prophylactic irradiation: For more than a decade, based on the Rosenberg-Kaplan hypothesis, it has been believed that tumors originate from a single center and primarily metastasize to adjacent lymph nodes. Therefore, radiotherapy should not only target the clinically identified tumor area but also include prophylactic irradiation of adjacent lymph node regions. This shift in perspective has significantly improved the treatment outcomes for Hodgkin's disease.

(3) Selection of radiation: Currently, ⁶⁰Co or 4–8 MeV X-rays are commonly used.

2. Radiotherapy for Non-Hodgkin’s Lymphoma

(1) Radical dose and principles of radiotherapy for tumors: The optimal dose for non-Hodgkin’s lymphoma is not as clearly defined as for Hodgkin’s disease, and clinical reports vary widely in the doses used. For diffuse non-Hodgkin’s lymphoma, 40–50 Gy over 5–6 weeks is recommended, while for follicular types, the dose may be reduced, especially for superficial lymph node involvement. However, for diffuse histiocytic types, which are less radiosensitive and prone to local recurrence, a control dose of 50–60 Gy is required. For bulky tumors or residual lesions post-irradiation, an additional 5–10 Gy may be administered locally. For primary head and neck cases, 45–55 Gy is typically given.

(2) Radiotherapy for nodal non-Hodgkin’s lymphoma: Based on histological prognosis and staging, the radiotherapy principles are as follows: ① Favorable prognosis, stages I–II: Most cases are treated with radiotherapy alone, favoring involved-field irradiation rather than extended-field irradiation. ② Favorable prognosis, stages III–IV: Chemotherapy is primarily used. If the lesion is larger than 7–10 cm before treatment or persists after chemotherapy, local radiotherapy may be added. ③ Poor prognosis, stages I–II: Intensive combined chemotherapy plus involved-field irradiation, followed by additional chemotherapy post-radiotherapy. ④ Poor prognosis, stages III–IV: Due to rapid progression, early intensive chemotherapy is recommended. If lesions do not fully resolve, supplemental local radiotherapy may be given.

(3) Radiotherapy for extranodal non-Hodgkin’s lymphoma: Early cases originating in the Waldeyer’s ring can be controlled with radiotherapy, covering the entire ring and cervical lymph nodes, typically at 40–60 Gy. For nasal cavity primaries, the field includes the nasal cavity and involved sinuses, with prophylactic nasopharyngeal irradiation, using an anterior nasal field as the primary field and bilateral preauricular fields as secondary fields. The radical tumor dose is 55 Gy over 5–6 weeks, with a prophylactic dose of 40–45 Gy. For maxillary sinus primaries, the field is similar to maxillary sinus cancer but broader, with a radical dose of 55 Gy over 5–6 weeks, without subsequent surgery. Primary cervical malignancy with cachexia in the abdomen has poor outcomes with radiotherapy alone and is often combined with surgery or chemotherapy. Techniques vary by lesion site, including whole-abdomen, regional, or tumor-site irradiation. Indications include: ① Radical surgery with tumor invasion of the serosa or regional lymph node involvement. ② Radical surgery for multicentric lesions or tumors >7 cm in diameter. ③ Tumor-positive margins or direct invasion of adjacent organs. ④ Postoperative local recurrence. The recommended dose ranges from 25–50 Gy, with doses above 35 Gy preferred. Prophylactic doses should exceed 30 Gy, and therapeutic doses should exceed 40 Gy, as lower doses are ineffective for prevention or treatment.

bubble_chart Prognosis

(一) Efficacy evaluation criteria for cervical malignancy with cachexia

1. Complete remission (CR): The tumor completely disappears for more than one month.

2. Partial remission (PR): The product of the two largest diameters of the tumor shrinks by more than 50%, with no increase in other lesions, and this condition is maintained for more than one month.

3. No change (NC): The product of the two largest diameters of the tumor shrinks by less than 50%, or there is no significant change in size.

4. Progressive disease (PD): The tumor increases by more than 25% or new metastatic lesions appear.

(二) Short-term efficacy of cervical malignancy with cachexia

Most patients with cervical malignancy with cachexia can achieve short-term remission with appropriate treatment. The short-term remission rate of HD is higher than that of NHL. The short-term remission rate for stages I-II of HD is as high as over 95%; NHL can also achieve a short-term remission rate of around 80% after detailed typing, careful staging, and selection of appropriate treatment plans.

(三) Long-term efficacy of cervical malignancy with cachexia

The 5-year survival rate for stages I-II of HD has reached over 95%, and for stages III-IV, it can also reach around 90%. Although treatment for more advanced stages of NHL is more challenging, the 5-year survival rate has still reached 80%. Therefore, efforts should be made to cure early-stage lymphocyte-predominant HD, nodular sclerosing HD, and low-grade NHL. For more advanced stages of highly malignant cervical malignancy with cachexia, the goal is to improve the 5-year survival rate.

(四) Factors affecting prognosis

1. Age: The survival rate for Hodgkin's disease patients under 50 is higher than for those over 50. The prognosis for children and elderly patients with non-Hodgkin's lymphoma is generally worse than for those aged 20-50.

2. Gender: Among Hodgkin's disease patients, females have a higher post-treatment survival rate, while in non-Hodgkin's lymphoma, there is little difference in prognosis between males and females.

3. Pathology: Among Hodgkin's disease patients, lymphocyte-predominant type has the best prognosis, with a 5-year survival rate of 94.3%, followed by nodular sclerosing and mixed cellularity types, while lymphocyte-depleted type has the worst prognosis, with a 5-year survival rate of only 27.4%. In non-Hodgkin's lymphoma, follicular lymphoma with well-differentiated lymphocytes has a 6-year survival rate of 61%; diffuse lymphoma with poorly differentiated lymphocytes has a 6-year survival rate of 42%; lymphoblastic lymphoma has a 4-year survival rate of 30%.

4. Stage: For Hodgkin's disease patients, the 5-year survival rate is 92.5% for stage I, 86.3% for stage II, 69.5% for stage III, and 31.9% for stage EF.

5. Systemic symptoms: Hodgkin's disease patients with systemic symptoms have a worse prognosis than those without systemic symptoms, while for non-Hodgkin's lymphoma, systemic symptoms have a smaller impact on prognosis.