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CARCINOMA OF UNKNOWN PRIMARY

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Carcinoma of unknown primary (CUP) is a biopsy-proven metastatic malignant tumor ... 2. Women with papillary serous adenocarcinoma of the peritoneal cavity ... – PowerPoint PPT presentation

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Title: CARCINOMA OF UNKNOWN PRIMARY


1
CARCINOMA OF UNKNOWN PRIMARY
Daniel Morgensztern, M.D.
2
CARCINOMA OF UNKNOWN PRIMARY
  • Definition
  • Epidemiology
  • Biology
  • Clinical manifestations
  • Diagnostic evaluation
  • Treatment
  • - Favorable subsets
  • - Unfavorable subsets
  • Prognosis
  • Conclusions

3
DEFINITION
  • 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

4
EPIDEMIOLOGY
  • 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

5
BIOLOGY
  • 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

6
CLINICAL 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

7
DIAGNOSTIC 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)

8
DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
9
DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
10
DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
11
DIAGNOSTIC 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

12
DIAGNOSTIC EVALUATIONPATHOLOGY ELECRON
MICROSCOPY
  • Identification of neuroendocrine tumors,
    melanoma, and poorly differentiated sarcomas
  • Differentiate between
  • 1. Lymphoma and carcinoma
  • 2. Adenocarcinoma and squamous cell carcinoma

13
DIAGNOSTIC EVALUATIONPATHOLOGY CYTOGENETIC
ANALYSIS
14
DIAGNOSTIC 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

15
DIAGNOSTIC 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

16
TREATMENT
  • 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

17
TREATMENTFAVORABLE 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

18
TREATMENTFAVORABLE 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

19
TREATMENTFAVORABLE 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

20
TREATMENTFAVORABLE 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

21
TREATMENTFAVORABLE 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

22
TREATMENTFAVORABLE 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)

23
TREATMENTFAVORABLE 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)

24
TREATMENTFAVORABLE 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

25
TREATMENTUNFAVORABLE 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

26
TREATMENTUNFAVORABLE 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

27
TREATMENTUNFAVORABLE SUBSETS
28
PROGNOSIS
  • 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

29
PROGNOSIS
Tumor-related characteristics
70
30
30
PROGNOSIS
31
PROGNOSIS
Role of histology update with 1,109 patients
32
PROGNOSIS
  • Number of involved sites update with 1,109
    patients

33
CONCLUSIONS
  • 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

34
CONCLUSIONS
  • 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

35
GENERAL 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
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