SPECIMEN HANDLING

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SPECIMEN HANDLING PATHOLOGY REPORT BEFORE AND
AFTER BREAST CANCER NEOADJUVANT TREATMENT

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• DR. Mervat Mohamed Fouad
• Assistant Lecturer, Pathology Department NCI

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European Congress of Pathology September 2005
held in Paris(update in pathology)

• Consensus conference was convened in
  Philadelphia in April 2003, discuss issues
  related to routine application of neoadjuvant
  chemotherapy establish more formal guidelines
  for its use in patients with all stages of breast
  carcinoma.
• The full proceedings of the conference was
  published in Cancer 2004,100 2512-2532
• The panel recognized the major role of the
  pathologist in providing essential tumor
  parameters necessary to tailor this type of
  treatment

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MAGNITUDE OF THE PROBLEM OF BREAST CANCER

• The breast cancer is more prevalent in well
  developed countries
• USA
• -1.15 million new cases 2002
• -Accounting for 23 of all female cancers
• -Highest mortality 411.000 death /year 2002
• -99.6 /100.000 population (Globcan)
• Egypt
• -NCI 10.000 new cancer cases are diagnosed each
  year
• -Breast cancer constitutes 19.1 in both sexes
  37.6 in females.
• -According to population based registry
  El-Gharbih incidence of breast cancer is 49.6
  /100.000

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• Neoadjuvant chemotherapy (NAC) is also termed
  primary, preoperative or induction chemotherapy.
  NAC or hormonal therapy is used before surgery in
  breast cancer to down stage the tumor so that
  less extensive resection is needed breast
  conservation becomes increasingly feasible.
• Although it is the standard therapy for
  patients with locally advanced breast cancer it
  is increasingly used for early stage operable
  disease.
• NAC prevent changes in metastatic cells such as
  acceleration of growth development of drug
  resistance subclones upon resection of the
  primary tumor. Furthermore micrometastasis that
  may be present are thus treated at the earliest
  possible moment. Third rapid assessment of tumor
  sensitivity to chemotherapy within 3-4 months.

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Essential tumor parameters to tailor this
treatment Predictive parameters for treatment
response on pretreatment biopsy

• 1-Confirm the diagnosis by true cut or core
  biopsy, in cases diagnosed by fine needle
  aspiration cytology (FNAC) as cytologic
  examination can not differentiate between in situ
  and invasive tumors . but palpable regional lymph
  nodes with detection of malignant cells in L.N
  denote invasive cancer.

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• 2-Histological type , nuclear grade mitotic
  index (MI)

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• -Histologic type lobular carcinoma is a low
  responder
• High tumor grade, high nuclear grade high MI
  all exhibits high response rate. Grade 1 tumors
  / or lobular carcinomas are not responding

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• -Immunohistochemical evaluation of ER ,PR
  HER-2/neu predictors for targeted therapy
• -ER PR proved to be necessary to predict
  response to NHT tamoxifen antiaromatse.
• -Her-2/neu trials of preoperative trastuzumab
  show very high level of complete response rate
  among Her-2/neu amplified overexpressed tumors
  (up to 70)

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• -ER PR negative tumors respond to certain
  chemotherapeutics as high grade poorly
  differentiated tumors are more likely to be ER
  PR negative.
• -HER-2 predict response to NAC anthracycline
  based.
• -Proliferative markers cell proliferation
  correlate
• with response of breast carcinomas to
  preoperative chemotherapy disease outcome
  but it is not used to select patients . There is
  no consensus on method used SPF, MI KI-67 may
  indicate possibility of obtaining pCR

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• Topoisomerase II is a vital DNA binding
  enzyme. It helps DNA repair following strand
  cleavage. Topo II is the specific target of
  several chemotherapeutic agents including
  anthracyclins.
• Topo II gene is located at 17q 12-21 close to
  HER-2/neu gene , coamplification of HER-2/neu
  gene Topo II gene was observed in 44 of
  breast cancer whereas the Topo II gene was
  deleted in another 42. This complex
  relationship between the two genes may explain
  the altered sensitivity to anthracyclins of
  HER/-2/ amplified breast carcinomas.

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• Because most tumors respond well to treatment
  tumor localization is important. This is can be
  performed using either externally visible or
  radioopaque marker or metal coil simple mean to
  provide landmark for localization excision when
  the breast lump become impalpable
  radiologically undetected.
• Sentinel node if the tumor is small , it is
  likely to be lymph node negative therefore SLNB
  result will guide subsequent treatment . In
  addition number of positive lymph nodes indicates
  necessity of postoperative radiotherapy.

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Criteria for evaluating response to systemic
treatment according to WHO IUAC

• 1-Complete responsecomplete disappearance of
  all clinically detectable disease
• 2-Partial response.more than 50 reduction in
  the sum of the products of the 2 longest
  perpendicular diameters of measurable tumor
  deposits.
• 3-Progressive disease 25 -30 increase in the
  sum of products of the 2 longest perpendicular
  diameters of tumors or appearance of new lesions
• Combined clinical radiological examination is
  needed to detect extent sites of residual
  cancer in order to determine geography of the
  tumor and to plan surgery.
• Although clinical response is often selected as
  the primary endpoint in trials of NAC ,main goal
  of therapy should be a pathological complete
  response (pCR). The most objective information
  concerning effectiveness of NAC is provided by
  microscopic assessment of the extent type of
  residual tumor.

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Gross examination of breast specimen

• -Inspection- palpation X-ray appearance
• 1-Fresh-fixed (state of the specimen)
• 2-Type .excision biopsy or mastectomy
• 3-Side, size 3 dimensional
• 4-Dominant lesion site size (maximum
  diameter is most important), texture
  (consistency), color, outlines relationship to
  surrounding tissues.
• 5-Margins . Proximity to specimen margin
• 6-X-ray appearance ( when relevant)

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• If a complete clinical remission is achieved,
  resection of area surrounding marker is performed
  to detect the presence of microscopic residual
  disease as complete clinical regression does not
  imply complete pathological regression
• Excision biopsy
• -Mark tumor
• -Orient specimen
• -Margins inked or marked
• -Radiograph / or ultrasound image of the
  specimen
• -Section at 3-5 mm thick if the specimen is too
  large. Step sectioning aid in Semi quantitative
  estimation for residual tumor size based on the
  number of positive histological slides.

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• In mastectomy specimens
• -Laterality
• -Site of tumor
• -Size before therapy
• -residual tumor --tumor bed
• -Margins
• -Imaging

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Pathology report

• -Residual tumor ve or ve , invasive or
  intraductal component . No evidence that
  residual DCIS confer either distant recurrence
  liability or difference in long term survival. So
  that if no invasive cancer in breast axilla
  this denote complete pathological response.
• -Histological type, histologic grade, nuclear
  grade , MI
• Many studies conducted to assess pathologic
  response to chemotherapy described 2
  characteristic histologic features associated
  with chemotherapy exposure namely fibrosis
  cytonuclear changes.
• -Defined fibrosis as scar-like tissue , appeared
  as hyaline- rich , cell deprived desmoplastic
  stroma only if located at peripheral edge of the
  tumor.
• - Regressive cytonuclear alterations scored if
  marked anisocytosis, vacuolization increase in
  the nuclear size.

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• - Pathological complete remission (pCR) No
  residual carcinoma macroscpically or
  microscopically
• - Microscopic residual disease (pMRD) minimal
  tumor residues were found in the breast or in the
  axilla.
• Histopathological changes in a macroscopic
  residual tumor (pH RTM) Histopathological
  characteristic of NAC exposure but as macroscopic
  residual tumor mass.
• No response (p NR) No quantitative or
  qualitative histopathological evidence of tumor
  response.
• Sataloff et al., Grading of the therapeutic
  effect related to the primary tumor site ALNs
  as defined by microscopic changes
• T-A total/near total therapeutic effect
• T-Bsubjectively gt 50 therapeutic effect but lt
  total/near total therapeutic effect
• T-Clt 50 therapeutic effect, but effect evident
• T-D no therapeutic effect

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• ALNs response classification
• N-Aevidence of therapeutic effect , no
  metastasis
• N-Bno therapeutic effect, no nodal metastasis
• N-Cevidence of therapeutic effect, nodal
  metastasis present
• N-Dno therapeutic effect, viable metastatic
  disease
• Factors predictive for response to NAC
• -ER status
• -LN involvement
• - p53
• -Tumor size
• -Ki-67
• -HER-2/NEU

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