Download CANCER OF UNKNOWN PRIMARY SITE (CUPS)

CANCER
OF UNKNOWN PRIMARY SITE
(CUPS)
Matteo G. Della Porta
INCIDENCE AND FEATURES
CANCER OF UNKNOWN PRIMARY SITE (CUPS)
Incidence
• ~ 2 - 3% of all cancers (~ 24,400 - 30.000 cases
in 2000 in USA; most pts > 60 yrs);
• ↓ incidence (more frequent clues that an organ
is site of origin in first considered as CUP)
CANCER OF UNKNOWN PRIMARY SITE
Features.
no universally accepted definition, but CUPS probably
must fulfill all following criteria:
1. biopsy - proven malignancy;
2. histology not consistent with a primary tumor at
biopsy site;
3. unrevealing history, physical examination and usual
examinations
4. failure of additional diagnostic studies to identify
primary site
BIOLOGICAL CONSIDERATIONS
Primary site detection
obscure
Obscure even
even at
at autopsy
autopsy
At autopsy
at
autopsy
~ 20%
~ 55%
~ 25%
During the course
during
theof the disease
course
of illness
METASTASES
* unusual patterns of metastatic spread:
- e.g., pancreatic cancer presenting with bone
metastases;
* incidence of metastatic sites # between
unknown and known primary carcinomas: e.g.,
bone involvement:
- lung cancer: 4% → 30 - 50%;
- pancreatic cancer ↑ 4 - fold;
- prostatic cancer ↓ 3 - fold
CLINICS
AND
USUAL DIAGNOSTIC EXAMINATION
Clinical presentation. Symptoms
* fatigue, weight loss and other systemic symptoms;
* pain;
* abnormal bleeding;
* abdominal swelling;
* subcutaneous masses;
* lymphadenopathy
Clinical presentation. History
- history of skin lesion, polypectomy, prostate biopsy →
review of original histology;
- occupational exposure (e.g., asbestos → mesothelioma;
no prior smoking ↓ likelihood of lung cancer);
- localization symptoms (cough, hematochezia,
hemoptysis, change in bowel habits, unusual vaginal
bleeding, nipple discharge → specific diagnostic
approach)
Clinical presentation. Physical examination
• all pts: general visit (including lymph nodes,
thyroid, skin)
• men pts: prostate;
• women pts: breasts and pelvis
Clinical presentation. Laboratory evaluation
* complete blood count; liver function tests; calcium,
electrolytes, creatinine levels;
* stool evaluation for occult blood;
* urinalysis;
* serum levels of β - human chorionic gonadotropin (β hCG), α - fetoprotein (ΑFP), prostatic specific antigen
(PSA, men), CA.125 (women), CEA and CA - 19.9 (all);
* chest x - ray;
* abdominal and pelvic CT;
* mammography
PATHOLOGIC REVIEW
Routine histochemistry
* identifies “simple”, common pathologies
squamous cell carcinoma
adenocarcinoma
undifferentiated cancer
Routine histochemistry
… but usually does
not identifies the
tissue of origin
Carcinoma?
Linfoma?
Sarcoma?
undifferentiated cancer
Pathologic review. Histochemistry
* ~ 50%: well (G1) or moderately (G2)
differentiated adenocarcinomas;
- ~ 30%: poorly (G3) differentiated carcinomas
/ adenocarcinomas;
- ~ 15%: squamous cell carcinomas, and
- ~ 5%: poorly differentiated, unclassifiable
neoplasms
POSSIBLE PATHOLOGIC EVALUATION OF BIOPSY SPECIMENS
FROM PTS WITH METASTATIC CANCER OF UNKNOWN PRIMARY SITE
EVALUATION / FINDINGS
SUGGESTED PRIMARY SITE OR NEOPLASM
HISTOLOGY (HEMATOXYLIN AND EOSIN STAINING)
psammoma bodies, papillary configuration,
signet ring cells
ovary, thyroid,
stomach
IMMUNOHISTOCHEMISTRY
leukocyte common antigen (LCA, CD45)
Leu-M1
epithelial membrane antigen
cytokeratin
CEA
HMB45
desmin
thyroglobulin
calcitonin
myoglobin
PSA / prostatic acid phosphatase
AFP
placental alkaline phosphatase
B, T cell markers
S-100 protein
ross cystic fluid protein
factor VIII
lymphoid neoplasm
Hodgkin's disease
carcinoma
carcinoma
carcinoma
melanoma
sarcoma
thyroid carcinoma
medullary carcinoma of the thyroid
rhabdomyosarcoma
prostate cancer
liver, germ cell cancer
germ cell
lymphoid neoplasm
neuroendocrine tumor, melanoma
breast, sweat gland
Kaposi's sarcoma, angiosarcoma
* lymphoma identified by Ab
against leukocyte common
antigen (LCA, CD45)
* a variety of
carcinomas and
sarcomas identified
by specific types of
filament proteins
* cytokeratin (common to epithelial tumors) → carcinoma
- specific types of cytokeratis → firm diagnosis (e.g.,
ovarian cancers = CK20 / CK7+, colorectal cancers =
CK20+ / CK7 and pancreatic - biliary tumors = CK20+ /
CK7+)
* desmin → sarcomas;
- sarcoma subgroups
identified by expression
of myoglobin
(rhabdomyosarcoma) or
factor VIII
(angiosarcoma or
Kaposi's sarcoma)
immunohistochemical
staining for prostate
specific antigen
(= prostatic
adenocarcinoma)
immunohistochical
staining for
thyroglobulin
(= thyroid carcinoma)
α - fetoprotein
immunohistochemistry
(= germ cell tumor)
s100p
immunohistochenistry
(= melanoma)
OTHER DIAGNOSTIC APPROACHES
ELECTRON MICROSCOPY
* identifies cell junctions (i.e., desmosomes, typical of
epithelial cancers), neuroendocrine granules,
melanosomes and muscle filaments
* electron microscopy of carcinoid tumor, with numerous, fairly
uniformly sized neurosecretory granules
CYTOGENETIC ANALYSIS: FISH
gene amplification
at chr 20q (green) in a breast cancer
cell line
ENDOCRINE RECEPTORS
* detection of Er-Pg receptors or other antigens sensitive
to fixation (p53, HER -2 - neu) requires fresh tissue
Er
p53
HER - 2 - neu
* Er+, p53+ and HER - 2 - neu+++ CUP (= breast cancer?)
MOLECULAR MARKERS
* DNA analysis for signature gene rearrangements (e.g., for
Igs = B cell; for T cell receptor = T cell) assaying lineage
MICROARRAY TECHNOLOGY
CANCER OF UNKNOWN PRIMARY SITE
A DISTINCT CLINICO - PATHOLOGIC
ENTITY
• pts and physicians often frustrated by unknown primary
cancer
• once completed considerations and evaluation (no
additional helpful information expected), physicians
should stop, discuss with pts and family and all accept
and understand diagnosis:
= pts and physicians have distinct clinico - pathologic
diagnosis of unknown primary cancer;
with diagnosis accepted and understood, pts better
served and physicians comfortable and managing pts
more effectively
CLINICO-PATHOLOGICAL
SUBGROUPS
CLINICO - PATHOLOGIC FEATURES
SITE
SUSPECTED PRIMARY
adenocarcinoma, liver metastases,
malignancy
↑ CEA
gastrointestinal
poorly differentiated lung or
retroperitoneal or mediastinal
mass or lymph nodes,
↑ serum β - hCG or ΑFP
germ cell tumor
(extragonadal)
carcinoma, axillary nodes (female)
breast cancer
squamous cell carcinoma,
cervical nodes
head and neck cancer
CLINICO - PATHOLOGIC FEATURES
SITE
peritoneal carcinomatosis (female)
SUSPECTED PRIMARY
ovarian cancer
pleural effusion, adenocarcinoma
With cells estrogen and / or
progesterone receptor+
breast cancer
bony metastases (male)
prostate cancer
undifferentiated, nodes
lymphoma
TREATMENT
CUPS – TREATMENT:
GENERAL CONSIDERATIONS
Favourable prognostic factors (not consistent in all
studies) include:
• good performance status (ECOG, Karnofsky)
• no weight loss,
• site (e.g., lymph node presentation, except
supraclavicular)
• ≤2 metastases,
• serum LDH,
• histology (G3; squamous, germ, lymphoma and
neuroendocrine features)
• response to chemotherapy
CUPS – TREATMENT:
GENERAL CONSIDERATIONS
• Regression tree (CART) analysis → prognostic index
ranging from:
→long median survival (40 mos): 1 - 2 organ sites
involved, not adenocarcinoma and no adrenal, bone,
liver or pleural involvement
→ short median survival (5 mos): liver metastases,
adenocarcinoma histology, age > 62 yrs
REGRESSION TREE (CART) ANALYSIS
CUPS – TREATMENT:
GENERAL CONSIDERATIONS
Clinically CUPS fall into:
- favorable prognostic subset (20% → important,
search for treatable and potentially curable
neoplasms);
- unfavorable prognosis subset (80%, mainly
dissemineted CUPS)
“FAVOURABLE” PROGNOSTIC SUBGROUPS
(~ 20% OF CUPS)
1. women with adenocarcinoma involving only axillary lymph
nodes (breast cancer?);
2. women with papillary adenocarcinoma of peritoneal cavity
(ovary cancer?);
3. poorly differentiated carcinoma with midline distribution
(extragonadal germ cell syndrome);
4. poorly differentiated neuroendocrine carcinomas;
5. squamous cell carcinoma involving cervical lymph nodes (head
and neck cancer?);
6. pts with a single, small, potentially resectable tumor;
7. isolated inguinal adenopathy (squamous carcinoma → genito urinary tract cancers?);
8. men with blastic bone metastases and elevated PSA
(adenocarcinoma → prostate cancer);
9. lymphoma
ISOLATED AXILLARY NODE
INVOLVEMENT IN FEMALE
CARCINOMA IN AXYLLARY NODES IN FEMALE.
• adenocarcinoma or G3 (undifferentiated) carcinoma in
axylla considered as stage II - III breast cancer;
• only 0.3% confirmed (ER+ and / or PR+ in 20 - 30% of
pts; N1 disease in 70% of pts)
CARCINOMA IN AXYLLARY
NODES IN FEMALE.
- CK 20+ / CK7- CEA+
- E and PG receptors+ or -
CEA
CK20+
CARCINOMA IN AXYLLARY NODES IN FEMALE.
• with no mastectomy, local breast recurrence in ~ 50%
of pts even with no lesion in breast;
• modified radical mastectomy or breast irradiation ↓ risk
of local recurrence;
• adjuvant systemic therapy (CT and / or tamoxifen)
based on pt’s age (pre - or post - menopausal), nodal
disease bulk and ER status) before / after surgery or
radiotherapy ↓ risk of metastatic breast cancer;
PERITONEAL CARCINOMATOSIS
IN FEMALE
PRIMARY PERITONEAL PAPILLARY SEROUS CARCINOMA
(PPSC) IN FEMALE.
- ascites and peritoneal
masses, without evidence of
primary tumor in ovaries in
pts with median age of 60 yrs;
- usually ↑ CA 125;
- biopsies from
peritoneal deposits →
papillary serous
adenocarcinoma ±
psammoma bodies
PRIMARY PERITONEAL PAPILLARY SEROUS
CARCINOMA (PPSC) IN FEMALE.
PPSC commonly ascribed to ovarian cancer, even with
apparently normal ovaries at laparotomy.
- maximum surgical cytoreduction → cisplatin (or
carboplatin) + paclitaxel, especially with psammoma bodies
or papillary configuration or ↑ CA - 125 level;
- stage-specific response to therapy ~ that of pts with
proven ovarian cancer (22% of pts with complete response
to chemotherapy; median survival = 18 mos)
POORLY DIFFERENTIATED CARCINOMA
WITH MIDLINE ADENOPATHY
“SYNDROME OF EXTRAGONADAL
GERM CELL CANCER”
SYNDROME OF UNRECOGNIZED EXTRAGONADAL GERM CELL
CANCER
* subset of CT - responsive pts with undifferentiated or poorly
differentiated CUPS with ≥ 1 of following features:
- age < 50 yrs;
- tumor in midline structures (mediastinal or retroperitoneal lymph
nodes) or in lung parenchyma;
- ↑ serum ΑFP or β - hCG;
- evidence of rapid tumor growth
SYNDROME OF UNRECOGNIZED EXTRAGONADAL GERM CELL
CANCER
another possibility:
* CD30 (Ki - 1 antigen),
expressed by Reed Sternberg cells of
Hodgkin’s disease,
useful in evaluation of
mediastinal tumors
(embryonal carcinoma
= only non - lymphoid
tumor with CD30 as
tumor - specific marker)
SYNDROME OF UNRECOGNIZED EXTRAGONADAL GERM
CELL CANCER
TREATMENT
* good response to platinum - based combination
chemotherapy (response rates > 50% , with 10 - 15%
long – term )
SYNDROME OF UNRECOGNIZED EXTRAGONADAL GERM
CELL CANCER
* pts with abnormalities of chr 12 (as in germ cell
cancer) more likely to respond to platinum - based CT
normal chr 12 isochr 12
METASTATIC CUPS
TO LYMPH NODES
CERVICAL NODE INVOLVEMENT
CERVICAL LYMPH NODE METASTASES. I.
FROM HEAD & NECK CANCERS
* → primary tumor of upper aerodigestive tract (1 - 2% of head and
neck cancers), until proven different source;
* squamous cell or G3 (worse prognosis) carcinomas
metastases of squamous cell
carcinoma (at right)
higher
magnification
CERVICAL LYMPH NODE METASTASES.
FROM HEAD & NECK CANCERS
- with early - stage disease (I - II = minimal local
extension whithout node involvement) → definitive local
therapy (external beam radiation or radical neck
dissection)
- with bulky N2 / N3 lymph node disease, role of
chemotherapy (platinum - based) undefined
CERVICAL LYMPH NODE
METASTASES.
FROM THYROID CANCER
* thyroid examination, US
scan and cytology to rule out
primary thyroid tumor,
especially with no definitely
squamous histology;
- PET sometimes useful in
localising primary tumour
CERVICAL LYMPH NODE
METASTASES
FROM THYROID CANCER
TRG
* thyreoglobulin (TRG,
restricted to follicular thyroid
epithelium);
TTF1
* TTF1: a member of
trascriptional factor family (so
called “homeodomain”)
controls gene expression in
thyroid, lung and brain
“UNFAVOURABLE”
PROGNOSTIC SUBGROUPS
ADENOCARCINOMA
AND LIVER METASTASES
ADENOCARCINOMA AND LIVER METASTASES
* not well characterized syndrome, poorly responsive to CT;
- ~ 25% of all CUPS (sometime metastases to other organs);
- often G2-G3 adenocarcinomas from stomach, biliary or colorectal
tumors → resection (with limited hepatic involv.)
ADENOCARCINOMA AND LIVER METASTASES.
* colonoscopy or gastroscopy for detecting a
potentially obstructive colonic or gastric lesion;
- if found, resection may be beneficial (depending on
tumor's size);
- if not found, palliative treatment with 5 - FU (+
leucovorin or + oxaliplatin or + irinotecan), with pt
informed of risks due to severe diarrhea and relative
resistance of gastrointestinal tumors to
chemotherapy
SUMMARY. I.
* pts with CUP should undergo diagnostic search for
primary tumor from clinical and pathologic data;
- subsets of pts with prognostically favorable disease
(as defined by clinical or histologic criteria) substantially
benefit from directed, aggressive treatment and expect
prolonged survival;
- however, poor prognosis for most pts with advanced
CUP, with early resistance to available cytotoxic therapy
SUMMARY. II.
* research into metastatic phenotype will improve
understanding of CUP tumor biology;
- whether CUP clone is distinct molecular genotype phenotype # from metastases of known primary tumors
still to be elucidated;
- identification of specific CUP - related molecular and
biochemical targets may help exploit therapeutic
targeted agents