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PARANEOPLASTIČNI SINDROM

dr Branka Miloševićdr Nikolina Poletan

dr Danica Momčičević

DEFINICIJA Klinički efekti tumora koji se ne mogu objasniti lokalnim

dejstvom tumora ili udaljenih metastaza ili dejstvom hormona koje luči tkivo koje je ishodište tumora

Pojavljuje se kod 10-15% pacijenata sa karcinomima

Mogu biti prva manifestacija tumora

ZNAČAJ PARANEOPLASTIČNOG SINDROMA1. Može predstavljati najraniju manifestaciju okultnog tumora

2. Može predstavljati značajan problem i biti čak letalan

3. Može imitirati metastasku bolest i zbog toga se ne tretira adekvatno

De Beukelaar JW, Sillevs Smitt PA. The Oncologist. 11:292-305, 2006.

PATOGENEZA

PATOGENEZA

• TUMORSKA ĆELIJA

• HORMONI (PROTEINSKI I STEROIDNI)• ANTITIJELA, CITOKINI, ENZIMI....

• CILJNI/UDALJENI ORGAN

KLINIČKE MANIFESTACIJE

NEUROLOŠKI I PSIHIJATRIJSKI POREMEĆAJI

RENALNI POREMEĆAJI I ELEKTROLITNI DISBALANS

ENDOKRINOLOŠKI POREMEĆAJI

HEMATOLOŠKI POREMEĆAJI

KOŽNE I KOLAGENO-VASKULARNE MANIFESTACIJE

NESPECIFIČNE MANIFESTACIJE

Reproduced from Scagliotti, 2001 and Carbone et al, 1970 with kind permission from European Respiratory Monthly and Annals of Internal Medicine respectively.

NON-SMALL CELL LUNG CANCER AND PARANEOPLASTICSYNDROME: A STUDY OF 15 PATIENTS.

On May, 28, 2013: 19,529 people who have non-small cell lung cancer are studied. Among them, 15 (0.08%) have Paraneoplastic Syndrome.

This is a study of Paraneoplastic syndrome among people who have Non-small cell lung cancer. The study analyzes the Non-small cell lung cancer patients by their gender and age, drugs used, and common conditions other than Non-small cell lung cancer. In total 19,529 Non-small cell lung cancer patients are studied. The study is created by eHealthMe based on reports from FDA and is updated regularly.

Non-small cell lung cancer and Paraneoplastic syndrome: a study of 15 patients. Available at: http://www.ehealthme.com/cs/non small+cell+lung+cancer/paraneoplastic+syndrome


Gender of people who have non-small cell lung cancer and experienced Paraneoplastic syndrome :

Female MaleParaneoplastic syndrome 14.81% 85.19%



Age of people who have non-small cell lung cancer and experienced Paraneoplastic syndrome :

0-1 2-9 10-19 20-29 30-39 40-49 50-59 60+

Paraneoplastic syndrome

0.00% 0.00% 0.00% 0.00% 0.00% 5.00% 55.00% 40.00%


NON-SMALL CELL LUNG CANCER AND PARANEOPLASTICSYNDROME: A STUDY OF 15 PATIENTS.Most common drugs used by these people : Dexamethasone (8 people, 53.33%) Ramipril (8 people, 53.33%) Arixtra (8 people, 53.33%) Pantoprazole (8 people, 53.33%) Haldol (8 people, 53.33%) Metoclopramide (7 people, 46.67%) Gemcitabine (6 people, 40.00%) Cisplatin (6 people, 40.00%) Tpn electrolytes in plastic container (6 people, 40.00%) Durogesic-100 (6 people, 40.00%)

Non-small cell lung cancer and Paraneoplastic syndrome: a study of 15 patients. Available at: http://www.ehealthme.com/cs/non-small+cell+lung+cancer/paraneoplastic+syndrome


Često prisutni kod karcinoma pluća

Paraneopastični efekti tumora su rezultat oštećenja ilidisfunkcije nervnog sistema bez znakova njegove direktnezahvaćenosti

Patomorfološki supstrat kod ovih poremećaja je gubitaknervnih ćelija i njihova zamjena gliozom, ili nastanakdemijelinizacije

Poremećaj može biti na bilo kojem nivou- moždana masa,kičmena moždina, periferni nervi (senzorne, motorne imješovite neuropatije), neuromišićna spojnica i mišić

NEUROLOŠKI I PSIHIJATRIJSKI POREMEĆAJI Eaton-Lambert mijastenični sindrom (ELMS) javljase kod pacijenata sa limfomom,

timomom, karcinomom pankreasa, bubrega, rektuma, dojke, prostate i uterusa

ELMS može se povući nakon hirurške resekcije primarnog tumora ali ne i nakon HT i RT!

U osnovi je degeneracija presinaptičkih motornih nervnih završetaka, a zbog autoimunog odgovora na voltažno zavisne Ca-kanale

Manifestuje se bolom u mišićima, slabošću proksimalnih ekstremiteta, arefleksijom, suvoćom usta i imptencijom

Dijagnostika: EMNG-elektromijeloneurografija

Terapijska opcija: plazmafereza, imunosupresija, guanidin


Paraneoplastični limbički enecefalitis je rijetki poremećaj koji se karakteriše psihijatrijskim poremećajima, napadima, gubitkom kratkoročnog pamćenja

Simptomi mogu prethoditi dijagnostici tumora i mjesecima

Kod oko polovine pacijenata se mogu naći anti Hu antitijela

Javlja se kod 1-6% oboljelih od svih karcinoma, a najčešće je udružen sa SCLC, timomom, karcinomom janika i dojke

Marija Semnic et all: Paraneoplastic limbic encephalitis in a patient with non-Hodgkin’s lymphoma, Arch Oncol 2004;12(1):71-3.


Patomorfološki supstrat je glioza, mikroglijalni infiltrati, naročitoperivaskularno, kao i gubitak neurona, kolekcija limfocita,degeneracija amigdaloidnih jedara, hipokampusa

Encefalitis moždanog stabla može da se manifestujecentralnom hipoventilacijom i sleep apneom

Druge manifestacije: izmjenjeno ponašanje, demencija,agitacija...

Dijagnostika: NMR endokranijuma, ali u razvoju oboljenjamože biti uredan; dok druge strane isključuje drugu etiologiju;te izolacija anti Hu antitijela u likvoru i krvi (kod 50 %bolesnika)

Terapija: plazmafereza


Duralna infiltracija frontalne parasagitalne regije

Marija SEMNIC et all: Paraneoplastic limbic encephalitis in a patient with non-Hodgkin’s lymphoma, Arch Oncol 2004;12(1):71-3.


CASE REPORT: MONONEURITIS MULTIPLEX :Lung Carcinoma with Anti-Hu Paraneoplastic Syndrome: A 54-year-old female smoker presented with a three-month history of anorexia, fatigue, weight loss, dizziness, and a burning sensation in her hands and feet. She had marked postural hypotension. Her pupils were irregular, asymmetric (Panels A and B), and unresponsive to light and accommodation. Nerve-conduction studies confirmed a mononeuritis multiplex. Computed tomography of the thorax showed an irregular centimeter-sized nodule within the right middle lobe (Panel C, arrow). A screen for antineuronal antibodies identified anti-Hu. This antibody is usually found in patients with neuroendocrine lung carcinomas in the context of a paraneoplastic neurologic syndrome. It has been implicated in the development of tonic pupils, autonomic dysfunction, and painful sensory neuropathies. The pulmonary lesion was excised, and a localized large-cell neuroendocrine tumor was confirmed. The clinical presentation and the presence of anti-Hu enabled us to predict the primary pathological abnormality in this case. The patient received three cycles of adjuvant chemotherapy (carboplatin and etoposide), and she has subsequently shown a steady improvement, with weight gain and a slow resolution of her sensory and autonomic symptoms.

William C. Gordon, M.R.C.P., and Michael T.J. Leach, M.R.C.Path. N Engl J Med 2006; 355:e4


William C. Gordon, M.R.C.P., and Michael T.J. Leach, M.R.C.Path. N Engl J Med 2006; 355:e4

CASE REPORT: MONONEURITIS MULTIPLEX


Nefrotski sindrom

Hiperkalciurija, hipokaliemija, hiponatremija, hiperfosfatemija, acidoza...

Amiloidoza

Neadekvatna sekrecija ADH


Nefrotski sindrom: karakteriše se edemima koji su posljedica hipoalbuminemije i proteinurije (>3 g/24 h).

Može biti prisutna hiperholesterolemija

Kao patofizološki mehanizam pominje se amiloidoza i taloženje imunih kompleksa u nefronima i posljedični membranoproliferativni glomerulonefritisis


In most cases, including bronchogenic carcinoma, membranous glomerulonephritis is found.

In membranous glomerulonephritis, subepithelial deposition of circulatory immune complexes with tumour

antigen damages the glomerular basement membrane, leading to protein leakage. IgG and complement can predominantly be demonstrated. Carcinoembryonic antigen (CEA) could also be demonstrated in glomeruli in cases

of colonic carcinoma. Some authors report cases of bronchogenic carcinoma with glomerular deposition of immunoglobulin A (IgA), which is intriguing, as it may beencountered in other tumours arising from mucosal areas

Minimal change glomerulonephritis is the principal cause of nephrotic syndrome in Hodgkin's disease.

The hypothesis is that T-cell dysfunction leads to cytokine release, which may damage the glomerular basement membrane

E.S. Boon, A.A. Vrij, C. Nieuwhof,J.A. van Noord, E. Zeppenfeldt,Small cell lung cancer with paraneoplasticnephrotic syndrome,Eur Respir J, 1994, 7, 1192–1193


The syndrome of inappropriate anti-diuretic hormone secretion (SIADH) is characterized by hyponatremia caused by retention of free water secondary to dysregulated release of anti-diuretic hormone (ADH) .

We now know that it is a common paraneoplastic phenomenon and that approximately 70% of malignancy-related cases are the result of small cell lung cancer (SCLC).

Lymphoma, thymoma, mesothelioma, Ewing’s sarcoma, and a variety of carcinomas including squamous cell carcinoma of the head and neck have all been associated with the development of SIADH

Philip McDonald1, Colleen Lane, Graciela E Rojas and Ashiq Masood, Syndrome of inappropriate anti-diuretic hormone in non-small cell lung carcinoma: a case report, Available at: ecancermedicalscienc


Hypercalcaemia is frequently found in patients with lung cancer. Its incidence ranges from 2 to 6% at presentation to 8 to 12% throughout the course of disease

It may arise from bone metastasis but can also be induced in a paraneoplastic manner by secretion of parathyroid hormone-related protein (PTHrP), calcitriol or other cytokines, including osteoclast activating factors.

Heinemann et al: Paraneoplastic syndromes in lung cancer: Cancer Therapy Vol 6, 687-698, 2008

ENDOKRINOLOŠKI POREMEĆAJI Paraneoplastic Cushing’s syndrome is caused by ectopic

adrenocorticotropin is common in patients with neuroendocrinetumors such as bronchial carcinoid tumors, small cell lung cancers, medullary carcinoma of thyroid, and pancreatic neuroendocrine tumors.

This syndrome is associated with poor clinical outcome and short survival due to a wide range of complications among them opportunistic infections owing to the high levels of cortisol.

Nadav Sarid et all: Cushing’s Syndrome as a Harbinger of Relapsed Non-Small Cell Lung Cancer, IMAJ 2012; 14: 523-524

ENDOKRINOLOŠKI POREMEĆAJI

HEMATOLOŠKI POREMEĆAJIEritrocitozaAnemijaDIKTrombocitopenijaTrombocitoza Leukemoidne reakcije LeukopenijaKrioglobulinemija

HEMATOLOŠKI POREMEĆAJI Eritrocitoza -posljedica pojačanog lučenja eritropoetina koji može biti

odgovor na hipoksiju, ektopično lučenje eritropoetina ili eritropetinu sličnih supstanci ili zbog izmjenjenog katabolizma eritropoetina. Javlja se kod karcinoma jetre, bubrega, nadbubrežnih žlijezda, pluća, timusa, tumora CNS-, ginekoloških tumora i miosarkoma. UVIJEK NESTAJE NAKON OTKLANJANJA PRIMARNOG TUMORA

Anemija –često prisutan simptom kod tumora, kao posljedica hronične hemoragije ulcerisanog tumora, poremećene apsorpcije vitamina B6 i B12, povećane destrukcije ili nedovoljne produkcije eritrocita

Najčešće se susreće 3 tipa : Hronična anemija uzrokovana anti-eritropoetinim faktorom, koji

skraćuje životni vijek eritrocita i uzrok je loše iskoristljivosti gvožđaMikroangiopatska hemolitička anemija koja posljedica DIK-a, sa

formiranjem fibrinskih niti u kapilarima, i posljedičnom mehaničkom hemolizom

Autoimuna hemolitička anemija koja je rezultat stvaranja anti-eritrocitnih antitjela

HEMATOLOŠKI POREMEĆAJI DIK-tipičan za epitelne tumore, leukemije i limfome (naročito akutna

promijelocitna leukemija). Najčešće, ima sporiji razvojni tok ali u nekim slučajevima ide u akutnoj formi i karakteriše se tipičnim trombocitnim i/ili hemoragičnim manifestacijama, te ponekad vodi ka trombocitopeniji

Trombocitopenija-često uzrokovana At Trombocitoza-nepoznata etiologija Leukemoidne reakcije-vjerovatno uzrokovane mehaničkom

stimulacijom koštane srži, a koje su posljedica koštanih metastaza, ili su posljedica oslobađanja blast-faktora iz fokusa tumorske nekroze. Često su udružene sa hipereozinofilijom i svrabom, koje susrećemo kod limfoma, karcinoma pluća, dojke i želuca

Leukopenija- nije česta i uglavnom je povezana sa metastazama u koštanu srž

Krioglobulinemija-može se javiti kod karcinoma pluća ili mezotelioma


Acanthosis nigricans Herpes zoster Pruritus Urticaria Sweet’s syndroma (febrilnost, neutrofilija, osip) Ihtioza Eritemi Vaskulitisi SLE Dermatomiozitis


Acanthosis nigricans: pojava lokalizovane hiperpigmentacije, najčešće perioralno, umbilikalno, aksillarno, ingvinalno

Posljedica je pojačanog lučenja faktora rasta i hiperkeratoze a ne pojačane produkcije pigmenta!

Najčešće se javlja kod karcinoma pluća i GIT tumora (od toga u 55% slučajeva kod karcinoma želuca)

Tretman: zabilježen je sporadičan uspjeh sa 12%-tnim amonijum-laktatnim kremama i 0,05% tretinoinskim kremama*

• Pipkin CA, Lio PA. Cutaneous Manifestations of Internal Malignancies: an Overview. Dermatol Clin. 2008: 26:1-15. 2.


Pruritus: čest kod Hodgkin limfoma (ali i drugih hematoloških malignoma), kolorektalnog karcinom i karcinoma prostate

Patofiziološki mehanizam: oslobađanje citokina i disfunkcija T-limfocita

Th: mentol/fenol 1-2% kremelokalni i sistemski antihistaminicilokalno lidokainlokalno 10-20% stroncijum nitratsistemski kortikosteroidi

Pipkin CA, Lio PA. Cutaneous Manifestations of Internal Malignancies: an Overview. Dermatol Clin. 2008: 26:1-15. 2.

NESPECIFIČNE MANIFESTACIJE Cancer cachexia is perhaps the most common manifestation of advanced

malignant disease (50%) and is responsible for approximately 25% of deaths from cancer

The degree of cachexia is inversely correlated with survival time and always implies a poor prognosis.

Symptoms of cachexia include anorexia, weight loss, muscle loss, anemia, and alterations in carbohydrate, lipid and protein metabolism.

A variety of mediators has been described to be involved in development of cachexia

The tumour behaves like a new metabolically active organ. However, it is not clear whether the metabolic changes result from

mediators released by the cancer or the host response



Cancer-related fatigue is also extremely common. Up to 90% of cancer patients report fatigue symptoms Fatigue is a highly subjective multidimensional

experience. Individuals may perceive fatigue as physicaltiredness or exhaustion, a need for reduced activity,reduced motivation, and/or mental fatigue



Fever is thought to result from the release of endogenous pyrogens (lymphokines or tissue pyrogenes).

Fever may also be related to necrotic-inflammatory phenomena of the tumor and/or to alterations in liver function and consequent disorders of steroidogenesis.

Luigi Santacroce et all: Paraneoplastic Syndromes Clinical Presentation, Available at: http://emedicine.medscape.com/article/280744-clinical

“I think you have a paraneoplastic syndrome”

UMJESTO ZAKLJUČKA

SUMNJATI, SUMNJATI I SAMO SUMNJATI....

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