Preliminary Exploration of TCM Diagnosis and Treatment of Neuroblastoma (1)

TCM's understanding of neuroblastoma is very limited, and TCM has no advantage in diagnosing it. So TCM diagnosis and treatment of neuroblastoma must rely on relevant Western examinations as a reference. When clinical TCM doctors treat neuroblastoma, they should be able to read Western examination reports for neuroblastoma and have the ability to judge the trend of the disease from those reports.

At the present stage, TCM can only serve as an adjunct—not the main—treatment for neuroblastoma. First, most parents will not readily choose pure TCM treatment after their child is diagnosed with neuroblastoma. Second, from the standpoint of medical ethics, TCM diagnosis and treatment of neuroblastoma has not yet met evidence-based medicine standards and cannot ensure a high effective rate, so parents should not be encouraged to abandon standard treatment in favor of pure TCM.

But for children who have failed standard Western treatment, or for some who are seriously ill but not yet at the end stage and still worth treating, one should as far as possible consider conservative TCM treatment, avoiding the excessive harm that over-zealous chemoradiotherapy inflicts on the child's body.

(The following is excerpted from the Guidelines for Diagnosis and Treatment of Childhood Solid Tumors edited by Jin Xianqing and Shi Chengren, for note-taking purposes only.)

Neuroblastoma (NB) is a common malignant childhood tumor arising from the sympathetic ganglia or the adrenal gland. In the United States, NB accounts for 7.2% of malignancies in children under 14. From 1975 to 2000, an NCI survey in the United States showed the incidence of neuroblastoma was 10.2 per million (children under 15), with the highest incidence among whites.

China currently has a large number of children with neuroblastoma, but relatively few Western and TCM doctors who specialize in treating it. Most local hospitals still lack the sophisticated testing capacity to perform the relevant examinations for neuroblastoma children.

Epidemiological studies suggest the following factors may promote the occurrence of neuroblastoma: premature infants and low-birth-weight infants; sex hormone use before or during pregnancy; a history of daily alcohol consumption during pregnancy; and parents engaged in electronics-related occupations.

The oncogene MYCN associated with neuroblastoma is located at 2p24, and MYCN amplification is strongly associated with poor prognosis. So some places now perform MYCN gene testing on children; children who are MYCN-positive with a high index have a poor prognosis.

The following markers are important in the diagnosis and differentiation of neuroblastoma.

1. Catecholamine metabolites. Among all neuroblastoma markers, catecholamine metabolites have the highest sensitivity and specificity. They mainly include vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine; the first two are of greater clinical significance. The samples tested are urine and blood; clinically urine samples are mostly used because their sensitivity and specificity are relatively high. For younger children from whom it is hard to obtain a urine sample, one or more spot urine samples may be used, while simultaneously testing urine creatinine, and then calculating the ratio of urinary VMA or HVA to urine creatinine (ug/mg) as an evaluation index. This ratio is a prognostic indicator for neuroblastoma.

2. Neuron-specific enolase (NSE). NSE is synthesized by neuroblasts and is an important marker for immunohistochemical staining. It may be elevated in serum, but its specificity is relatively poor because it is also highly expressed in Ewing family tumors, small-cell lung cancer, pheochromocytoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Current research suggests that blood NSE level is related to prognosis and clinical stage; clinically it is mainly used to judge prognosis and detect recurrence.

3. Ferritin. Ferritin secreted by neuroblasts differs biochemically from ferritin secreted by normal cells, mainly in glycosylation and electrophoretic properties. High serum ferritin can also appear in children with Hodgkin's disease and leukemia, so its specificity is low. Because routine blood transfusion during chemotherapy can raise serum ferritin, it cannot be used as a monitoring indicator during treatment. Given that ferritin shows the highest expression in stage-4 children with poor prognosis, it is used clinically as a fairly efficient prognostic indicator.

4. Lactate dehydrogenase (LDH). Multivariate analysis found that LDH, like age, stage, and other biological molecules, is an independent prognostic factor; an elevated level represents rapid turnover and proliferation of tumor cells and a high tumor burden. Its specificity is poor, so it cannot be used as a differential diagnostic indicator.

Bone marrow assessment has a role in the prognosis of neuroblastoma. More than half of neuroblastomas have bone marrow involvement, which affects prognosis, so all children with suspected or confirmed neuroblastoma should undergo bone marrow assessment.

Imaging mainly includes ultrasound, computed axial tomography (CT), magnetic resonance imaging (MRI), bone scan, meta-iodobenzylguanidine (MIBG) scintigraphy, and positron emission tomography/computed tomography (PET/CT).

Various imaging findings can provide reference for the doctor's clinical medication. In addition, the clinical TCM doctor must also be able to read routine blood, urine, liver and kidney function, and other relevant reports, to provide a basis for judging the child's overall condition.

Many stage-4 high-risk children, after repeated surgery, radiotherapy, and chemotherapy, still cannot have their disease controlled, while their physical condition has become quite poor. At this point one should heavily use TCM root-supporting treatment. At this stage the child's various test results may all be quite abnormal—markers abnormal, the tumor spread throughout the body. Continuing Western chemoradiotherapy is inadvisable, and even when using TCM anticancer drugs, one must pay attention to the strength.

Children with neuroblastoma usually have no obvious abnormality before onset; among the neuroblastoma children I have taken on, what I hear most in the inquiry is constipation of many years' duration, with few other abnormalities; a few children had diarrhea instead.

If the local tumor enlarges, corresponding compressive symptoms may appear. Some children are found to have a huge abdominal mass, discovered by their parents by chance. Others are found to have neuroblastoma when they seek care for symptoms such as abdominal pain, fever, limb pain, anemia, and periorbital ecchymoses.

Children with stage 4S may present with abdominal distension and breathing difficulty, caused by tumor invading the liver and producing hepatomegaly. Intra-abdominal tumors compressing renal blood vessels or the bowel can cause renal dysfunction and intestinal obstruction. Skin metastases may present as palpable nodules, some shaped like blueberries.

There are also some less common clinical symptoms.

Transverse myelopathy: Neuroblastomas in the neck, chest, or abdomen that grow rapidly can invade the spinal canal through the intervertebral foramina, compress the spinal cord, and produce corresponding neurological symptoms; the mass is often dumbbell-shaped.

Opsoclonus-ataxia syndrome: "Dancing eyes"—rapid, irregular eye movements that may persist during sleep—and "dancing feet," limb ataxia and myoclonus; many patients have delayed cognitive, motor, behavioral, and language development. The pathogenesis is still unclear; some believe it is mediated by immune mechanisms, based on the diffuse lymphocytic infiltration seen in the tumor nests of such patients.

Horner's syndrome: When the cervical sympathetic ganglion is affected by neuroblastoma, Horner's syndrome appears, presenting as unilateral facial anhidrosis, ptosis, miosis, enophthalmos, and heterochromia iridis.

Treatment-resistant diarrhea: About 4% of children have treatment-resistant diarrhea, presenting with hypokalemia and dehydration. The cause is excessive secretion of vasoactive intestinal peptide by maturing neuroblastoma or mature ganglioneuroma; symptoms ease once the primary lesion is resected.

Hypertension: Some patients have hypertension, mainly because the tumor compresses the renal artery, causing renal ischemia and activating the renin-angiotensin system; secondarily it is caused by tumor cells secreting vasoactive catecholamine metabolites. Common Western treatments for this kind of hypertension are antihypertensive drugs or surgery to free the renal artery, relieving the tumor compression and restoring renal blood flow, thereby reducing renal hypertension.

Judging from the neuroblastoma children I have taken on, most sought medical help for symptoms such as fever and abdominal pain or limb pain. Many local hospitals lack the experience and the relevant testing means to diagnose and treat this disease, so it is easily misdiagnosed; some patients are misdiagnosed for months on end, and some children are initially treated for infectious or orthopedic diseases.

Many neuroblastoma children report constipation of many years' duration; I have not yet seen this symptom recorded in any standard textbook. In addition, many NB children have had severe night sweats for years. After chemotherapy is effective, the night sweats and constipation improve markedly in these children.

According to Qian Yi, children are mostly constitutionally of pure yang without yin. The pulse of the great majority of children is rapid; only a few children, after repeated chemoradiotherapy, have a slow, weak, forceless pulse.

So from the perspective of TCM pattern differentiation, neuroblastoma children who have not yet been treated, or who have had Western treatment but are still in good physical condition, mostly belong to the excess-heat and yin-deficiency patterns.

Treatment should mainly use herbs that clear heat and detoxify, drain heat and guide stagnation, and nourish yin. Liuwei Dihuang Wan (Six-Ingredient Rehmannia Pill) was historically a famous pediatric formula, and it is also very commonly used in neuroblastoma children; it can resolve the symptom of night sweats.

After neuroblastoma children undergo Western chemoradiotherapy, their blood picture is poor—both white blood cells and platelets are low—and when hair loss is severe, they should be treated as a deficiency pattern, with the emphasis on supporting the root and fortifying the foundation. If Chinese herbs are needed to accompany chemoradiotherapy, formulas such as Erzhi Wan, Buzhong Yiqi Wan, Guipi Tang, and Shiquan Dabu Tang should be chosen and modified according to the child's condition.

After repeated chemotherapy, when the child's body is already extremely weak, chemotherapy should be stopped, and a comprehensive treatment using the TCM approach of supporting the root and fortifying the foundation, with formulas that fortify the spleen and boost the kidneys, should be adopted. Once the child's body has somewhat recovered, use the corresponding formulas according to the child's specific symptoms. One may support the root while simultaneously using the approach of softening hard masses and dissipating nodules and using poison to attack poison.

Fritillaria, scrophularia, raw oyster shell, centipede, scorpion, toad venom, sparganium, curcuma, musk, cow-bezoar, frankincense, and myrrh are commonly used antitumor herbs in pediatrics, and the dosages must be carefully controlled. Musk and cow-bezoar are too precious for most families to afford. Fritillaria should mainly be high-quality Sichuan fritillary, combined with zhe fritillaria and tu fritillaria. But Sichuan fritillary is too expensive for most families to afford in a decoction; it should be put into pills or powders to reduce the dosage.