Andrea M.Isidori

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Sindromi paraneoplastiche

• Andrea M.Isidori
• Dipartimento di Fisiopatologia Medica
• Dir. Prof. Andrea Lenzi

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Effetti sistemici delle neoplasie
Alterazioni funzionali degli organi interessati
dal tumore primitivo
Alterazioni funzionali degli organi interessati
dalla crescita metastatica
Effetti metabolici
Effetti tossici
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Tumor Host Interactions

• Local and Systemic Effects (primary site)
• Metastases (secondary site)(? dedifferentation)
• Cancer Cachexia
• Paraneoplastic Syndromes
• Endocrinopathies
• Neuromyopathies
• Gastrointestinal motility syndromes
• Osteochondral Disorders
• Vascular Phenomena
• Fever
• Dermatological Syndromes

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Paraneoplastic syndromes

• Le Sindromi paraneoplastiche, per definizione,
  sono fenomeni legati allinterazione
  neoplasia-ospite, ma NON direttamente
  riconducibili ad effetti metastatici,
  compressivi, tossici, infettivi o metabolici
  tumorali.
• Sono importanti poiché
• Si associano a severa morbilità e mortalità (es.
  Cushings)
• Sono spesso un presenting symptom di una
  neoplasia misconosciuta (early diagnosis) e un
  riconoscimento precoce spesso ottimizza le
  possibilità di intervento
• Rientrano nella diagnosi differenziale di
  sindromi comuni (ipercalcemia, iponatriemia,
  ipopotassiemia)

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Paraneoplastic syndromes

• Le neoplasie più frequentemente associate a
  sindromi paraneoplastiche sono
• Lung carcinoma (most common)
• Renal carcinoma
• Hepatocellular carcinoma
• Leukemias
• Lymphomas
• Breast tumors
• Ovarian tumors
• Neural cancers
• Gastric cancers
• Pancreatic cancers

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Cancer Cachexia

• Progressive weakness, loss of appetite, anemia
  and profound weight loss (gt20 lbs.)
• Often correlates with tumor size and extent of
  metastases
• Etiology includes a generalized increase in
  metabolism and central effects of tumor on
  hypothalamus
• Probably related to macrophage production of
  TNF-a and IL-1

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Endocrine syndromes
Hematologic syndromes
Cutaneous or dermatologic syndromes
Neurologic syndromes
Osteoarticular or rheumatologic syndromes
Ocular syndromes
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Sindromi paraneoplastiche endocrine
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I primi reports su sindromi endocrine in pazienti
affetti da neoplasie maligne non endocrine
risalgono agli anni 20...
Lancet 1928 A case of pluriglandular syndrome
diabetes of bearded women. Brown WH
Surg Gynecol Obster 1923 Parathyroid hyperplasia
and bone destruction in generelized
carcinomatosis. Klemperer P
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Spectrum of paraneoplastic endocrine
HYPERCALCEMIA
HYPONATRIEMIA
PTHrP, TGFs, ILs, Vit D, PTH
GYNECOMASTIA
Vasopressin, ANP
HCG
CUSHINGs
ACTH, CRH
ACROMEGALY
Paraneoplastic Endocrine Syndromes
GH, GHRH
HYPOGLYCEMIA
IGF II
ONCOGENIC OSTEOMALACIA
HYPERGLYCEMIA
FGF23
HPL, PRL, VIP, Renin, LH, GRP
Glucagone, GH,
DIVERSE SYNTOMS
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Endocrine Pathology 2003 Paraneoplastic Endocrine
Syndromes A Review DeLellis RA, Xia L. A
number of criteria have been proposed for the
diagnosis of paraneoplastic endocrine syndromes

• Demonstration of elevated hormone concentrations
  in the blood
• Finding of normal or suppressed endogenous
  hormone production
• Demonstration of hormone concentration gradients
  across the tumor
• Biochemical or clinical resolution of the
  syndrome following surgery, radiotherapy or
  chemotherapy
• Demonstration of hormone messenger RNA and
  corresponding hormonal product in tumoral cells

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Endocrine Pathology 2003 Paraneoplastic Endocrine
Syndromes A Review DeLellis RA, Xia L.
Meccanismi patogenetici
Theory of randon genetic derepression
Attivazione di geni normalmente inattivi per
effetto di mutazioni o modificazioni epigenetiche
Dedifferentiation Theory
Regressione delle cellule tumorali ad uno stato
maturativo precoce con produzione di proteine e
ormoni fetali ed embrionali (ex. PTHrP)
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Paraneoplastic Syndromes Endocrinopathies

• Hypercalcemia (Cancer is the most common cause of
  hypercalcemia by either humoral or metastatic
  mechanisms)
• Squamous cell lung cancer (PTH-like peptide)
• Multiple myeloma and T-cell lymphoma (IL-1 and
  perhaps TGF-a)
• Renal cell carcinoma (prostaglandins)
• Breast ( Prostate) carcinoma, usually by bone
  metastasis
• Parathyroid carcinoma (PTH)

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Paraneoplastic Syndromes Endocrinopathies

• Inappropriate ADH syndrome (Hyponatremia)
• Small cell undifferentiated lung cancer
  (vassopressin-like hormone.
• Hypothalamic tumors (vasopressin)
• Cushings Syndrome
• Small cell undifferentiated lung cancer (ACTH)
  released through cleavage of pro-opiomelano-cortin
  gene product.
• MTC, Thymoma, Ovarian Cancer, Mesothelioma

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Ipercalcemia 0,1 della popolazione
generale
fino a 3-5 gt50aa Fino al 58 dei pz adulti
oncologici ospedalizzati 0,5-1,3 in età
pediatrica lt5 tumori maligni tratto genitale
femminile Mieloma, K squamoso del polmone
(quasi nel 100 dei casi), K mammario, k
renale, k del tratto genitale femminile, Linfoma
HTLV,
Am J Med 1997 Hypercalcemia of Malignancy Mundy
G, Guise TA
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Hypercalcemia
Primary hyperparathyroidism
23 Paraneoplastic syndrome Metastasis 72 (
lung, breast cancer, multiple myeloma) Granulomato
us desease (tuberculosis, sarcoidosis) Genetic
disorders (Familial hypocalciuric hypercalcemia)
Long immobilization Medications (lithium,
thiazide diuretics, supplements)
Dehydration Hyperparathyroidism and cancer are
responsible for more than 90 of sustained
hypercalcemia.
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Ipercalcemia osteolitica localizzata (Localized
Osteolytic Hypercalcemia -LOH-) da produzione
locale di fattori paracrini, quali citochine
(IL-6, TGFa e b, TNFa), prostaglandina E e
metaboliti della Vitamina D, con effetto
stimolatorio sugli osteoclasti
Ipercalcemia Maligna (Humoral Hypercalcemia of
Malingnancy -HHM-) da produzione di PTH-RP
(PTH-related peptide) o più raramente di PTH
Ipercalcemia Assenza di metastasi ossee PTH
ridotto, PTHrP aumentato
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New Engl J Med 1988 Humoral Hypercalcemia of
cancer. Identification of a novel parathyroid
hormone-like peptide Broadus AE, Mangin M, Ikeda
K, Insogna KL, Weir EC, Burtis WJ, Stewart AF
New Engl J Med 2000 The physiology of parathyroid
hormone related protein Strewler GJ
Il PTHrP viene individuato nella seconda metà
degli anni 80, espresso in innumerevoli tessuti
normali (es. endometrio, placenta, miometrio e
decidua durante la gravidanza)
3 ISOFORME
La porzione NH2-terminale è simile a quella del
PTH e determina simili effetti biologici, mentre
il resto della molecola possiede altre funzioni
(es. regolazione proliferazione
cellulare/apoptosi)
Cancer 1991 Immunohistochemical evaluation of
PTHrP in human lung cancer and normal tissue with
newly developed monoclonal antibody Kitazawa S et
al
Dosabile con metodo RIA (kit specifici per la
porzione C-terminale), PCR, IRMA
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Am J Clin Pathol 1996 The Humoral hypercalcemia
of benignancy. A newly appreciated syndrome -
Knecht TP et al
PTHrP nelle lesioni tumorali BENIGNE
It has become recently appreciated that the
hypercalcemia of malignancy is commonly caused by
the increased production of parathyroid
hormone-related protein (PTHrP) by the cancer. In
fact, the demonstration of increased PTHrP
production in a patient with hypercalcemia is
regarded as pathognomonic of malignancy. The
authors describe a patient with a benign ovarian
lesion that produced PTHrP and caused
hypercalcemia. They identify other reports of
hypercalcemia associated with hypercalcemia and
benign tumors, and refer to this syndrome as the
humoral hypercalcemia of benignancy. Although
apparently rare, a benign PTHrP-producing tumor
should be considered in the differential
diagnosis of hypercalcemia.
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IPERCALCEMIA NEOPLASTICA

• Nel 10-20 dei pz oncologici si presenta come
  emergenza metabolica
• Emergenza per Ca gt14 mg/dl (3.5 mmol/L)
• Gravità dei sintomi correlata alla velocità di
  aumento del calcio ionizzato e alla sua
  concentrazione, alle condizioni generali del e
  malattie concomitanti

LIVELLI CORRETTI DI CALCIO SIERICO Calcio
misurato 0.8 x (4.0 albumina sierica)
Trattamento Idratazione NaCl ev 0,25-1 L/h
(controllare PVC) Diuretici dellansa
(furosemide) 20-40 mg ev ogni 2-4h (controllo
elettroliti) Bisfosfonati ev Calcitonina sc/ev
4-8 U/kg ogni 6-12h Corticosteroidi (cortone
acetato-prednisone) Emodialisi
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Paraneoplastic SIADH
La Seconda più frequente S. Paraneoplastica Micro
citoma polmonare (60), NET, k tratto
urogenitale Iposodiemia (lt130 mmol/L) /
Sodiuria gt20 mEq/L Osmo urin gt 100 mOsm/L /
Osm plasma lt 260 mOsm/L
Ann NY Acad Sci 1992 Oxytocin and vasopressin
from genes to peptide Gainer H, Wray S
J Intern Med 1995 Syndrome of Inappropriate
secretion of antidiuretic hormone (SIADH) in
malignant diseases Sorensen JB, Anderson MD,
Hansen HH
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Causes of hyponatraemia
Urinary Nalt20 mmol/l
Urinary Nagt40 mmol/l
GI losses Diuretics Mucosal losses Pancreatitis
Sodium depletion post diuretics
Diuretics Addisons disease Cerebral salt
wasting Salt wasting nephropathy
Hypovolaemic
30-40
Hypothyroidism SIADH with ongoing fluid
restriction Primary polydipsia Inappropriate
fluid replacement
SIADH ACTH deficiency
Euvolaemic
Cardiac failure or cirrhosis on diuretic therapy
Cirrhosis Cardiac failure Nephrotic syndrome
Hypervolaemic
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Small cell lung cancer 75 dei
casi Nasopharyngeal cancer Mesothelioma GI tract
malignancy Pancreatic malignancy GU tract
malignancy Lymphoma Sarcoma
Pulmonary
Malignancy
Pneumonia, especially Legionella Mycoplasma Tuberc
ulosis Abscess Vasculitis Positive pressure
ventilation
Desmopressin Selective serotonin
reuptake inhibitors Carbamazepine Prostaglandins T
ricyclic antidepressants Phenothiazines Haloperido
l 3,4-Methylenedioxymethamphetamine Quinolones Lev
eteiracetam Cyclophosphamide Vincristine
Intracranial pathology
Tumour Meningitis Encephalitis Abscess Vasculitis
Subarachnoid haemorrhage Subdural
haemorrhage Traumatic brain injury
Drugs
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Between 1964 and 2002 413 patients with CS were
investigated 60 had an adrenal adenoma, 30 had
an adrenal carcinoma, 5 had macronodular adrenal
hyperplasia, 274 of pituitary origin (CD) 44
from an ectopic source of ACTH
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A COMPARISION BETWEEN THE TWO LARGEST SERIES ON
ECTOPIC ACTH SYNDROME EUROPE (UK) vs. USA
(NIH) (n40) (n90) Median follow-up
60m 26m Are there regional differences
in the ectopic ACTH syndrome in different parts
of the developed world in tertiary referral
centres?
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ECTOPIC ACTH SYNDROME

• 4 patients had markedly fluctuant levels of ACTH
  cyclical Cushings syndrome
• 1 pancreatic carcinoid
• 1 thymic carcinoid
• 1 bronchial carcinoid
• 1 occult source

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St. Bartholomews NIH

• LUNG ? 47.5 (major organ)
• CARCINOID 30
• SCLC 17.5
• Intrathoracic in general ? 55
• OCCULT ? 12.5

• LUNG ? 42.2 (major organ)
• CARCINOID 38
• SCLC 3
• Tumorlets 0.9
• Intrathoracic in general ? 52
• OCCULT ? 19

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ECTOPIC ACTH SYNDROME

• 40 patients
• 26 revealed on imaging (overt)
• 14 not apparent
• 9 became apparent (covert)
• 5 remained hidden (occult)

Barts experience 1969-2001
(Isidori et al., 2005)
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COVERT ECTOPIC ACTH SYNDROME

• Of 9 tumours not initially identified
• Revealed by CT 4
• Revealed by whole-body catheter 2
• Found at surgery/autopsy 3

USING MODERN CROSS-SECTIONAL IMAGING VIRTUALLY
ALL ECTOPICS WHICH CAN BE FOUND WILL BE FOUND
(Isidori et al., 2005)
before high-quality CT
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St. Bartholomews NIH

• Mean ACTH levels
• Overt ? 205 ng/l
• Covert ? 109 ng/l
• Mean UFC
• Overt ? 8810 nmol/24h
• Covert ? 12170 nmol/24h
• Mean K levels
• Overt ? 3.4 mmol/l
• Covert ? 3.5 mmol/l
• Hypokalaemia in 74

• Mean ACTH levels
• Overt ? 207 ng/l
• Covert ? 125 ng/l
• Mean Cortisol levels
• Overt ? 1422 nmol/l
• Covert ? 1065 nmol/l
• Mean K levels
• Overt ? 2.7 mmol/l
• Covert ? 2.8 mmol/l
• Hypokalaemia in 70

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ECTOPIC ACTH SYNDROME

• Dynamic Stimulation Tests
• High-dose dexamethasone suppression
• 91 show absent suppression (gt50)
• CRH stimulation test
• 94 show absent rise (gt20)
• One patient showed a response to both tests
  (1/402)

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ECTOPIC ACTH SYNDROMENIH experience
Dynamic Stimulation Tests

• High-dose dexamethasone suppression
• 86 show absent suppression (UFC)
• CRH stimulation test
• 92 show absent rise (gt20)

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ECTOPIC ACTH SYNDROME

• BILATERAL INFERIOR PETROSAL SINUS SAMPLING
• 1/12 patients showed a central gradient gt3
  (mesothelioma)
• At NIH, 1/67 patients showed a central gradient
  (esthesioneuroblastoma)
• Therefore, false positive responses in 2/79 (2)

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ECTOPIC ACTH SYNDROME

• TUMOUR MARKERS
• 28 show raised gastrin
• 28 show raised calcitonin
• 10 show raised urinary 5-HIAA
• At NIH
• 31 show raised calcitonin
• 30 show raised 5-HIAA

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ECTOPIC ACTH SYNDROME

• WHOLE BODY VENOUS CATHETER STUDIES
• 4/22 WERE POSITIVE
• 2 thymic carcinoids
• 1 mediastinal lymph node
• 1 medullary thyroid carcinoma
• BUT THESE WERE ALL STUDIED BEFORE HIGH-RESOLUTION
  CT SCANNING

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ECTOPIC ACTH SYNDROME

• IMAGING
• CT LOCALISED TUMOUR IN 82 (NIH92)
• 111In-octreotide localised tumor in 2/8 (25)
• At NIH, 21/43 (49) were positive
• BUT IT VERY RARELY IDENTIFIES TUMOURS NOT
  OTHERWISE SEEN!

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ECTOPIC ACTH SYNDROME

• TREATMENT
• 28/40 treated with steroidogenesis inhibitors
  for median 9 months
• Metyrapone
• Ketoconazole
• Mitotane
• One patient needed intravenous etomidate

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ECTOPIC ACTH SYNDROME

• TREATMENT
• 12 patients had primary resection, 10 curative
• 12 patients had bilateral adrenalectomy
• 14 patients received radiotherapy
• 11 patients received chemotherapy
• 2 patients received 131I-MIBG therapy
• CONCLUSION Control cortisol excess, remove
  tumour where possible, consider removing adrenals
  where not

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Kaplan-Meier survival curve for ectopic ACTH
patients
(Isidori et al., 2005)
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Prevalence of Tumours responsible of EAS
60
Percentage ()
Total n383
Thoracic Tumours
50
40
30
Abdominal Tumours
20
10
0
Never-found
GI carcinoids
Localized NET
Thymic tumours
Islet Cell Tumours
Disseminated NET
Medullary Thyroid K
Pheochromocytomas
GI adenocarcinomas
Lung SCLC / Adenok
Lung/Mediast. Carcinoids
Miscellaneous Tumours
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Paraneoplastic Syndromes Endocrinopathies

• WDHA syndrome (watery diarrhea, hypokalemia, and
  achlorhydria) - caused by tumor production of
  vasoactive intestinal polypeptide (VIP).
• Islet cell tumors, Intestinal carcinoid tumors
• Polycythemia - caused by tumor production of
  erythropoietins
• Renal cell carcinoma, Cerebellar hemangioma,
  Hepatocarcinoma

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Sindromi paraneoplastiche Gastro-motorie
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Paraneoplastic GI dismotility syndromes

• A small proportion of patients with occult or
  established neoplasms develop a gastrointestinal
  motility disorder, referred to as paraneoplastic
  dysmotility.
• The diagnosis of a paraneoplastic dysmotility
  requires the onset of gastrointestinal
  dysmotility associated with the presence of a
  tumor and presence of specific serum antibodies

Kashyap P and Farrugia G, Gastroenterol Clin
North Am. 2008
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Clinical presentation of a para-neoplastic
dysmotility syndrome

• Pseudoachalasia
• Gastroparesis
• Paraneoplastic chronic intestinal
  pseudoobstruction (CIPO)
• Chronic constipation

Kashyap P and Farrugia G, Gastroenterol Clin
North Am. 2008
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autonomic paraneoplastic neurological Hu-related
syndromes
Autoimmunity Reviews 6 (2007) 162168
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Treatment of paraneoplastic dysmotility

• No treatments have been convincingly shown to
  alter outcome (steroids, cyclophosphamide,
  plasmapheresis, immunoglobulin)
• Treatment of the underlying primary malignancy
• Nutritional support either enterally or
  parenterally
• Prokinetics, treatment of bacterial overgrowth
• One additional management strategy is to use high
  dose IV steroids for 3 days and if there is a
  clinical response switch to 6-mercatopurine or
  azathioprine (difficult in the case of
  chemotherapy)

Kashyap P and Farrugia G, Gastroenterol Clin
North Am. 2008
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Pemfigo
Da autoanticorpi contro la desmoplakina I,
proteina dei desmosomi delle cellule epiteliali.
Le lesioni bollose pemfigoidi sono conseguenza
della perdita della normali adesioni
intercellulari a livello dellepidermide.
Linfomi, timoma, sarcomi ed altre neoplasie,
soprattutto ematologiche
Acanthosis nigricans
Iperpigmentazione vellutata, di colore marrone
scuro o nero, a livello di ascelle, aree
sottomammarie e pieghe inguinali Soprattutto K
gastrico.
Malattia di Paget
Placca eritematosa, simile ad un eczema Quando
localizzata a livello delle areole mammarie è
quasi sempre associata a K duttale della
mammella, mentre la malattia di Paget
extramammaria si associa in circa il 50 dei casi
a neoplasie genitali.
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Dermatomiosite
Miopatia infiammatoria associata ad un rash
cutaneo violaceo, più evidente nelle aree esposte
al sole, edema ed eritema periorbitale, placche
eritematose a livello delle articolazioni
metacarpofalangee e interfalangee prossimali
(papule di Gottron) K polmone, stomaco, utero,
ovaio
Ittiosi
Associata ai linfomi di Hodgkin Placche cutanee a
scaglie
Snd di Leser-Trèlat
Comparsa improvvisa o aumento in numero e
dimensioni di cheratosi seborroica Neoplasie
gastrointestinali
Snd di Sweet
Dermatosi neutrofila febbrile acuta (febbre,
leucocitosi neutrofila, placche o noduli
eritematosi a livello di testa, collo e arti
superiori In particolare in corso di leucemia
acuta mieloblastica, sindromi mielodisplastiche e
malattie mieloproliferative.
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Paraneoplastic Syndromes

• Think about it

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