CARCINOMA OF UNKNOWN PRIMARY

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CARCINOMA OF UNKNOWN PRIMARY
Daniel Morgensztern, M.D.
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CARCINOMA OF UNKNOWN PRIMARY

• Definition
• Epidemiology
• Biology
• Clinical manifestations
• Diagnostic evaluation
• Treatment
• - Favorable subsets
• - Unfavorable subsets
• Prognosis
• Conclusions

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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

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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

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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

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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

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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)

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DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
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DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
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DIAGNOSTIC EVALUATIONPATHOLOGY
IMMUNOHISTOCHEMISTRY
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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

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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

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DIAGNOSTIC EVALUATIONPATHOLOGY CYTOGENETIC
ANALYSIS
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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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)

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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

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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

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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

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TREATMENTUNFAVORABLE SUBSETS
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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

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PROGNOSIS
Tumor-related characteristics
70
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PROGNOSIS
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PROGNOSIS
Role of histology update with 1,109 patients
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PROGNOSIS

• Number of involved sites update with 1,109
  patients

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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

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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

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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