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Small cell lung carcinoma is a highly aggressive tumor, with a high proliferative capability, rapid tumour doubling time and early onset of metastases carrying poor prognosis. These features make SCLC a systemic disease in most cases, with 70% of SCLC patients presenting an extensive disease (ED) at diagnosis. The median overall survival of treated patients in the ED stage varies between 6 and 11 months, whereas 2- and 5-year survival rates hardly reach 5% and 1%, respectively as reported by Stupp et al 2004. In spite of this discouraging statistical data, cases of long survivors have been reported, although no predictors of such course have been identified. There are case reports to show that the prognosis in a patient of solitary brain metastasis and occult small cell lung carcinoma is not always as dismal as compared with the patients with brain metastasis occurring after the evidence of SCLC and synchronous metastasis to other sites (Harrison ML, Goldstein D 2002).
LEMS on the other hand is an autoimmune disease occurring in association with a carcinoma in about 60% of the patients, majority of which constitutes SCLC (O'Neill et al 1988) . The SCLC is a tumor of neuroendocrine origin which shows many features of a neurone including expression of Voltage gated calcium channel (VGCC) on the tumor cells. Antibody response to these channels trigger P-LEMS. Long term survival of patients of PLEMS associated with SCLC has been reported (Roberts et al 1985). Rarely both a paraneoplastic syndrome in the form of LEMS and solitary brain metastasis can occur in a patient before the primary SCLC causing it can be detected. Long term follow up with palliative care is the cornerstones in managing these patients. Our experience with a single case suggets that these patients carry a better prognosis than patients with full blown metastasis detected after the evidence of SCLC.
LAMBERT-EATON MYESTHENIC SYNDROME:
The Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated autoimmune disorder of neuromuscular transmission characterised by muscle weakness, hyporeflexia or areflexia and autonomic dysfunction.
In 1953 Anderson et al, reported the case of a 47-year-old man with a bronchial neoplasm, progressive proximal muscle weakness and hyporeflexia .They concluded that there was "strong clinical evidence for believing that the severe muscle weakness was of the myasthenic type" (Anderson et al 1953). This patient showed the features of what we today call as LEMS. In 1957, Eaton and Lambert summarised the clinical and electrophysiological characteristics of this myasthenic syndrome and concluded that the features are distinct from what is expected in cases of myesthenia gravis (Eaton LM, Lambert EH 1957).
PARANEOPLASTIC AND NON-PARANEOPLASTIC LEMS :
LEMS is rare with a prevalence of about 1 per 100 000, equally common in men and women.There are two types of LEMS-LEMS associated with malignancy (P-LEMS) and LEMS without malignancy (NP-LEMS). Patients with either type have an autoimmune basis and similar electrophysiological characters. About 60 % of LEMS patients have associated SCLC. Other less commonly associated malignancy includes lymphoploriferative disorder, papillary carcinoma of thyroid, thymoma, colonic carcinoma, renal cell carcinoma, intrathoracic carcinoid, adenocarcinoma of lungs, pancreas and prostate (O'Neill et al 1988).
NPLEMS is characterised by presence of various other autoimmune diseases like thyroiditis, Addison's disease, vitiligo, pernicious anaemia, SLE/DLE, rheumatoid arthritis and other immunological disorders which provides further evidence for autoimmunity involved in the pathogenisis of LEMS. Overall about 25 % of patients of LEMS have associated other autoimmune disease and approximately 35-45 % have circulating organ-specific antibodies. Prevalence of autoantibodies is higher in the NPLEMS group (Lennon et al 1982). Generally NPLEMS occurs at a younger age as compared to PLEMS (mean ages 48 and 57.9 years, respectively). However, 80% of patients with LEMS are older than 40 years (Seneviratne et al 1999). O'Neill et al, in their series of 50 cases, found a statistically significant male predominance in the group without associated carcinoma and when both groups were considered together (O'Neill et al 1988).
There is a significant association noted with HLA-B8 in both the groups , which appears to be stronger in the NPLEMS group. The levels of immunoglobulin G (IgG) heavy chain marker G1m(2) is also found to be increased in both the groups ( Willcox et al 1985 ).
The common pathogenic mechanism involved in both the groups of LEMS includes antibody mediated blockage of voltage-gated calcium channel ( VGCC) at the presynaptic neurones. This results in failure of calcium influx at the channels in response to the stimulus, thereby decreasing the neurotransmitter release at the presynaptic motor nerve terminals of the neuromuscular junction and autonomic neurones producing symptoms of weakness and autonomic dysfunction ( Kim and Neher 1988).
The VGCC based on their electrophysiological and pharmacological charecterstics are classified as L, N , P/Q, R and T. In LEMS, IgG auto-antibodies against P/Q type VGCC results in decreased release of acetylcholine both at the motor nerve terminals and at the postganglionic sympathetic and parasympathetic neurones.
The SCLC tumour cells have been shown to express VGCCs of L,N and P/Q sub-types. In patients of SCLC, LEMS is initiated by an immune reaction to these VGCC expressed on the surface of the tumour cells. The resulting antibodies react with VGCC at the presynaptic nerve terminal of the neuromuscular junction resulting in P-LEMS (4). Similarly, VGCCs are expressed in the cerebellum and patients with SCLC, with or without LEMS, may also have cerebellar dysfunction.
The cardinal clinical features described by Lambert and Eaton were weakness and fatigability of muscles, temporary increase in strength after voluntary exercise, diminished or absent tendon reflexes, marked sensitivity to curare (as in myasthenia gravis) and relatively poor response to neostigmine. Tendon reflexes shows marked potentiation after sustained contraction of the appropriate muscle for about 10-15 seconds (3). It is usually gradual and insidious in onset. The weakness usually starts with the lower limbs and involves proximal more than the distal muscle groups. Cranial nerve involvement is seen in about 70% of the patients which produces symptoms like diplopia, ptosis, dysphagia, nasal regurgitation, weakness of neck flexion. Autonomic symptoms like dry mouth , dry eyes and orthostatic hypotension is seen in about 80 % of the patients. Autonomic dysfunction can be elicited by testing even when the symptoms are mildly present (3).
Serum Antibodies to VGCC:
Antibodies against P/Q type VGCCs is detected in about 90% of patients with LEMS belonging to both the groups. This finding appears to be particularly strong in carcinoma-associated LEMS where almost all patients are found positive for antibodies against the P/Q type of VGCCs. Antibodies to N-type VGCCs are detected in less than 50 % of cases, but more commonly in patients with underlying lung carcinoma. Therefore detection of this type of antibody increases the possibility of an underlying primary lung carcinoma(11).
Electrodiagnostic tests :
Electrophysiological tests are used both for the diagnosis as well as for monitoring the course of the illness. Compound muscle action potential (CMAP) after a supramaximal stimulus, postactivation potentiation (increase in the CMAP amplitude immediately after maximal voluntary contraction), repetitive nerve stimulation, and single fibre electromyography are the modalities which help to differentiate LEMS from myasthenia gravis (table 3). Postactivation exhaustion (decrease in the CMAP amplitude 2-4 minutes after maximal voluntary muscle contraction) can be seen in both the LEMS and myasthenia gravis. The results should be interpreted taking the entire picture, including the clinical presentation, into consideration. Electrophysiologial tests reveals characteristic features like a low CMAP amplitude at rest, a decremental response at low stimulation frequency, and an incremental response at high-rate stimulation and post-tetanic potentiation ( Figure 1).
Ice -test shows no improvement in ptosis in patients with LEMS on application of icepacks to the eylelids for two minutes. A significant improvement is seen in patients with Mesthenia gravis.
The edrophonium test may be positive in LEMS but the response is usually weaker than that in myasthenia gravis.
The treatment strategy in patients of LEMS depends on the severity of symptoms, the degree of response to symptomatic treatment, and the presence or absence of an associated malignancy. 3,4 Diaminopyridine, guanidine, pyridostigmine, steroids, immunosuppresives, plasma exchange, intravenous immunoglobulins are some of the therapeutic options available for patients of LEMS which needs to be used according to the clinical settings and availability . Except for 3,4 DAP all others are associated with significant side effects and poor responses(12).
Management of PLEMS :
3,4-diaminopyridine is the drug of choice in these patients for symptomatic relief of weakness and autonomic dysfunction. The specific treatment of the underlying tumour usually results in improvement or remission of symptoms. In such patients the only further treatment required may be continuation of 3,4-diaminopyridine. When the specific tumour therapy fails to resolve symptoms, further treatment with prednisolone should be considered. Those who present with severe weakness will benefit from plasma exchange or IVIG. Bain et al reported an onset of effect of IVIG in their patients at 2 to 4 weeks (13). Severity of symptoms should be the guide for the choice of therapies in these patients.
Management of NPLEMS :
3,4-Diaminopyridine therapy is useful in this group for symptomatic relief and, if successful, no additional treatment is required. Those who have not responded should be treated with prednisolone and/or azathioprine as long-term therapy. Once remission is achieved, prednisolone could be tapered to the minimum maintenance dose. If the weakness is severe, plasma exchange or IVIG should be considered in this group as well.
Table I summarizes the distinguishing features between P-LEMS and NP-LEMS.
LEMS and SMALL CELL LUNG CARCINOMA:
Only 1% to 3% of patients with SCLC have LEMS. Between 40% to 60% of LEMS patients have SCLC, which results in an a priori chance of 50% to carry an SCLC at the moment of diagnosis of LEMS (15,16). This is a major clinical concern for the patient as well as for the doctors. Smoking and the absence of HLA-B8 are risk factors associated with a higher risk of having an underlying malignancy.(17) Most SCLCs are found within 2 years of diagnosis of LEMS. Discovery of a tumor has been described at more than 5 years after diagnosis of LEMS, and one anecdotal case with an interval of even 12 years exists (18).
A diagnosis of LEMS should prompt clinicians for a careful search for an SCLC. Screening for SCLC should be done by: computed tomography (CT) -thorax, 18F_fluorodeoxyglucose (FDG) positron emission tomography (PET), and bronchoscopy. As SCLC may be too small to detect initially, these investigations need to be repeated every 6 months for at least 2 years from the initial diagnosis of LEMS. With this approach about 96% of SCLC are found within a year of diagnosing LEMS, while a delay of more than 2 years is extremely rare; nevertheless, some patients undergo many procedures with associated anxiety and costs(19). Care would be improved if those who require intensive investigations as well as those no longer at risk could be identified. Some of the factors to be kept in mind in evaluating for a cancer in a patient of LEMS includes Old age, smoking, development of multiple clinical symptoms within 6 months after onset, raised erythrocyte sedimentation rate (ESR) and Sry-like high-mobility group box protein 1 antibodies (SOX1).(20) Absence of an underlying SCLC is suggested by young age, no smoking history, slow evolution of clinical symptoms, and the 8.1 HLA haplotype. A recent Dutch English Lems Tumor Association Prediction score was published by Titulaer et al which predicts the association of SCLC in a patient diagnosed with LEMS.(21)
An SCLC has a profound impact on therapy and prognosis. Therapy in patients of LEMS with an underlying SCLC is focused on the tumor. Survival of SCLC associated LEMS is poor, compared to patients with NT-LEMS who are thought to have a normal life expectancy. However long-term survival in patients of SCLC who have an associated LEMS has been advocated compared to other patients of SCLC. The long-term survival in these patients despite presence of highly malignant tumour implies that the anti-VGCC antibodies may be playing a role in controlling tumour growth or, alternatively, that the small cell cancers that provoke LEMS may be slower growing (22).
DELTA-P SCORE :
A Dutch-English LEMS Tumour Association Prediction score (DELTA-P score) was developed allocating one point for the presence of each of the following items at or within three months from onset (21):
1. Age of onset â‰¥50 years,
2. Smoking at diagnosis,
3. Weight loss â‰¥5%,
4. Bulbar involvement,
5. Erectile dysfunction and
6.Karnofsky performance status <70.
The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0-2.6% chance of SCLC, whereas scores of 4, 5 and 6 corresponded to chances of SCLC of 93.5%, 96.6% and 100%, respectively. In conclusion, the simple clinical DELTA-P score discriminated LEMS patients with and without SCLC with high accuracy early in the course of LEMS.
The DELTA-P score, can be easily applied in the clinic to predict with higher than 94% reliability the likelihood of SCLC in patients with LEMS early in the course of their neurologic disease. The DELTA-P score can be used in routine clinical practice to prioritise high-risk patients for intensive tumor screening, while it also identifies those with very low tumor risk, who can be reassured in an early phase of the screening process.
BRAIN METASTASIS AND SMALL CELL LUNG CANCER:
The metastatic dissemination of a solid tumor to the brain is generally associated with a poor prognosis. Approximately 10% of SCLC patients present with brain metastases at the time of diagnosis, and over 50% will develop symptomatic brain metastases during their remaining lifetime (23).. We here discuss the clinical approach and therapeutic modalities in patients of brain metastasis presenting with an occult primary with special reference to small cell lung cancer.
Brain metastasis with occult primary :
In up to 15% of the patients presenting with brain metastases, the site of the primary tumor is not detected despite thorough investigations (24). Some authors find a better prognosis for patients presenting with brain metastases as the only manifestation of an unknown primary tumor than for patients with brain metastases and known primary (25). These results represent only a subset of patients with brain metastases and cancer of unknown primary (CUP). In majority of the patients, extracerebral metastases are present at diagnosis of brain metastases which carries a dismal prognosis. An aggressive treatment or even an extensive search for the primary in these patients may be of no benefit considering the often strongly limited prognosis of an advanced tumor. The period of time after which a patient is considered to have an 'unknown primary' has no generally accepted definition. It varies from no exact definition to a period of 2 months (25). The reports in the literature on patients with brain metastases from an unknown primary tumour are all retrospective. They include patients in whom the brain metastases were the first symptom of a tumour discovered at diagnosis (most often a lung tumour) as well as patients whose primary tumour remained undetected after a thorough investigation.(26.).
Serial follow-up and screening for underlying lung cancer in patients of solitary brain metastasis is mandatory as bronchogenic carcinoma is the commonest malignancy detected in patients of SBM with occult primary(29).
Brain metastasis and occult small cell lung carcinoma:
In cases of SCLC with brain metastasis, vast majority of the patients have synchronous metastases at other sites (26). Only a few case reports of a solitary brain metastasis (SBM) with an occult primary lung tumour at the time of diagnosis of SCLC have been reported in the medical literature. There is no data pertaining to the incidence of SBM in occult primary lung cancer available in the literature. Harrison and Goldstein reported a case of a 30-year-old male whose SBM preceded a diagnosis of the primary SCLC. The treatment involved brain tumour resection, WBRT, chest irradiation and carboplatin-based chemotherapy. The patient survived for 5 years and died because of the local recurrence and progression of the disease (27). Imai et al described the case of a 59-year-old male with a SBM as the only clinical presentation of SCLC. The treatment consisted of subtotal excision of the metastatic brain tumour followed by adjuvant brain irradiation and irradiation of the primary lung tumour, discovered soon after metastasectomy (28). The patient refused completing systemic chemotherapy and was followed-up for 5 years. These cases show that the prognosis for patients with brain metastases and occult small-cell lung carcinoma may not always be dismal.
Now the dilemma arises in these cases with regards to their treatment modalities. Wether to treat them as a Latent disease (LD) or Extensive disease (ED) is a matter of debate. Aggressive treatment in ED SCLC does not improve survival as mentioned above and standard treatment of newly diagnosed SCLC with symptomatic brain metastases is palliative and consists of whole-brain radiotherapy and chemotherapy. Although recently published practice guidelines based on randomized trials recommend the use of surgical resection plus post-operative WBRT, rather than WBRT alone, to improve local control and overall outcome in patients with newly diagnosed, single, resectable brain metastases, good performance status and no or limited extra-cranial disease, the data clearly indicate that the recommendation does not apply to relatively radiosensitive tumour histology like small-cell lung cancer . The alternative treatment option in such cases could be stereotactic radiosurgery (SRS), either as sole treatment or addition to WBRT. Unfortunately, there is still no evidence neither from prospective studies nor retrospective cohorts that SRS is more efficient in local tumour control than surgery +WBRT.
As far as the treatment of the primary site is concerned chemotherapy with thoracic radiotherapy remains the gold standard of treatment. However, there has recently been a growing number of papers underlining the need for a re-evaluation of the role of surgery in
small-cell lung cancer (31). The application of surgery involves the use of the TNM staging system in clinical practice and especially patients with T1-T2N0 lung primary, should be referred to surgery. Patients with solitary brain metastasis from small-cell lung cancer, should in our opinion, be treated radically, especially those in younger age with small lung primary, good performance status, and a lack of systemic dissemination. There are papers reporting unexpectedly prolonged survival achieved by combined radical treatment of resectable lung primary and solitary brain metastasis which supports this approach(32).
Usually, a diagnosis of SCLC indicates to a relatively large primary tumour mass. However there are reports of slow growing SCLC tumors in presence of solitary brain metastasis. This is unusual considering high proliferative potential of the cancer cells in SCLC. Some authors suggest that a subtype of slow-growing neuroendocrine small-cell cancer should be distinguished from the common type of SCLC (28). The long-term survival in these patients despite presence of highly malignant tumour implies that the anti-VGCC antibodies may be playing a role in controlling tumour growth or, alternatively, that the small cell cancers that provoke LEMS may be slower growing.