Paraneoplastic syndrome

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Paraneoplastic syndrome Microchapters
Patient Information
Overview
Classification Endocrine Musculocutaneous Neurological Hematological Others
Causes
Differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Gertrude Djouka, M.D.[2]

Synonyms and keywords: Paraneoplastic syndrome

Overview

Paraneoplastic syndromes are a rare type of disease that is caused by abnormal immune systems resulting from cancerous cells. Paraneoplastic syndromes are disorders due to the release of hormones, or peptides that cause immune cross-reactivity between cancerous cells and normal tissues. Sometimes the symptoms of paraneoplastic syndromes show even before the diagnosis of a malignancy. There is no screening for paraneoplastic syndromes. The stage and type of diagnosis of cancer determine the prognosis of a paraneoplastic syndrome. The causes are mostly related to the organ affected. The paraneoplastic syndromes are divided into four main categories such as musculocutaneous, neurological, hematological and endocrines. They are no cures for the paraneoplastic syndrome, but cancer treatment and some medications to reduce autoimmune responses are helpful.

Classification

• Paraneoplastic syndromes may be classified into 5 main categories accordingly:

Type of paraneoplastic syndrome	Subtype	Associated Cancers
Endocrine metabolic syndromes	Hypercalcemia	breast cancer and lung cancer (typically squamous cell) due to the production of PTHrP (Parathyroid hormone-related protein)multiple myeloma, renal cell carcinoma, ovarian cancer, endometrial cancer, and lymphoma
	SIADH	small cell lung cancer, mesothelioma, breast, prostate, adrenal, urethral, thymoma, lymphoma, GI, CNS, and Ewing sarcoma
	Ectopic ACTH secretion	small-cell lung cancer, carcinoid tumor, thymoma and other cancers
	Tumor induced osteomalacia
	Hypoglycemia	GI cancers, mesothelioma, lung, and sarcomas
Musculocutaneous paraneoplastic syndromes	Dermatomyositis
	Leser-Trélat sign	gastrointestinal adenocarcinomas (gastric, colon, rectal), breast cancer, and lymphoproliferative disorders/lymphoma, and melanoma.
	Acanthosis nigricans	gastric adenocarcinoma, endometrial cancer, and etc.
	Necrolytic migratory erythema
	Sweet's syndrome
	Pyoderma gangrenosum
Neurological paraneoplastic syndromes:	Paraneoplastic cerebellar degeneration
	Encephalomyelitis
	Limbic encephalitis
	Brainstem encephalitis
	Opsoclonus (involving eye movement)
	Encephalitis	teratoma
	Polymyositis
	Autonomic neuropathy
	Lambert-Eaton myasthenic syndrome (LEMS)	small-cell lung cancer
	Myasthenia gravis
	Subacute (peripheral) sensory neuropathy
Hematological paraneoplastic syndromes	Granulocytosis
	Thrombocytosis
	Pure red cell aplasia
	Eosinophilia
Others	Membranous glomerulonephritis

• • Endocrine metabolic syndromes:
    • Hypercalcemia in breast cancer and lung cancer (typically squamous cell) due to the production of PTHrP (Parathyroid hormone-related protein)
      • Seen also in multiple myeloma, renal cell carcinoma, ovarian cancer, endometrial cancer, and lymphoma
    • SIADH
      • Associated cancers: small cell lung cancer, mesothelioma, breast, prostate, adrenal, urethral, thymoma, lymphoma, GI, CNS, and Ewing sarcoma
    • Ectopic ACTH secretion associated with small-cell lung cancer, carcinoid tumor, thymoma and other cancers
    • Tumor induced osteomalacia
    • Hypoglycemia
      • Associated cancers: GI, mesothelioma, lung, and sarcomas
  • Musculocutaneous paraneoplastic syndromes
    • Dermatomyositis (25-50% of adult patients have an underlying malignancy)
    • Leser-Trélat sign, a sudden onset of many pigmented skin lesions.
      • Associated cancers: gastrointestinal adenocarcinomas (gastric, colon, rectal), breast cancer, and lymphoproliferative disorders/lymphoma, melanoma, and etc.
    • Acanthosis nigricans, seen in gastric adenocarcinoma, endometrial cancer, and etc.
    • Necrolytic migratory erythema which may be seen in pancreatic tumor.
    • Sweet's syndrome, most commonly associated with acute myeloid leukemia or another hematologic malignancy.
    • Pyoderma gangrenosum is associated with Squamous cell carcinoma, cutaneous lymphoma.
  • Neurological paraneoplastic syndromes:
    • Paraneoplastic cerebellar degeneration associated with lung, ovarian, breast, lymphatic, and other cancers
    • Encephalomyelitis (inflammation of the brain and spinal cord)
    • Limbic encephalitis
    • Brainstem encephalitis
    • Opsoclonus (involving eye movement)
    • Encephalitis triggered by a teratoma
    • Polymyositis
    • Lambert-Eaton myasthenic syndrome (LEMS) in small-cell lung cancer
    • Myasthenia gravis
    • Subacute (peripheral) sensory neuropathy
    • Autonomic neuropathy
  • Hematological paraneoplastic syndromes
    • Granulocytosis (increased granulocytes) due to the production of G-CSF
    • Eosinophilia
    • Pure red cell aplasia
    • Thrombocytosis
  • Others:
    • Membranous glomerulonephritis

Causes

Common Causes

• The major causes of paraneoplastic syndrome include:
  • Small cell lung cancer
  • Non-small cell lung cancer
  • Myeloma
  • Breast cancer
  • Medullary thyroid cancer
  • Bronchial carcinoid
  • Pancoast's tumour
  • Pancreatic cancer
  • Hepatocellular carcinoma
  • Gastric tumors
  • Gastrointestinal neuroendocrine tumors (NETS)
  • Leukemias
  • Lymphomas
  • Skin cancers
  • Renal carcinoma

Causes by Organ System

• Paraneoplastic syndromes causes may be regrouped by organ system.

Dermatologic	Dermatomyositis Cutaneous T-cell lymphoma
Ear Nose Throat	Oropharyngeal cancer
Endocrine	Medullary thyroid cancer Adrenal cancer
Gastroenterologic	Pancreatic cancer Other GI cancers
Hematologic	Myeloproliferative disorders, Multiple myeloma, Melanoma Lymphoma HTLV-associated Lymphoma Hodgkin's lymphoma Chronic lymphocytic leukemia Cancers of the T-cells Adult T-cell leukemia Acute myeloid leukemia
Musculoskeletal/Orthopedic	Teratoma Sarcomas Ewing sarcoma
Neurologic	Brain Cancer
Obstetric/Gynecologic	Ovarian cancer Endometrial cancer
Oncologic	Breast cancer
Pulmonary	Small cell lung cancer Pancoast's tumour Oat cell carcinoma Non-small cell lung cancer Malignant Mesothelioma Bronchial carcinoid
Renal/Electrolyte	Renal cancer
Rheumatology/Immunology/Allergy	No underlying causes
Urologic	Ureteral cancer Prostate cancer Bladder cancer
Miscellaneous	Thymoma Testicular germ-cell tumors

Differential diagnosis

Paraneoplastic syndromes must be differentiated from others types of cancer depending on the location and type of organs.

Diseases	Clinical manifestations						Para-clinical findings							Gold standard	Additional findings
	Symptoms			Physical examination
							Lab Findings			Imaging			Histopathology
Small cell lung cancer	Cough Weakness	Weight loss Fatigue	Dyspnea GI symptoms	Lymphadenopathy	Digital clubbing	Bone tenderness	↑ Ca++	Hyponatremia	_	Chest CT Scan: Necrotic and hemorrhagic hilar mass and lymphadenopathy	Chest X-ray: Hilar mass	_	Small, round and oval cells Necrosis	Biopsy	_
Squamous lung cancer	Asymptomatic at first	Chronic cough Dyspnea Weakness	Weight loss Fatigue Hemoptysis	Confusion Lymphadenopathy	Decreased breath sound in lung auscultation	Fingers clubbing	↑ Ca++	_	_	Chest Ct scan : Ground glass opacity	Chest X-ray: Spiculated Mass, bulky hilum	_	Intracellular bridges Central necrosis with cavitation	Biopsy	_
Hepatocellular carcinoma	Asymptomatic at first	Fatigue Abdominal pain Nausea Vomiting Fever	Loss of appetite Pruritus yellow discoloration of skin	Jaundice Cachexia	Splenomegaly	Abdominal swelling with fluid shift	Prolonged PT	↑ Alpha fetoprotein	_	_	_	U/S : Small hypoechoic lesion Irregular border with fibrosis, and calcification	Polygonal tumor cells Granular eosinophilic cytoplasm	Biopsy	_
Diseases	Symptom 1	Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3	Histopathology	Gold standard	Additional findings
Breast cancer	Lump in the breast Nipple discharge	Bone pain Weight loss	Loss of appetite Shortness of breath	Enlarged Supraclavicular lymph nodes	Dimpling of skin Inverted nipples	Bloody nipple discharge Change in personality	_	_	_	Mammogram: Soft tissue mass Microcalcification	_	_	Numerous mitotic figures Pleomorphism	Biopsy	_
Renal cancer	Hematuria Flank pain	Weight loss Loss of appetite	Abdominal mass Fatigue	Cachexia Abdominal bruit Palpable abdominal mass	Supraclavicular lymphadenopathy	High blood pressure Pallor	↑ Ca++ Polycythemia ↑ Platelets	↑ ALP ↑ LFT ↑ LDH	↑ creatinine ↑ cancer cells in urine cytology	Abdominal CT scan: Thickened irregular walls neoplastic mass	_	_	Depends on the subtypes	Needle Biopsy	_
Pancreatic cancer	Epigastric pain Nausea Yellow discoloration of skin Dark urine	Weight loss Abdominal pain	Loss of appetite Greasy stools Lack of energy	Cachexia Migratory superficial thrombophlebitis on the skin	Abdominal distention and tenderness Left Supraclavicular lymphadenopathy	Palpable periumbilical mass	↑ Bilirubin	↑ ALP ↑ LFT	Low albumin and cholesterol	Abdominal CT scan: Pancreatic duct dilation Pancreatic atrophy Obstruction of common bile duct	_	U/S: hypoechoic mass	Small nuclei Pleomorphism Granular cytoplasm	Spiral CT scan with contrast	_
Gastric cancer	History of gastric ulcer Early satiety Hematemesis	Weight loss Loss of appetite	Difficulty swallowing Abdominal discomfort	Palpable abdominal mass	Left supraclavicular lymphadenopathy	_	↑ CA 19-9	Anemia	_	Abdominal CT scan: Thickened gastric wall Loss of rugal fold Mucosal irregularity Ulcerative lesion	_	Endoscopy: Ulcer	Irregular tubular structure Minimal stroma and cellular Pleomorphism Nucleus located at the periphery	Endoscopy and biopsy	Microangiopathic hemolytic anemia Hypercogulable state Menbranous nephropathy Polyarteritis nodosa Acanthosis nigricans
Lymphoma	Weight loss Abdominal pain	Fever Fatigue	Night sweat	Lymphadenopathy	Hepatosplenomegaly	_	↑ ESR	↑ LDH	_	CT scan of abdomen, pelvic, and chest: for metastasis to distant organs	_	_	Depends on the type of lymphoma	Biopsy	_
Ovarian cancer	Asymptomatic at first	Abdominal pain Bloating	Early satiety Urinary frequency and urgency	Palpable adnexal mass Abdominal swelling with fluid shift	Leg swelling and tenderness	Diminished breath sound due to the effusion	↑ CA-125	↑ Ca++	_	Pelvic U/S: Solid irregular mass with irregular thick septation	Abdominal CT scan: findings depend on the subtypes	_	Nuclear pleomorphism Macronucleolus Eccentric nucleus Psammoma bodies Necrosis	Biopsy	Trousseau syndrome