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Carcinoma of unknown primary IHC Approach

Based on a review article in ARPA. Approach to CUP with the help of IHC

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Carcinoma of unknown primary IHC Approach

  1. 1. Carcinomas of Unknown Primary Site Kandalaft et al (Arch Pathol Lab Med.doi: 10.5858/arpa.2015-0173-CP)
  2. 2.  Approximately 4% of all patients with cancer present as CUPs  IHC remains a gold standard at diagnosis  2 classes of antibody markers that can help - Antibodies to keratins - Antibodies to organ restricted markers
  3. 3. Determine the cell line of differentiation Determine the CK type or types of distribution Determine co expression of vimentin Determine expression of supplemental Ags (CEA, EMA, PLAP) Organ specific markers
  4. 4.  Low molecular weight CK - “simple” epithelium - K8, K18 - Glandular epithelium of GIT, hepatocytes  High molecular weight CK - “complex” epithelium - K5, K14, K17 - Stratified epithelium - Ductal and basal cells The subclassification of carcinomas by HMW and LMW keratins has largely been superseded by subclassification using antibodies to K7 and K20 which is a far more powerful discriminator
  5. 5. Cancer of Unknown Primary MD Anderson Cancer Center
  6. 6.  Urothelial tumors  Ovarian mucinous adenocarcinoma  Pancreatic adenocarcinoma  Cholangiocarcinoma  Gastric carcinoma
  7. 7.  Lung adenocarcinoma  Breast carcinoma  Thyroid carcinoma  Salivary gland carcinoma  Esophageal carcinoma  Endometrial carcinoma  Cervical carcinoma  Cholangiocarcinoma  Pancreatic carcinoma  Gastric carcinoma As a rule, gastric adenocarcinoma can show almost any K7/K20 phenotype
  8. 8.  Colorectal carcinoma  Merkel cell carcinoma (dot like pattern)
  9. 9.  Hepatocellular carcinoma  Renal cell carcinoma  Prostate carcinoma  Squamous cell and small cell lung carcinoma  Head and neck carcinoma
  10. 10.  Keratin 5 (and its pair 14) – marker of squamous, transitional cell, myoepithelial and mesothelial differentiation  Keratin 17 – when expressed at high levels  good marker for distinguishing between carcinomas of pancreatobiliary origin from gastric carcinomas
  11. 11. CARCINOMAS  Anaplastic thyroid carcinoma  Endometrial carcinoma  Mesothelioma  Metaplastic breast carcinoma  Myoepithelial carcinoma  Renal cell carcinoma  Sarcomatoid carcinoma  Thyroid carcinomas MESENCHYMAL  Adamantinoma  Chordoma  DPSRCT  Epithelioid angiosarcoma  Epithelioid sarcoma  Leiomyosarcoma  Malignant rhabdoid tumor  Synovial sarcoma
  12. 12. CYTOPLASMIC - Level of expression and fraction Function of the state of differentiation of the tumor NUCLEAR - When positive  entire tumor population - Independent of the state of differentiation
  13. 13.  2/3rd to 3/4th of primary breast  Lower fraction of breast cancer in metastatic sites  Primary in endometrium and ovary  Papillary carcinoma thyroid  Skin adnexal tumors  10-20% of lung adenocarcinomas (focally)  Rare in adenocarcinoms of GIT
  14. 14.  23A3 monoclonal antibody- 80% sensitivity  Function of histological subtype  Greatest in lobular (particularly those with signet ring cells) and those with apocrine features  Very small fraction of basal like carcinomas  Salivary gland carcinomas and sweat gland carcinomas  5-10% primary ovarian and endometrial carcinomas  5-6% lung adenocarcinomas
  15. 15.  Sensitivity as a marker of breast cancer is LESS than that of GCDFP 15 (50-70%)  7% breast cancers are Mammaglobin A positive but GCDFP 15 negative  10% of ovarian and endometrial  Skin adnexal and salivary gland tumors
  16. 16.  1 of 6 members of zinc finger transcription factor family  Very sensitive for breast and urothelial carcinoma  Ductal 91%, lobular 100% diffuse and strong nuclear staining  UNLIKE previous two seen in 43% of triple negative and 54% of metaplastic breast cancers  Maintained in metastatic breast cancer (>90%)  Skin adnexal, endometrial, pancreatic, salivary gland carcinomas
  17. 17.  NKX2 family of DNA binding transcription factors  Selectively expressed during embryogenesis in the thyroid, diencephalon and respiratory epithelium  Expressed in both neuroendocrine and non neuroendocrine tumors of the lung
  18. 18.  Sensitivity of TTF-1 is greatest among adenocarcinomas and nonmucinous bronchioloalveolar carcinomas  Lowest in mucinous adenocarcinomas and squamous cell carcinomas  Appears to retain similar sensitivity in metastatic sites  Small subset of ovarian, endometrial, and colorectal carcinomas, although the extent of positivity is usually focal, often in isolated clusters of cells
  19. 19.  TTF-1 expression cannot be considered specific for high-grade neuroendocrine carcinomas of lung origin  Variable subset of small cell (neuroendocrine) carcinomas of the genitourinary and gynecologic (GYN) tract  Cell blocks of pleural fluids, which contain material that has been either fixed in alcohol or is nonfixed before creation of a formalin-fixed cell pellet, can manifest a profound loss of TTF-1 antigenicity
  20. 20.  Aspartic protease that is crucial to the maturation of surfactant B and present in the cytoplasm of type 2 pneumocytes and alveolar macrophages  Very sensitive marker for detecting pulmonary adenocarcinomas  Subset of renal cell carcinomas  Minority of endometrial adenocarcinomas and papillary thyroid carcinomas  Virtually all cases of clear cell carcinomas of the ovary
  21. 21.  Nuclear transcription factor  controlling the proliferation and differentiation of intestinal epithelial cells  Virtually 100% of colorectal adenocarcinomas  MSI  reduced or even absent expression  CRC  uniform staining pattern  Most adenocarcinomas of the stomach, pancreas, and biliary tract  variegated or focal staining pattern
  22. 22.  ½ gastric (more in intestinal type) and 1/3 of pancreatobiliary  Ovarian mucinous carcinomas, bladder adenocarcinomas, and sinonasal intestinal type adenocarcinomas  Limited subset of mucinous and nonmucinous pulmonary adenocarcinomas (enteric subtype)
  23. 23.  Endocervical and endometrial  mucinous differentiation  ‘‘Squamous’’ morules of endometrioid hyperplasia and carcinoma  Germ cell tumors  intestinal differentiation  GI neuroendocrine tumors, including those primary to the intestine (eg, carcinoid tumors) and, to a variable degree, the pancreas (islet cell tumors)
  24. 24.  Actin-binding protein, found preferentially in microvilli  Expression is largely (but not entirely) restricted to glandular epithelium and corresponding adenocarcinomas of the GI tract  Expression is greatest and most reliably found in CRC  Lower levels of expression are found in adenocarcinomas primary to the pancreatobiliary tract and stomach
  25. 25.  Scoring of the membranous or ‘‘brush border’’ signal is most significant  Cytoplasmic immunostaining can be seen in other types of tumors, particularly neuroendocrine carcinomas  Can also be seen in adenocarcinomas of other sites that display a GI-type histology and immunophenotype Although the individual sensitivities of CDX2 and villin are each approximately 50%, their combined sensitivity is in excess of 75%.
  26. 26.  Detects a liver (hepatocyte)-specific marker, subsequently found to represent the enzyme carbamoyl phosphate synthase  Helps to distinguish metastatic carcinomas from primary HCCs  (1%–10%) subset of adenocarcinomas primary to the lung, pancreas, stomach, ovaries, and adrenal cortex  hepatoid morphology
  27. 27.  Enzyme involved in the urea cycle  Appears to represent the most-sensitive (and, perhaps, most-specific) marker of HCC to date  Cytoplasmic, granular pattern  High level of sensitivity even in the context of high- grade HCC
  28. 28.  It is not expressed in ‘‘hepatoid’’ and other non-HCCs (particularly carcinomas of the lung, stomach, and kidney) This is the marker of choice for identifying HCC
  29. 29.  Oncofetal protein  Proven useful in distinguishing HCC from nonneoplastic hepatic lesions and hepatic adenomas  In mets vs primary  high level of sensitivity and specificity of arginase-1 to surpass the use of glypcian-3
  30. 30.  Nuclear transcription factor implicated in tumorigenesis and in specifying normal urogenital development  Mesothelial cells, ovarian surface epithelium, mesangial cells in the kidney, a subset of smooth muscle cells, and granulocytic cells and precursors
  31. 31.  Marker of ovarian carcinomas in the context of adenocarcinomas  Mesothelioma distinguishing it from nonovarian adenocarcinomas  Desmoplastic small, round cell tumors  Ovarian serous carcinomas, primary peritoneal adenocarcinomas, and fallopian tube serous carcinomas  Very high sensitivity and specificity, both in excess of 90%.
  32. 32.  In a poorly differentiated ovarian carcinoma, nuclear WT1 reactivity favors a serous neoplasm because endometrioid, clear cell and mucinous carcinomas are negative  In the breast, WT1 is expressed in around 6% of the cases, usually at low levels in pure mucinous (65%) and mixed mucinous (33%) subtypes
  33. 33.  Subset of carcinomas arising within the female genital tract, exhibit nuclear expression for ER  In endometrial carcinomas of endometrioid type (type 1), ER antibodies are reactive  Whereas in uterine serous and clear cell carcinomas (type 2), they usually are not
  34. 34.  Can be part of a panel to differentiate endometrial adenocarcinoma from endocervical adenocarcinoma  No value in the distinction between a primary ovarian adenocarcinoma (mainly including endometrioid and serous carcinoma) and a metastasis from the breast or from elsewhere within the female genital tract
  35. 35.  Transcription factor, which is critical to embryogenesis of the thyroid gland, kidney, and mullerian system  Nonciliated, mucosal cells of the fallopian tubes, endocervix, endometrium, and simple ovarian inclusion cysts BUT NOT on the surface of the epithelial cells of the ovary  90% to 100% of serous, endometrioid, clear cell, and transitional cell ovarian carcinomas
  36. 36.  PAX8 is not expressed in mammary carcinomas, including ductal and lobular types  Because the ovary is a common site of involvement for metastasis by breast carcinoma, PAX8 can be a useful marker in the differential diagnosis of ovarian and breast carcinomas
  37. 37.  Highly expressed in clear cell carcinomas of the ovary  100% of tumors  Clear cell carcinomas of the endometrium (82%)  Few endometrial serous carcinomas (8%)  NO endometrioid endometrial carcinoma
  38. 38.  Very high sensitivity of this marker, apparently independent of Gleason score  Overall sensitivity in the range of 95% and specificity approaching 100%  Expressed by a subset of breast cancers  Also expressed focally in salivary gland and pancreatic carcinomas
  39. 39.  Antibody to the prostatic tumor suppressor gene NKX3.1  Recently reported to be an extremely sensitive marker for identifying metastatic prostatic adenocarcinoma (positive in 99%)  Level of sensitivity of NKX3.1 is maintained in high- grade prostatic carcinomas
  40. 40.  More than 90% of urothelial carcinomas are positive  Useful marker in distinguishing TCC from other non– small cell carcinomas potentially in the differential diagnosis, such as, prostatic adenocarcinoma (especially high grade)
  41. 41.  Glycoprotein of the asymmetrical unit membrane, which forms plaques on the apical surfaces of urothelial umbrella cells  First, specific, urothelial-restricted marker described  High sensitivity in non invasive; low sensitivity in invasive
  42. 42.  Critical to the embryogenesis of the kidney, is identified in renal tubular epithelium and vas deferens, but not glomeruli  Most of the renal epithelial neoplasms  Clear cell > Papillary > Chromophobe = Sarcomatoid = Xp11 Translocation  Not expressed in bladder TCC  Subset of renal pelvic urothelial carcinomas
  43. 43.  Specific and sensitive markers of both primary and metastatic carcinomas of the thyroid  Excellent marker of papillary and follicular carcinomas  Poor marker of anaplastic  NOT a marker for medullary
  44. 44.  Even more-sensitive marker of thyroid carcinomas than thyroglobulin  Medullary also  Anaplastic  negative
  45. 45.  Critical to the organogenesis of the thyroid gland and is highly expressed in the thyroid follicular epithelium  Papillary and follicular  100%  Anaplastic  80%  PAX8 is useful in discriminating between a TTF-1 + lung adenocarcinoma and a TTF-1+ thyroid carcinoma because PAX8 expression has not been identified in primary lung adenocarcinomas
  46. 46.  Expressed in a restricted subset of healthy cells, including ovarian granulosa cells, testicular Leydig cells, and adrenal cortical epithelium  Excellent marker for the identification of primary adrenal cortical tumors and their distinction from metastatic carcinomas to the adrenal gland  Ovarian and testicular stromal tumors
  47. 47.  Alternative or supplementary marker of adrenal cortical differentiation  Sensitivity is comparable or even greater than that of Inhibin
  48. 48.  100% specificity at discriminating these neoplasms from other tumors with clear cell morphology, such as renal cell carcinoma, ovarian clear cell carcinoma, and chordomas  High levels in sex cord-stromal tumors of the ovary  Lower levels in testicular sex cord-stromal tumors
  49. 49.  Unique among epithelial tumors  very low level of keratins  Unique among nonneuroendocrine tumors  synaptophysin
  50. 50.  Uniformly and strongly p63 and p40 positive  pure SCC (lung and cervix)  Thymomas can also be positive
  51. 51.  Uniform expression of p63 and p40, even in the setting of poorly differentiated tumors, such as spindle cell, bladder TCC
  52. 52.  Carcinomas demonstrating myoepithelial differentiation (eg, adenoid cystic and other salivary gland carcinomas)  Carcinomas demonstrating trophoblastic differentiation.
  53. 53.  73 years old man  Long term smoker  Needle biopsy of single left lower lobe lung nodule
  54. 54. CK 20 CDX 2 TTF 1
  55. 55. Metastatic adenocarcinoma from rectosigmoid
  56. 56.  63 years old male  Cervical lymph node needle biopsy  No known primary  Suspicious for lymphoma
  57. 57. CK 7 PSA VILLIN
  58. 58. Metastatic prostatic adenocarcinoma
  59. 59.  55 years old woman  Right axillary lymph node biopsy  Ill defined density seen on mammogram  PET positive uptake in right parotid gland
  60. 60. GCDFP-15 GATA 3 HER 2
  61. 61. Metastatic ductal carcinoma from breast
  62. 62.  73 years old woman  Needle biopsy of retroperitoneal lymph node  History of hysterectomy for unknown reasons many years back  Retroperitoneal lymphadenopathy, possible splenic metastasis  Left pelvic sidewall mass on CT scan - ?residual ovary
  63. 63. ER WT 1 PAX8
  64. 64. Metastatic high grade serous carcinoma of ovary
  65. 65.  58 years old man  Needle biopsy of mediastinal lymph node  Recent diagnosis of prostate adenocarcinoma (Gleason score 4, “hypernephroid”)  Nephrectomy 5 years ago for sarcomatoid renal cell carcinoma  Remote history of melanoma  Presented with mediastinal and lung masses
  66. 66. CK PSA PAX 8
  67. 67. PAX 8 + male  thyroid and renal TTF negative Metastatic renal cell carcinoma

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Based on a review article in ARPA. Approach to CUP with the help of IHC

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