Title: CARCINOMA OF UNKNOWN PRIMARY
1CARCINOMA OF UNKNOWN PRIMARY
Daniel Morgensztern, M.D.
2CARCINOMA OF UNKNOWN PRIMARY
- Definition
- Epidemiology
- Biology
- Clinical manifestations
- Diagnostic evaluation
- Treatment
- - Favorable subsets
- - Unfavorable subsets
- Prognosis
- Conclusions
-
3DEFINITION
- Carcinoma of unknown primary (CUP) is a
biopsy-proven metastatic malignant tumor whose
primary site can not be identified during
pretreatment evaluation including - Thorough history and physical exam
- Laboratory and radiographic studies
- Detailed histological evaluation
4EPIDEMIOLOGY
- CUP constitutes 2.3 of all cancers in US (SEER
1973-87) - Annual age-adjusted incidence in US is 7-12 cases
per 100,000 population - Median age at presentation is 60 years
- Slightly more prevalent in males
5BIOLOGY
- CUP represents a heterogeneous group of
malignancies characterized by - Early dissemination in the absence of a
detectable primary tumor - Unpredictable metastatic pattern
- Aggressive biological and clinical behavior
- The hypothesis is that the primary tumor either
remains microscopic and escapes clinical
detection or disappears after seeding the
metastasis
6CLINICAL MANIFESTATIONS
- Patients usually present with a short history of
local findings related to the metastatic sites
and constitutional symptoms - Physical exam is often abnormal with effusions,
adenopathy, hepatomegaly and other abnormalities
related to the involved sites - The majority of patients have multiple metastatic
sites
7DIAGNOSTIC EVALUATIONPATHOLOGY LIGHT MICROSCOPY
- Light microscopy with hematoxylin and eosin stain
can identify four main histologic subtypes of CUP - 1. Adenocarcinoma (50-60)
- 2. Poorly differentiated carcinomas (30)
- 3. Squamous cell carcinomas (5-15)
- 4. Undifferentiated malignant neoplasms (5)
8DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
9DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
10DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
11DIAGNOSTIC EVALUATIONPATHOLOGY ELECRON
MICROSCOPY
- Electron microscopy allows the visualization of
ultrastructural features of the tumors such as
organelles, granules and cell junctions - Since it is expensive, time consuming, and not
widely available, the use should be reserved for
selected cases with unclear lineage after
extensive work-up
12DIAGNOSTIC EVALUATIONPATHOLOGY ELECRON
MICROSCOPY
- Identification of neuroendocrine tumors,
melanoma, and poorly differentiated sarcomas - Differentiate between
- 1. Lymphoma and carcinoma
- 2. Adenocarcinoma and squamous cell carcinoma
13DIAGNOSTIC EVALUATIONPATHOLOGY CYTOGENETIC
ANALYSIS
14DIAGNOSTIC EVALUATIONPATHOLOGY TUMOR MARKERS
- Commonly used tumor markers (CEA, CA 19-9, CA
125) are nonspecific and have limited value in
the diagnosis of patients with CUP - - They may have a role as a prognostic marker
and to evaluate response to therapy - Serum ?-HCG and AFP may be used to exclude
testicular cancer - Serum PSA can identify cases of prostate cancer
- Elevated thyroglobulin in patients with bone
metastases suggests occult thyroid primary
15DIAGNOSTIC EVALUATIONImaging Studies and
Endoscopy
- Initial evaluation includes chest radiograph and
CT scan of the abdomen/pelvis - The role of chest CT has not been established
- Mammogram is indicated in all women with CUP
adenocarcinoma - The experience with PET is limited
- Endoscopy is not recommended as a routine work up
for asymptomatic patients and should be used
according to the clinical presentation
16TREATMENT
- Once the diagnosis of carcinoma is established,
the main objective is determine whether the
patient belong to one of the favorable subsets,
for which there is a specific treatment
17TREATMENTFAVORABLE SUBSETS
- 1. Women with isolated axillary adenopathy
- Lymph nodes should be tested for ER, PR, and
HER-2/neu - In cases of negative mammogram, the primary may
be seen on MRI or after mastectomy - Prognosis is similar to lymph node positive
breast cancer - Mobile lymph nodes (N1) - Treat as stage IIA
breast cancer - Fixed lymph nodes (N2) - Treated as stage IIIA
breast cancer - MRM AND ? chemotherapy hormonal therapy/RT
- Neoadjuvant chemotheray for N2 disease
18TREATMENTFAVORABLE SUBSETS
- 2. Women with papillary serous adenocarcinoma of
the peritoneal cavity - The germinal epithelium of the ovary and
peritoneal mesothelium share the same
embryological origin - More common in women with BRCA-1 mutation and may
also be seen after prophylactic oophorectomy - Outcomes are similar to ovarian cancer at
equivalent stage - Patients should be treated as stage III ovarian
carcinoma - Surgical debulking followed by chemotherapy
19TREATMENTFAVORABLE SUBSETS
- 3. Squamous cell carcinoma of the cervical lymph
nodes - Despite aggressive diagnostic approach, the
primary site is not found in the majority of
patients - Ipsilateral tonsilectomy is often performed since
the primary can be found in 10 to 25 of cases -
Small tumors may originate in the deep crypts and
not be detected by superficial biopsy - Treat as locally advanced head and neck cancer
- Low stage (N1) Surgery ? RT or RT alone
- High stage (N2-N3) - Chemoradiotherapy
20TREATMENTFAVORABLE SUBSETS
- 4. Isolated inguinal squamous cell carcinoma
- Tumor is usually located in the genital or
anorectal area - Patients without an identifiable primary tumor
may benefit from inguinal lymphadenectomy, with
or without adjuvant radiation therapy - The role for chemotherapy in the adjuvant setting
is not well defined - Surgery RT, ? chemotherapy
21TREATMENTFAVORABLE SUBSETS
- 5. Men with bone metastases, elevated serum PSA,
or PSA positive on tumor staining - Prostate cancer is the most likely diagnosis
- 1. Elderly men with adenocarcinoma of unknown
primary and predominantly blastic bone metastases - 2. Patients with increased PSA or positive PSA
staining on the biopsy specimen despite atypical
presentation - Hormonal therapy
22TREATMENTFAVORABLE SUBSETS
- 6. Men with poorly differentiated carcinoma of
midline distribution - Young males with tumors of predominant midline
distribution (mediastinum and retroperitoneum)
should be treated as extragonadal germ cell
tumors - Cisplatin-based chemotherapy (BEP)
23TREATMENTFAVORABLE SUBSETS
- 7. Poorly differentiated neuroendocrine
carcinoma - IHC usually stains positive for chromogranin or
NSE - Patients frequently present with diffuse
metastases to the liver or bones - Platinum-based chemotherapy (platinum
etoposide)
24TREATMENTFAVORABLE SUBSETS
- 8. Single metastatic site
- Although other metastatic sites may become
evident within a short period, some patients may
achieve a prolonged disease-free interval with
local therapies such as surgery or radiotherapy - Adjuvant chemotherapy may also be considered
- Surgery or RT
25TREATMENTUNFAVORABLE SUBSETS
- With the exception of the favorable subsets, most
patients with CUP have a tumor that is resistant
to chemotherapy - The prognosis is very poor, with median survival
of 2 to 3 months in unselected patients and 6 to
10 months in those enrolled into clinical trials - Patients with good performance status may benefit
from systemic chemotherapy
26TREATMENTUNFAVORABLE SUBSETS
- There is no chemotherapy of choice although the
most commonly used regimens use the combination
of a platinum and a taxane - The role for a third agent such as gemcitabine or
etoposide remains unclear
27TREATMENTUNFAVORABLE SUBSETS
28PROGNOSIS
- Classification and regression tree (CART)
Analysis of 1,000 patients referred to UT MD
Anderson from 1987 to 1994 - Median age 59 (range 17 to 89)
- lt 50 26
- 50-69 57
- gt 70 17
- Male 52, female 48
29PROGNOSIS
Tumor-related characteristics
70
30
30PROGNOSIS
31PROGNOSIS
Role of histology update with 1,109 patients
32PROGNOSIS
- Number of involved sites update with 1,109
patients
33CONCLUSIONS
- CUP represents a group of heterogeneous tumors
sharing the unique characteristic of metastatic
disease without identifiable origin at the time
of initial therapy - Although identification of the primary tumor may
provide valuable information regarding both
treatment and prognosis, aggressive diagnostic
workup is usually of little value and not cost
effective - The recommended approach is to pursue a limited
diagnostic approach to identify favorable subsets
34CONCLUSIONS
- Potential roles for DNA microarray technology
- Identify the primary site
- Identify clinically relevant subsets of tumors
with similar gene expression profiles - Identify specific and novel targets for treatment
- Targeted therapies such as EGFR inhibitors and
anti-angiogenesis agents may have a role in the
treatment of CUP, particularly in patients with
unfavorable subsets - - Bevacizumab erlotinib 4/49 PR (8), PFS
4.7m, MS 7.5m - Hainsworth JD, Proc Am Soc Clin Oncol 2006 Abstr
3033
35GENERAL APPROACH
Diagnosis of metastatic carcinoma
Search for primary site
AND
Rule out non-carcinoma histology Lymphoma,
melanoma, sarcoma
Identify favorable subgroups
Good PS
Unfavorable subgroup
BSC
Poor PS
?Clinical trial ? Platinum-taxane chemotherapy