Cancer of Unknown 1 Site
(CUPS)
Presenting Finding may not
reveal site of origin
Difficult diagnostic and
Therapeutic Dilemna:
Additional Studies: Costly
uncomfortable
Poor overall survival rate
Accounts for 2-3% of all
cancers
Most Patients are over age of
60
A truly occult neoplasm should fullfill
all of the following criteria:
1. Biopsy proven malignancy
2. Unrevealing history, PE, CXR,
Abdominal and pelvic CT, CBC,
Chemistry survey,
Mammogram, B HCG levels,
AFP, PSA
3. Histologic Evaluation is
inconsistent with primary
tumor at biopsy site
4. Failure of additional diagnostic
studies to identify primary site
Histologic Considerations:
Biologic behaviour of CUPS is
unique compared to other
nonhematopoietic neoplasms
Display unusual patterns of
spread
Biopsy of involved site reveal
poorly differentiated histology
Grow in distant locations,
suggesting they can
proliferate in the absence of
specific host factor important
in the development of more
typical cancers
Clinical Presentation:
History and PE are essential:
Fatigue, Weight loss, Pain,
Abnormal Bleeding, Abdominal
Swelling/masses,
lymphadenopathy
Do thorough History and PE
and identify symptoms
referrable to a given location.
Do pelvic and rectal exam if
necessary
Question patient about
occupational exposure.
Pathology
Evaluate tissue obtained at
biopsy site and look for vital
clues
If inadequate using light
microscopy,
immunohistochemical,
ultrastructural immunologic,
karyotypic and molecular
biologic studies -
REBIOPSY
Generally:
Approximately 60% CUPS
identified as adenomas by
light microscopy and
histochemical analysis
10% - Squamous Cell Ca
30% - Poorly differentiated
(Sarcomas, Germ Cell Ca,
Lymphomas,
Neuroendocrine Tumors)
Immunohistochemical analysis
used to assess Poorly
Differentiated Cancers:
LCA, CD45 Lymphoid CA
Filament proteins
Carcinomas and Sarcoma
Keratin Carcinoma, Some
Sarcomas, GCT,
Mesotheliomas
Desmin Sarcomas
Antibodies to PSA Prostate
Alkaline PO4Tase- Breast
Thyroglobulin Thyroid
Myoglobin
Rhabdomyosarcomal
Factor VIII Angiosarcoma
/Kaposi Sarcoma
AFP, B HCG Germ Cell
Tumors
 S-100 Protein- Melanomas,
Neuroendocrine tumors
HMB 45- Melanoma
Other Diagnostic Approaches:
1. Electron Microscopy
2. Cytogenetic analysis of Solid
Tumors
3. Flourescence in situ
4. Fresh Tissues (FR/PR)- Breast
Ca
5. DNA ANALYSIS
Additional Studies
Mammogram
Abdominal / Pelvic CT (1 site
identified in 35% of cases)
Tumor Markers
Fiberoptic Bronchoscopy
Anoscopy/ Colposcopy
Autopsy: Reveals that most likely
primary site of origin include
epithelial tissue (Lung, Stomach,
Colon and Kidney): Poor response to
chemotherapy
Treatment:
Exclusion of treatable and
potentially curable neoplasms
is important
Favorable prognostic factors
should be identified (Limited
Sites
Survival Rates:
Adenocarcinoma 4- 6 mos
Squamous Cell Ca 9 mos
Lymphoma, Germ Cell,
Sarcoma, Neuroendocrine,
Breast, Prostate Therapy
should be instituted
(Chemotherapy,
Radiotherapy or
combination)
Subgroups:
1. Syndrome of Unrecognized
Extra Gonadal Germ Cell
CA
Poorly Differentiated but
they have good response to
chemotherapy
Affects <50 yrs old
individual
Involve the midline
structures
Increased AFP and B HCG
Rapidly growing
Tumor responsiveness to
previously administered
chemotherapy
Treatment: Cisplatin +
Etoposide + Vinblastine
25%- undergo complete
response
33%- Partial response
If no response, do not give
more than 2 cycles
2. Peritoneal Carcinomatosis
Females
Increased abdominal girth/
Pelvic Mass
Adenocarcinoma in peritoneal
cavity without clear site of
origin
Ascribed to ovarian but can be
produced by breast, GI Ca
Treatment: Platinum Based
Chemotherapy
3. Carcinoma In an Axillary
Lymph Nodes in Females
Axillary Mass
Adenocarcinoma or poorly
differentiated
Treatment: Treat as stage 2
breast ca since breast
recurrence will develop in 50%
of patients
MRM/ Breast irradiation and
adjuvant systemic therapy
(Recurrence).
4. Bone Metastases in Males
 Osteoblastic Lesions
Do PSA
Treatment: Empirical
Hormonal Therapy
Leuprolide Flutamide
5. Cervical Lymph Node
Metastases
Neck Mass, High or Midcervical
Squamous; If not, 1 Thyroid
is considered
Treatment: Local Treatment
(Radiation with Dissection)
with platinum based
chemotherapy. If done,
prolonged survival.
6. Adenocarcinoma and Liver
Metastases
1 - Biliary or Colorectal
Increased CEA,
Sigmoidoscopy, Colonoscopy
Treatment: Resection if tumor
is round with 5 FU +
Leucoverin
Palliative Treatment -
Patients not falling into any
subgroup
Radiation Treatment
Patients with local disease
causing bony pain or
neurologic compromise
Modified-Well
Differentiated
Adenocarcinoma- Largest
and most poorly responsive
subgroup. Combination
chemotherapy has response
rates of 60%.
Before combination
chemotherapy is attempted,
Potential Benefits must be
weighed against side effects.