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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