An elderly male with a history of 60-pack-year of smoking is now diagnosed with carcinoma lung. Histological evaluation of the tumor revealed small, highly mitotic cells, scant cytoplasm with hyperchromatic nuclei. Which of the following clinical presentation might occur in the patient during the course of his illness?

Ans is 'a' i.e. Thin extremities, central obesity Small, highly mitotic cells, scant cytoplasm with hyperchromatic nuclei suggest small cell ca. Paraneoplastic syndromes are common in patients with lung cancer, especially those with small cell ca, and may be the presenting finding or the first sign of recurrence. Small cell ca are paicularly associated with ACTH and ADH secretion causing Cushing's syndrome and SIADH. Small Cell Carcinomas have a distinctive cell type. The epithelial cells are relatively small, with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin (salt and pepper pattern), and absent or inconspicuous nucleoli. The mitotic count is high. The cells grow in clusters that exhibit neither glandular nor squamous organization. Basophilic staining of vascular walls due to encrustation by DNA from necrotic tumor cells (Azzopardi effect) is frequently present. Squamous cell carcinoma is characterized by the presence of keratinization and/or intercellular bridges. Keratinization may take the form of squamous pearls or individual cells with markedly eosinophilic dense cytoplasm. Mitotic activity is higher in poorly differentiated tumors. Adenocarcinomas vary histologically from well-differentiated tumors with obvious glandular elements to papillary lesions resembling other papillary carcinomas to solid masses with only occasional mucin-producing glands and cells. The majority are positive for thyroid transcription factor-1 (TTF-1) and about 80% contain mucin. Large Cell Carcinoma is an undifferentiated malignant epithelial tumor that lacks the cytologic features of small-cell carcinoma and glandular or squamous differentiation. The cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm. Paraneoplastic Syndromes. Lung carcinoma can be associated with several paraneoplastic syndromes, some of which may precede the development of a detectable pulmonary lesion. The hormones or hormone-like factors elaborated include: Antidiuretic hormone (ADH), inducing hyponatremia due to inappropriate ADH secretion Adrenocoicotropic hormone (ACTH), producing Cushing syndrome Parathormone, parathyroid hormone-related peptide, prostaglandin E, and some cytokines, all implicated in the hypercalcemia often seen with lung cancer Calcitonin, causing hypocalcemia Gonadotropins, causing gynecomastia Serotonin and bradykinin, associated with the carcinoid syndrome Any one of the histological types of tumors may occasionally produce any one of the hormones, but tumors that produce ACTH and ADH are predominantly small cell carcinomas, whereas those that produce hypercalcemia are mostly squamous cell tumors. Cushing syndrome ACTH secretion is almost always associated with small cell carcinoma. About 30% of all cases of SCLC are associated with hypersecretion of ACTH. However, a clinical apparent Cushing syndrome is rare. Cushing syndrome has been described in 1 to 5% of patients with SCLC following symptoms : Centripetal obesity, facial plethora, glucose intolerance, weakness, proximal myopathy, hypeension, psychological changes, easy bruisability, hirsutism, oligomenorrhea or amenorrhea, impotence, acne, oily skin, abdominal striae, ankle edema, osteoporosis, polydipsia, polyuria, hyperpigmentation, headache, fungal infection specially oral thrush and hypokalimea. Treatment with standard medications, such as metyrapone and ketoconazole, is largely ineffective due to extremely high coisol levels. The most effective strategy for management of Cushing's syndrome is effective treatment of the underlying SCLC. Bilateral adrenalectomy may be considered in extreme cases. Hypercalcemia resulting from ectopic production of parathyroid hormone (PTH), or more commonly, PTH-related peptide, is the most common life-threatening metabolic complication of malignancy, primarily occurring with squamous cell carcinomas of the lung. Clinical symptoms include nausea, vomiting, abdominal pain, constipation, polyuria, thirst, and altered mental status. If untreated hypercalcaemia may lead eventually to confusion and coma. Renal failure and nephrocalcinosis are late manifestations. Syndrome of inappropriate antidiuretic hormone secretion Caused by elevated levels of antidiuretic hormone (ADH) SIDAH is frequently caused by small cell carcinoma. Anorexia, nausea, and vomiting are common symptoms. A rapid onset of hyponatremia can cause cerebral edema. This may lead to irritability, restlessness, personality changes, confusion, coma, seizures, and respiratory arrest. Skeletal-connective tissue syndromes include clubbing in 30% of cases (usually NSCLCs) and hyperophic primary osteoahropathy in 1-10% of cases (usually adenocarcinomas). Patients may develop periostitis, causing pain, tenderness, and swelling over the affected bones and a positive bone scan. Neurologic-myopathic syndromes are seen in only 1% of patients but are dramatic and include the myasthenic Eaton-Lambe syndrome and retinal blindness with SCLC, while peripheral neuropathies, subacute cerebellar degeneration, coical degeneration, and polymyositis are seen with all lung cancer types. Paraneoplastic encephalomyelitis and sensory neuropathies, cerebellar degeneration, limbic encephalitis, and brainstem encephalitis occur in SCLC in association with a variety of antineuronal antibodies such as anti-Hu, antiCRMP5, and ANNA-3. Coagulation, thrombotic, or other hematologic manifestations occur in 1-8% of patients and include migratory venous thrombophlebitis (Trousseau's syndrome), nonbacterial thrombotic (marantic) endocarditis with aerial emboli, and disseminated intravascular coagulation with hemorrhage, anemia, granulocytosis, and leukoerythroblastosis. Thrombotic disease complicating cancer is usually a poor prognostic sign. Cutaneous manifestations such as dermatomyositis and acanthosis nigricans are uncommon (1%).