mediterranean school of oncology rome, march 6, 2010 università degli studi di palermo facoltà di...

Mediterranean School of Oncology Rome, March 6, 2010

Università degli Studi di Palermo

Facoltà di Medicina e Chirurgia

Dipartimento di Oncologia

Cattedra di Oncologia Medica

Uos Terapie Oncologiche Innovative

Prof. S. Palmeri

Clinical approach

to the patient

What is my tumor origin?

“Despite the increasing array of sophisticated diagnostic tools, oncologists have struggled to

understand a subset of pts with metastatic cancer in whom detailed investigations fail to identify a

primary anatomic site (3-5%)”

Unknown primary tumor

Unknown primary tumor:definition

Histologically confirmed metastatic cancer Failing to identify the primary site after: 1. Detailed medical history2. Complete physical examination (including breast and

pelvic in women,testicular and prostate in men)3. Full blood count and biochemistry, urinalysis and stool

occult blood testing4. Chest rx5. Abdomen and pelvis CT6. Mammography

7. Other (sign or symptom-guided!!)….but:

Not yet standardized (different diagnostic work up)!

Unknown primary tumor A clinical study of 302 consecutive autopsied

patients(Le Chevalier 1988)

Pancreas 26%

Lung 17%

Unknown 16%

Kidney 0.5%

Gynaecological 0.4%

Colon 0.3%

Gastric 0.3%

Esophagus 0.3%

H&N 0.3%

Thyroid 0.3%

Adrenal glands 0.3%

N=302 pz

Unknown primary tumor: clinical and biological features

The most frequent primary tumors in CUP pts don’t include some of the most common neoplasms in the general pop, as breast and prostate

Early dissemination Clinical absence of the primary tumor at diagnosis Unpredictable metastatic pattern Wide spectrum of signs and symptoms (> 50% of

pts present with multiple sites of disease) Aggressive behaviour Life expectancy:6-9 mo

Unknown primary tumor: main sites of disease

Le Chevalier Kirsten Abbruzzese (n=302) (n=286) (n=657)

Nodes 37% 14% 37%Lung 19% 16% 28%Bone 13% 16% 28%Liver 5% 19% 31%Pleura 2% 12% 12%Peritoneum 1% 6% 6%Brain 10% 8% 8%Skin 9% 1% 2%Adrenal gl 0 0 2%

Unknown primary tumor: comparison of metastatic involvement of

common sites with known primary carcinomas vs CUP

Bone Lung Liver

Primary site

Known CUP-Primar

y*

Known CUP-Primar

y*

Known CUP-Primar

y*

Lung 38 40 28 NA 15 19

Breast 49 34 27 19 34 19

Pancreas 4 14 14 3 82 76

Prostate 88 50 6 50 4 0

Colorectal 3 4 21 20 77 92

Metastatic organ site involvement (%)*

*Pts presenting with CUP in whom the primary site was subsequently discoveredKnown primaries:2287, CUP in whom primary site discovered:413

Unknown primary tumor: the dilemma for the oncologist

Unknown primary tumor: the dilemma for the oncologist

Search? Rapidly treat?


More tailored therapy Better knowledge about prognosis

and natural history The physician may believe to fail

serving the patient adequately The patient is reassured The family is reassured

Why search?


Poor prognosis Extensive diagnostic work-up may be expensive

and not conclusive < 20% of CUP pts have a primary site of their

cancer identified antemortem and in 15-30% of cases the origin remain occult even at autopsy

Avoid long waitings Risks from invasive diagnostic modalities The patient is reassured The family is reassured

Why rapidly treat?

Unknown primary tumor: clinical approach to the patient


The natural history is diverse and dependent on multiple variables:

Age N. of metastatic sites Dominant area of disease Histology


evaluation of the patient

Unknown primary tumor: evaluation of the patient

Obiettivi: History Physical Examination Clinical manifestations Laboratory studies Pathologic evaluation Imaging


History: Critical !! It can define areas of concerns (e.g.

respiratory system in a smoker with a supraclavicular node,cough and hemoptysis)

History of previous biopsies or removed lesions or past spontaneously regressing lesions

Family history can be helpful (specific ethnic group, hereditary syndromes)


Physical Examination: Should be rigorous Include careful palpation of the thyroid,

breasts, nodes, liver, prostate DRE Genital examination Aspects often overlooked in CUP patients

Can provide the probable diagnosis

Formulate a directed laboratory and radiographic evaluation


Clinical manifestations: Extremely varied Symptoms and signs similar to those of pts with

advanced malignancies of known origin The most common symptoms/signs at presentation:- general deterioration : 73%- digestive symptoms: 58%- liver enlargement: 58%- abdominal pain: 56%- respiratory symptoms: 45%- ascites: 26%- node enlargement: 16%


Site of metastasis Presumptive origin

Above the diaphragm

All sites Lung

Axillary nodes Breast, lung, GI

Supraclavear nodes H&N,thyroid,lung,GI

Cervical nodes H&N ,thyroid,lung

Below the diaphragm

All sites Pancreas

Umbilical GI (++ stomach),ovary, uterine

Inguinal Anal canal, rectum, prostate, vulva, testicular


Laboratory studies: Complete blood cell count (anemia) Iron metabolism (iron deficiencypossible

chronic GI blood loss) Urinalysis (microscopic hematuria or

proteinuria) Liver function studies including HBV,HCV

markers Tumor markers (b-HCG, AFP, PSA, CEA, CA

125) ?

Unknown primary tumor: tumor markers

CLINICAL PRESENTATION

SUSPECT MARKER

Young pts with mediastinal or retroperitoneal mass

Extragonadal germ cell tumor

αFP, βHCG

♀,adenoca,axillary nodes Breast CA 15-3,CEA

♀, ascitis ± pelvic mass Ovarian CA 125

♂, multiple bone or lung mts Prostate PSA,PAP

Pts with disseminated adenopaties

Lymphomas β2microglobulin

Unknown primary tumor:definition

Not standardized (extent of evaluation) Histologically confirmed metastatic cancer Failing to identify the primary site after: 1. Detailed medical history2. Complete physical examination (including breast and

pelvic in women,testicular and prostate in men)3. Full blood count and biochemistry, urinalysis and stool

occult blood testing4. Chest rx5. Abdomen and pelvis CT6. Mammography7. Other (sign or symptom-guided)


Obiettivi:Pathologic evaluation: Accurate pathologic assessment is essential The lesion is neoplastic and

primary/metastatic Light microscopy Immunohistochemistry Electron microscopy Biological studies

Unknown primary tumor: histology

Well-moderately differentiated adenoca

50% Undifferentiated or poorly differentiated ca

30% Squamous cell ca

15% Undifferentiated neoplasms

5% (including neuroendocrine tumors, lymphomas,

germ cell tumors, melanomas, sarcomas and embryonal malignancies)


Pathologic evaluation: Light microscopy (classify the tumor into broad groups

such as carcinoma, sarcoma or lymphoma; not helpful in 35% of cases)

Immunohistochemistry (peroxidase-labeled Ab against AFP,b-HCG, PSA, CK7, CK 20, TTF-1)

Electron microscopy (adenoca: microvilli and mucin,neuroendocrine tumors: secretory granules, melanoma: premelanosomes)

Biological studies (abnormalities of chrom 12 in germ cell tumors, gene profiling, overexpression of p53, bcl-2, Her-2/neu)


Close communication clinician pathologist


Imaging: Initial radiographic studies: chest x-ray and abdomen

CT Abdomen CT :detection of the primary site in 30-35% Imaging or endoscopy of the upper and lower GI

tract indicated if abdominal complaints, ascites, liver metastases

Mammography and MRI (in the setting of isolated axillary adenopathy MRI very sensitive in detecting occult primary >75%)

PET (occult primary H&N cancers)

History A 52-year-old patient with history of metastatic squamous cell cancer of left posterior cervical lymph node from unknown primary.

PET Findings PET/CT localized the primary in the region of the left tonsil.


Integration of various diagnostic modalities in CUP management Varadhachary, Semin Oncol 2009

Recommended general approach directed evaluation based upon clinical presentation and pathologic findings


Unknown primary tumor: main aims in the evaluation of the patient

Unknown primary tumor: main aims in the evaluation of the

patient

Obiettivi: Research of the primary tumor Evaluation of the extent of disease Rapid identification of curable

patient subsets

Unknown primary tumor:prognosis

Histology: -squamocellular ca OS= 6 mo - adenoca OS =8 mo - undifferentiated or poor differentiated ca OS=19 mo - neuroendocrine ca better prognosis OS=23 mo

T

N° of involved sites ( OS 1 site= 10 mo, 2 = 8 mo, 3 = 6 mo)

PS

N vs liver

MD Anderson approach to the patient with newly diagnosed carcinoma of

unknown primary siteImportant treatable subsets and their management

Women with isolated axillary adenopathy Same as for stage II breast cancer Present recommended management: axillary

dissection, axillary RT, systemic CT, breast RT if MRI positive or suspicious

10 y DFS=65% Prognosis not as favorable in men with axillary

adenopathy only


unknown primary site

Important treatable subsets and their management

Women with peritoneal carcinomatosis (papillary adenocarcinoma)

Same as for stage III ovarian cancer Median survival=16 -24 mo




Extragonadal germ cell syndrome Same as for nonseminomatous germ cell

tumor




Neuroendocrine carcinoma Same as for carcinoid/pancreatic islet cell

carcinoma; cisplatin-based CT for poorly differentiated

neuroendocrine tumors




High- and mid-cervical adenopathy (squamous cell carcinoma)

Surgical resection of palpable disease + curative RT to the neck

30-50% 5-y survival rates

Unknown primary tumor: conclusions

Rational and calculated clinical approach Empathic physician-patient relation Oncological team Consider the individual patient’s needs Cost/benefit ratio 60% of CUP cases don’t fit into favorable clinical subsets > of pts visceral metastases New therapies Future trends: molecular characterization of CUP Need for centralized patient referral

mediterranean school of oncology rome, march 6, 2010 università degli studi di palermo facoltà di...

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