Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
 Home | Pathology Group Members | Our Hospital |  Search This Website:
        Breast Cancer "pearls" Collection
      
Breast Cancer pearls, tips, and rules of thumb:
  • Imaging limitations:
    1. MRI: August 2007 report = MRI 25% more effective than mammography, especially as to d-CIS, espicially high grade...think of MRI especially in high risk cases.
    2. even 2-8 cm. palpable tumors can be diagnostic mammogram invisible [LMC-01-4306; LMC-01-5411], and screening mammograms neg. but spot compression of palpable area may be pos.  [S-01-9364].
    3. lobular is notoriously occult [LMC-02-4686]. 
    4. ultrasound is poor in fatty (mostly postmenopausal) breasts because both fat & cancer are hypo-echoic.
  • "Possible breast cancer" question is not an emergency...except:
    1. breast redness (erythema): skin biopsies can be nonspecific or may show cellulitis (dermal interstitial polys [S07-10697]); inflammatory breast cancer (?even if just significant suspicion of it?) is so dangerous (see below) that one desires to start chemotherapy ASAP...why?:
      • to retard accelerated systemic spread that is promoted by dermal lymphatic invasion.
      • to reduce the probability of locally extensive, difficult to manage/treat,  chest wall recurrence (and mod. rad. mastect. removes the most skin).
    2. suspected in pregancy: These cancers must be addressed quickly because of the high levels of hormones and cancer being likely to be hormone dependent. When found post-partum during nursing, some call the cancer a "suckling breast cancer" [L-05-8375].
    3. NOTE: Judy Kneece has done studies to show that the fear and anxiety to women waiting for an original diagnostic declaration on their suspect breast is on the same order of waiting for the news on a missing or critically injured/sick child (hence, our "5 day from detection to diagnosis" program)
  • Sampling confidence15:
    1. open breast biopsy is 99% sensitive
    2. cutting/core needle biopsy without image guidance is 85%
    3. cutting/core needle biopsy with image guidance is 98%
    4. fine needle aspiration (FNA) is 96%
    5. ductal lavage can't even diagnose atypical cells except in 14% of cases of cancer scheduled for mastectomy.
  • Non-invasive lesions, implications:
    1. benign, simulate cancer: florid hyperplasia/adenosis, sclerosing adenosis.
    2. if larger than 5 cm and grade 2-3, there is a reasonable chance of acting like an invasive case (including node positivity [L-03-2156]) even if one cannot clearly demonstrate invasion even in the mastectomy. [see this]
    3. criteria for types
    4. ductal (ADH) & lobular (ALH) atypical hyperplasia: are considered to be morphological neoplastic risk markers indicating bilaterally increased risk for cancer. If the pathologist struggles over the DDX between ADH & d-CIS, the path report should clearly reflect this so that the clinician...in possession of more complete historical data...can decide whether to manage or treat as d-CIS or not.
    5. ductal (d-CIS or DCIS) and lobular (l-CIS or LCIS) carcinoma-in-situ (CIS): in biopsies indicate non-invasive breast cancer and are morphological neoplastic risk markers indicating increased risk of cancer in the biopsied breast and d-CIS is a lesion conventionally requiring entire removal, whereas ALH and LCIS often just followed.
    6. NOTES: 
      • since ductal and lobular (AH/CIS/invasive) distinction can be problematic, an E-cadherin (another line of evidence than just morphological) may help
      •  since our pathology reports are often copied to primary care doctors, it may be an advantage to comment to the above on these lesions
  • Microcalcifications:
    1. types:
      • phosphate salt type: visible on H&E...neg. by polarized light
      • calcium oxalate: not H&E visible but is polarized light visible
    2. prebiopsy: odds of being malignant vary with the pattern
    3. it helps to point out whether significant CIS components are negative (lack a localization marker) and whether microcalcification is in malignant, benign, or mixed types of foci.[LMC-01-2253 almost whole breast DCIS and few Ca++; LMC-01-872 only 10-20% of DCIS has Ca++]
    4. cancer case: trying to do CBS presents a problem because, as above, all of the invasion is not likely to be mammographically definable as microcalcification (not all CIS is marked by Ca++) & true, total lesion may be much larger than expected
    5. pre-XRT mammogram: in cases with CBS procedures...even when margins clear...may note residual micro-Ca++ which needs excision because could be CIS [S-01-10657]
    6. cancer case, post-XRT new micro-Ca++: especially if it develops after 1 year6, 58% of new micro-CA++ is malignant11
  • Invasive cancer types: special problems with lobular vs. ductal, medullary vs. atypical medullary, and invasive micropapillary vs. ?.
  • Factors impacting cytotoxic regimen: higher grade, higher proliferation rate, greater size & volume of tumor, higher-risk tumor variety, angiolymphatic invasion, "triple negative", HER-2 positivity with ER/PR negativity, patient's age & performance status, genomic risk category, etc. are factored in by medical oncologist to help decide doseage & cycles, etc. Pathology report can help by giving descriptive, quantitative details. Small ER & HER-2 positive invasive component in an excised larger d-CIS might get radiation, anti-estrogen, and Herceptin but no cytotoxic chemo if path report is really clear on details.
  • Decision Time pressures: to hope to duplicate the results of "standard of care", the treatment "window of opportunity" is fixed (with the clock running) at the time of histological diagnosis (and assumes that additional "definative treatment" and staging are promptly attended to).
    1. institution of cytotoxic/antibody chemotherapy: within about 8 weeks.
    2. institution of radiation therapy: within about 6 months.
  • Clinical axillary adenopathy:
    1. false positives: medullary ca. and "atypical medullary" ca. both can present with adenopathy which is histologically negative7
    2. false negatives: pathologists very commonly find positive sub-centimeter lymph nodes in node dissections
  • Presurgical neoadjuvant treatment cases:
    1. indications:
      • original, historical standard of care reasons:
        1. ulcerated inflammatory ca.
        2. obviously clinically pos. axillary nodes
      • additional standard of care reasons: size >3cm. and/or mult. masses [LMC-01-3091] and MRM closure is tenuous without reduction in tumor size [LMC-02-767].
      • other potential reasons:
        • high grade histology (especially the proliferative rate) plus other features which make one want to "slam" the tumor prior to surgery and contend, thereby, with any tendency for associated manipulational embolization of tumor cells [LMC-02-3255].
        • presentation with metastatic disease [LMC-01-4378] and MRM indicated.
        • current top indication: mass location and size make cosmetically acceptable CBS-type surgery difficult without tumor size reduction [LMC-01-5179 didn't].
        • to see, in vivo [LMC-02-5827], whether tumor is responsive to the chemo regimen6 or by assessment after the lesion is removed.
    2. notes:
      • neoadjuvant delivery is best if no more vascular interruption than core biopsies (less effective in tumor kill and in vivo response monitor when vascular supply disrupted...incisional biopsy...and if complicated by hematoma)6.
      • following neoadjuvant treatment, mass  (grossly & by imaging) may go away...pathology exam should document this with site sampling [LMC-01-4165]; more likely, there will be microscopic residual resistant cell clusters, being the reason that the primary must be removed, even if it appears to have been eliminated [LMC-01-7655].
      • following neoadjuvant treatment, mass may appear almost unchanged by gross exam and imaging, yet be such as 76%-100% necrotic or "gone" (responsive) [breast LMC-02-1831][rectal LMC-02-1961].
      • following neoadjuvant treatment, axillary nodes, having become "sterilized",  may contain foamy-cell foci [LMC-01-7655], fibroinflammatory scars, and/or mucin pools [LMC-02-1961 19 of 32 sterilized to negativity and 13 virginal negative] of previous positivity.
      • in neoadjuvant treatment situations, oncologists need to know some quantitative estimations of residual tumor in breast and nodes (25% reduction is responsive tumor; 50% reduction is better responsive; 75% reduction is even better, etc.) vs. a non-responding tumor [LMC-01-3091].
      • post neoadjuvant, presurgical PET scans can be woefully false negative because treatment has thrown the still-viable tumor cells into a metabolically "stunned" or inactive status.
      • following neoadjuvant treatment, best to have metallic marker or calcifications marker so that tumor site can be found by radiology follow up and/or by pathologist6.
      • in neoadjuvant treatment cases, need SLN status prior to chemo (& can place port at same time6).
      • primary tumor typically responds better than node mets6.
  • maintaining sensation:
    1. a radiated breast is a sensate breast (Lewinsky 9/00).
  • d-CIS with microinvasion (DCISM) and consideration of SLN biopsy:
    1. microinvasion defined (CIS-MI):
      • malignant epithelium lacking a basement membrane or ME cells.
      • French study14:
        1. DCIS: ALND in 206 of 209 cases negative. 
        2. DCIS-MI type I: periductal single-cell infiltrate, <16 cells...ALND of all 59 neg.
        3. DCIS-MI type II: periductal cell-cluster/tubular nongradable infiltrate...ALND of 90% are neg.
        4. IDC-DCIS: having infiltrating gradable clustered/tubular 20% or less of tumor surface area on slide in a case of predominant DCIS (28% ALND pos.) [IDC with EIC is bigger and not the same thing].
      • any focus of definite invasion 2 mm. or greater in size8.
      • any situation with a sum of invasion 2 mm. or greater in size4.
    2. in 14 cases with d-CIS and microinvasion (DCISM), total lesional size range 0.9-6.5 cm., 2 (15%) had positive SLN biopsy, both cases with 4.5 cm. lesions (Cancer 85:2439-2443, 1999)
    3. predicting microinvasion/invasion from d-CIS core biopsies13: 
      • target >4 cm. and lobular extension noted: 40% risk of invasion [LMC-02-2232/2586, 5cm target].
      • high nuclear grade and comedo-necrosis in a cribriform or papillary d-CIS portends a 72% risk.
    4. warning!: be careful to not overdiagnose microinvasion in cases of CIS growing within adenosis...may need IHC markers to prove still CIS [S-01-1380].
  • d-CIS and consideration of mastectomy:
    1. mastectomy has a 98% cure rate: (JAMA 283[4]:453-55, 26 Jan. 2000)
    2. if lesion "large" and biopsy indicates that a significant proportion IS NOT marked by microcalcification [S-01-8567]
    3. if the size of the d-CIS relative to breast size is too large to get a good cosmetic result, consider mastectomy with immediate reconstruction: (JAMA 283[4]:453-55, 26 Jan. 2000)
    4. if non-high-grade and even small amounts involve more than 1 quadrant (non-high more likely to poorly match mammographic microcalcifications)[LMC-01-7409]
    5. if the VNPI is 8 or 9 (with or without radiation, local recurrence rate of 60% at 8 years)
    6. at Moffatt cancer Center, the subset of multifocal d-CIS with micro invasion...disease free 5 years is 78%, all others 98% (radiation doesn't improve stats)
  • SIZE of invasive cancer:
    1. <1 cm. ANN tumor: long-term relapse rate (traditional node processing) is <10%5
    2. >3 cm., consider presurgical chemotherapy
    3. may need marker stains to find tumor size limit (ck8 stains all benign or malignant breast epithelium) and exert great care not to count in some admixed, dispersed adenosis cellularity (K-903 denotes the benign component) [LMC-01-5927].
    4. the larger the cancer the more likely ALNP: (Silverstein, Cancer 73:664-667, 1994)9
      • = to < 5 mm.    3% ALNP    (n=96)
      • 6-10 mm.        17%ALNP    (n=156)
      • 11-20 mm.       32%ALNP    (n=357)
      • 21-50 mm.        44%ALNP    (n=330)
      • >51mm./T3        60%ALNP   (n=92) 
    5. AMAZINGLY, size determination is still problematic for some pathologists [LMC-01-7775] such that many medical oncologists involved heavily in breast cancer treatment have a rule of thumb that says: when in doubt, guide decisions by the greatest diameter described in any official report of the pathologist or radiologist! In maybe 5% of cases, the tumor is binodular or trinodular, and the pathologist must confirm that it is one tumor of such configuration or 2 or 3 entirely separate nodules. Maybe once per year, we have a case where it turns out that the patient presented with a dominant mass within a large & vague "field effect" area containing multifocal tiny or larger cancers [LMC-06-5923 had a dom. 1.5cm nodule within a 6 by 8cm "field" of intramammary microcarcinomatosis]. In the absence of sufficient knowledge of imaging shape, a pathologist could fail to section along the longest axis of an ovoid or teardrop or comet shaped tumor and under-measure the greatest size measure.
  • Surgical margin status determination:
    1. friability of margin: watch out with fatty peritumoral tissue because the fat is friable during surgical, specimen radiographic, and pathologist manipulation (fatty margin can disrupt or be thinned out by pressure so that ink may touch tumor surface as a distorted-fat artifact)
    2. margin marking: various dyes can be used, and most can be quickly mordanted (adhered)  to the margin with a dip in dilute acetic acid (vinegar will work) and placement into fixative.
    3. slide/block correlation: because microtombing planes can be incomplete or fatty tissue flake off the slides during staining, it is a good idea to carefully lay each slide over each corresponding block face and use glass compatible ink to trace the true margins onto the slides.
    4. choice:
      • 10% neutral buffered formalin: IHC markers (ER, PR, HER2) require 10% NBF or alcoholic formalin (a portion of tumor can be removed into 10% NBF and the other fixatives used to advantage)
      • mercuric (B5; M2): bathing the dye-marked specimen in this for 15-30 minutes causes the dyed periphery to faintly harden; wash off and transfer into other fixative (either 10% NBF or Hartmann's)
      • Hartmann's: this is an alcoholic formalin containing some acetic acid; valuable advantage is that foci with increased DNA content turns white (only if FIRST fixed in Hartmann's) and fibrous stroma turns amber & semitranslucent. It helps in (1)finding the limits (tumor size) of a relatively dispersed or uncircumscribed tumor and (2) in locating multifocal tumor or satellite nodules
  • denoting decreased risk of local recurrence among 293 cases of partial mastectomy/lumpectomy (surgery only...median follow-up 8 years...Canada): node neg., age >/=50, negative for LVI, no comedo-DCIS, and ER pos.18
  • denoting increased risk of local recurrence, CIS or invasive:
    1. invasive ductal, on size alone, rule of thumb: 10% per cm. of tumor
    2. invasive ductal: if EIC (as an implication of multifocality or multicentricity: Holland, J. Clin. Oncol. 8:113-8, 1990): invasive ductal ca. (IDC) = to or < than 5cm. greatest diameter:
      • 74% recurrence when IDC with EIC and only CBS
      • 42% recurrence when IDC without EIC and only CBS
      • 9-50% recurrence when IDC with EIC and CBS and XRT9
      • 2-25% recurrence when IDC without EIC and CBS and XRT9
    3. African Americans present with larger, higher grade tumors and with 3x the percentage of invasive lobular ca. than non-blacks2
    4. d-CIS, close margins riskier IF:
      • in palpable d-CIS...palpable more likely multicentric (Semin. Surg. Oncol. 12:300-13, 1996)
      •  in pure or predominantly micropapillary or apocrine variants because they are more likely extensive and/or multifocal (Human Path. 28:967-73, 1997 & 29:1056-62, 1998)
      • when mammography shows:
        1. very dissociated, poorly clustered microcalcifications
        2. microcalc. and core biopsies show signif. proportion which is not assoc. with microcalc. (usually non-hi-grade)
      • when margins close and tumor has a highly dispersed tumor pattern
      • but, if lumpectomy margins only focally microscopically positive, NSABP B24 is interpreted to indicate only a 9-10% local 5 year recurrence rate without XRT; therefore, fairly safe to opt out [watch out if VNPI is 8 or 9] of XRT if good reasons and patient's desire6.[LMC-01-4306]
      • What about trimming flaps AFTER XRT and finding d-CIS or invasion...how do we know that the tumor in that tissue is still "active"? Maybe if it is XRT-damaged &/or chemo. damaged & heading toward death, the Ki67 would be negative or not elevated...the evolution to cell necrosis taking up to 18 months6 in prostate! [LMC-01-8292; LMC-03-1613]
    5. d-CIS, in general,  CBS needs XRT (NSABP B17...after 90 months)
      • with CBS alone, d-CIS recurs 10-15% of cases, 50% being IDC (only 20% as IDC if got XRT)6
      • CBS alone recurs with IDC 13.4% of cases12
      • CBS plus XRT recurs with IDC 3.9% of cases12
    6. invasive cancer, French study of 605 cases CBS plus ax. dissection and XRT, increased recurrence risk if:
      • positive axillary nodes
      • thin (not obese) body habitus (thin BMI)
      • <40 y/o
      • multifocal cancer
    7. invasive cancer & LCIS, Fox Chase study 1274 cases of CBS and XRT:
      • if no assoc. LCIS, 6% recur. @ 10 yrs
      • if assoc. LCIS, 29% recur. a@ 10 yrs
      • (if assoc. LCIS & take Tamoxifen, 8% @ 10 yrs)
    8. intuitively (no papers): invasive cancer with satellite mets in lump and/or intramammary lymphatics containing tumor micro-emboli (as with apocrine IDC and invasive micropapillary ca.)
  • denoting increased risk of distant recurrence of  invasive ductal NOS at 48 months (MPI better than node status):
    1. MPI greater than 0.6 and ALNN (7 of 13= 54%)
      [ALNN and MPI <0.6, only 8% dist. recurrence]
    2. MPI greater than 0.6 and ALNP (20 of 33= 61%)
      [ALNP and MPI <0.6, only 9% dist. recurrence]
    3. 4 or more ALNP by H&E about 50%
    4. presence of intramammary intralymphatic percolation of tumor9
    5. findings of unequivocal venous invasion in peritumoral breast, in perinodal venules [LMC-01-5654], or in axillary perinodal soft tissue? 
  • Lymph node status impact:
    1. historical benchmark:
      • ALNP (pos.) 5 yr disease-free surgery survival rate: 35-45%
      • ALNN (neg) 5 yr surgical-treatment death rate is: 20-35%
    2. ALNP cases, which do better or worse:
    3. ALNN cases, which do better or worse:
    4. very important to distinguish ATTDs (axillary tissue tumor deposits) from positive nodes (implications for XRT)[LMC-01-5517]
    5. ALND has pulled back from "complete" to just levels I & II because studies showed that "skip" metastases incidence was "only" 1.3-5.0%.9
    6. yet, in 1993, while about 66% of breast cancers stage as ALNN, about 20-30% of the ALNN cases will recur, implying new risk of death...how do we spot those bad ones? Could the "good" ones (small, low-grade, favorable type, no EIC, and no increased proliferation) just have surgery only?9
    7. further morphometric ALNN stratification with MAI and MPI
      [in general] [in premenopausal] [calculation sheet for MAI & MPI]
    8. number of positive nodes makes a difference even in T1 (Rosen, Surg. Clin. NA, 70;937-962, 1990): 1=80% 5 YOAS, >4=45% [table]
    9. amount of tumor in node:
      • a node filled with tumor can explain failure of radioactive or dye marker to point out the SLN (lymph gets shunted & bypasses that node) [LMC-01-5654]
      • presence micromets vs. macromets: macro.  may swing the decision for adjuvant chemo. and XRT 
    10. atypical primary situation for positive nodes:
      • very small primary, yet macromets [LMC-01-1809]
      • small grade I, ER/PR pos., yet mets [LMC-02-1659]
  • (1) Paget's Disease; &, also, (2) breast neoplasia indicators of increased risk that axillary nodes are positive [reminding why we do ALND]; where likely positive, you wouldn't want to do immediate plastic reconstruction because radiation needed & implants do worse radiated6 and chemo worse with implants6 in place:
    1. intramammary, intralymphatic tumor cells ("percolation"):
      • be careful to discount intralymphatic cells close to tumor or core biopsy tract...may just be mechanical dislodgement (AJCP, 113:259-265, 2/2000)
      • SLN marker may fail when lymphatics plugged by these "emboli" [LMC-02-4565]
      • 32% incidence of occult mets when peritumoral or intramammary lymphovascular invasion (AJSP 6:639-641, 1982) which is,9
      • equivalent alone to ALN positivity (Br. J. Ca. 50:771-777, 1984)(Cancer 69:1396-1403, 1992)
      • patients with this who are otherwise (T1N0M0) stage 1 are likely to have systemic mets (Ann. Surg. 193[1]:15-25, 1981)
      • this in any patient means distant mets are likely (Human Path. 17:984-987, 1986)
      • while apocrine adenoca. seems "prone" to it, others do so, too [LMC-00-461;LMC-01-5039]
    2. lymphovascular invasion, peritumoral1
    3. the larger the tumor the more likely ALNP1, 9
      • >4 cm. have 70% ALNP6
      • <5
      • 6-10
    4. those with HIGH NUCLEAR GRADE are riskier1
    5. palpable tumors are riskier1:
      • palpable and abnormal imaging: about 50% are cancer and 45% of the cancers have positive ALNs4
      • in IDC tumors 1-5cm. max. diameter:
        1. if palpable: 6-28% chance has a positive ax. node, and
          • lesser rate if no more than 0-trace comedonecrosis.
        2. if not palpable: 4% chance of  having a pos. ax. node, and
          • lesser rate if no more than 0-trace comedonecrosis
            • and if Paget disease, 65-84% ALN positive.
    6. if Paget disease (Sir James Paget, 1874) of nipple is present: 
      • underlying cancer...based on 1704 (adjusted from 1738) cases from 1988-200227:
        1. 859 (50.4%) of cases presenting first as PD & found to have invasive (IDC) cancer,
        2. 618 (36.3%) associated with non-invasive (d-CIS) cancer [B06-286],
        3. and 227 (13.3%) unassociated with a primary in that breast.
      • peripheral vs. central location of any underlying cancer27:
        1. if is d-CIS: a third as many peripheral.
        2. if is IDC: twice as many peripheral.
      • likelihood of ALNP:
        1. overall 37% chance that already has positive ax. nodes.
        2. if with palpable tumor, 65-84% node pos.
        3. if without palpable tumor, 0-13% node pos.
    7. subtypes prone to early node metastasis:
      • "invasive micropapillary ca." (MPC) variant of IDC
      • possibly the apocrine variant of IDC [LMC-01-5219]
    8. elevated S-phase (increased proliferation parameters...Ki67 is our marker) triggers cytotoxic chemotherapy (which would obviate the need for ALND to remove non-clinically positive nodes to decrease local recurrence) (Am. Surgeon 63(4):330-333, 1997)
    9. grade III IDC much higher local recurrence AND grade I & II with high HER2  and cathepsin D recur like grade III3
    10. cases with one positive lymph node have an increased recurrence risk if there is hilar tissue invasion (positive for HTI) and HTI & capsular infiltration and breeching better perceived with IHC [LMC-02-5028]
    11. as to SLN, Memorial Sloan-Kettering (MSKCC) study of 1849 SLN  in Tmic-T3 (1996-2000): younger age , larger tumor, presence of lymphovascular invasion (see above), worse nuclear grade, worse histologic subtypes, and breast location (outer) were predictors for increased rate of positive SLNs3
    12. Axillary risk calculator: SLN pathology results, if positive for cancer: MSKCC has an on-line calculator which takes SLN status and tumor status and produces percentage chance calculation that your axilla still has nodes in it with cancer. If the risk is high enough, additional surgery and/or axillary and collar-bone area radiation therapy are advisable.
  • When is early adjuvant chemotherapy (ACT) maybe not needed?
    1. premenopausals with MPI less than  0.0 and H&E negative nodes.
    2. premenopausals with MAI less than  10 and H&E negative nodes.
    3. when oncocyteDX value is low risk and H&E factors low risk.
  • When is post-surgical radiation therapy maybe not needed?
    1. after node negative small low grade cancer.
  • if SLN positive, predictors that non-SLN (NSLN) axillary node positivity is present:

    Remember that current standard of practice is to dissect the axilla if any SLN positivity (why?24: in order to stratify prognosis and treatment by knowing the total number of positive nodes, to provide better local control, and to increase survival (there is a 5.4% survival advantage in cases of clinically negative axillae).

    1. from Chapel Hill, 182 T1-T2: 80% with any extracapsular extension vs. 32.4% without...increased SLN metastasis size is worse3
    2. any SLN met is 1.0CM or greater (81% of cases had positive non-SLNs) and were 100% if primary tumor greater than 5CM, poorly differentiated, or pos. for HER-2 gene amplification;  and/or extranodal extension (76% of such cases had positive non-SLNs)22
    3. the MSKCC non-SLN risk calculation on-line tool. (some detail about process here23)
  • indicators of unusually low risk that nodes are positive:
    1. types not prone to metastasis:
      • adenoid cystic ca. (ACC) variant of IDC 
    2. microinvasive cancer:  (via 1/88-12/94 SEER data), 926 cases, 11.2% ALNP rate3
    3. d-CIS with microinvasion (DCISM): 15% have pos. nodes
  • indicators (M. D. Anderson) for postmastectomy radiation of chest wall AND the not-fully-dissected axilla (attack problem of increased locoregional recurrence)3:
    1. 4 or more positive lymph nodes
    2. >20% of removed nodes are positive
    3. one or more positive nodes have extracapsular extension of at least 2mm
    4. factors increasing locoregional recurrence, the 1031 MD Anderson cases in Int. J. Rad. Oncol. Biol. Phys. 50(3):735-742, 2001.
      • average rate with mastect. & chemo. is 17% @ 10 years
      • gross multicentric cancer, 37% @ 10 years
      • lymphovascular invasion, 25% @ 10 years
      • skin invasion, 32% @ 10 years
      • nipple involvement, 50% @ 10 years
      • margins pos. or < 5 mm, 45% @ 10 years
      • pectoralis fascia invasion (even if margin clear), 33% @ 10 years
      • 4 or more pos. nodes
      • >5 cm. max. tumor diameter
    5. small Netherlands study (Eur. J. Surg. Oncol. 27(3)250-255, 2001.)
      • of ALNN cases: medial tumors 73% less axillary recur. than lateral
      • of ALNP cases: 65% lower recurrence if radiate those with pos. apical nodes or extranodal extension
  • indicators of increased risk of internal mammary node positivity:
    1. positive ALN from a medial quadrant tumor: 50% risk [LMC-01-5654]
    2. medial and inframammary tumors more likely
  • indicators of increased risk of future cancer in contralateral breast:
    1. 2 or more grossly evident independent cancers in same breast (2% of nationwide USA cases in 1964)
    2. lobular-CIS is bilateral in 25-40% of cases (and 35% devel. invasive cancers of all types in 20 years) and indicate 4x the average risk in the other breast
    3. strong family history of breast cancer
  • indications supportive for bilateral mastectomy (with/without immediate reconstruction) in a patient desiring it:
    1. as above: 2 or more independent tumors
    2. lobular cell type
    3. strong family history
    4. large breasts...imbalance problems
    5. note: smokers and women who are sloppy about personal cleanliness double the risk of treatment delays due to complications (may be better to sequence their surgeries)8
  • tumor IHC markers:
    1. nobody's tumor is negative for everything
    2. in d-CIS, apocrine type: these apocrine cells are ER and PR receptor neg. but androgen receptor pos.
    3. apocrine-type invasive duct ca. must be ER & PR neg....androgen receptor should be pos.
    4. ER-PR neg. and HER-2 pos. lobular is bad
    5. true medullary ca. usually ER & PR neg., vimentin pos., and high proliferative markers
    6. HER-2 by IHC for product over-expression can be flat negative yet, in non-elderly, FISH can show oncogene amplification. And, there is a small percentage of cases with product clearly over-expressed and oncogene NOT amplified.
      7. Marker Status Usual Correlations
      estrogen receptor pos. tubular; lobular (70-92%); pleomorphic lobular 81%; grade I-II IDC; <2.0 cm (80%)
      estrogen receptor neg. true apocrine; >2.0 cm. (80%); grade III IDC.
      progesterone receptor pos. tubular; lobular (67%); grade I-II IDC.

      progesterone receptor neg.

      		 true apocrine
      androgen receptor pos.25 70-90% of invasive ca.
      true HER-2 positive pleomorphic lobular 81%
      true HER-2 negative well diff. cancer
      ER & PR neg., IHC HER-2 2+; but FISH non-amplified won't respond to Herceptin well6
      Ki-67 proliferation normal, low tubular & classic lobular; grade I IDC;
      Ki-67 proliferation clearly high medullary; high grade IDC
      nuclear DNA aneuploidy poor nuclear grade
  • >increased intensity of effort and thoroughness result in increased numbers and percentages of positive nodes :
    1. ***BE SURE IT IS A TRUE METASTASIS (see about micromets, below)
    2. NOTE: ALNN only mildly advantageous over 1 ALNP [table]
    3. in 78 previously ALNN, step cuts and H&E found occult mets in 24% (Fisher, Cancer 45:2025-31, 1978 )
    4. from Memorial Sloan-Kettering, in <1cm tumor, 258 had only ax. dissect. (ALND) of at least 10 nodes and another 596 with SLN3:
      • ALND [less intense search] cases with pos. nodes: 0/13 microinvasive; 8/68 T1a...11.8%; 26/177 T1b...14.7%;  34/258 all...13.2%
      • SLN [more intense search] cases with pos. nodes: 2/28 microinvasive...7.1%; 30/180 T1a ...16.7%; 91/395 T1b...23%; 123/603 all...20.4%
    5. from Baylor Breast Ctr.,  52 SLN cases, cancers ave. 1.35 cm.; nodes @ 2mm slices and  H&E and IHC at each 0.25mm step.: 
      • 58% occult node positivity (generally accepted rate, 20%)
        1. 6 H&E pos.
        2. 24 more only  IHC pos.
          • 12 had <10 met cells
          • 12 had larger clusters/small mets
  • lymph node micrometastases: cells/foci c/w the primary tumor...that is, the morphology is "right".
    1. "looks" like cells or cluster growing in node
    2. equal to or < 2 mm. diameter9
    3. otherwise:
      1. some say need >10 IHC pos. cells [LMC-01-5264?]
      2. some say >100 IHC pos. cells
      3. (IHC will see single cells in subcapsular sinus <10 cells) [LMC-02-5028]
    4. BUT, if not c/w primary and "growing", it may be best to diagnose such as, "21 H&E negative nodes, 3 with scant IHC positive cells of uncertain significance" and then let the micro. descriptively and quantitatively reflect your assessment of the findings 
  • Node status & outcomes: remember that, as of May 2001, all generally accepted outcomes data is derived from ordinary processing of nodes and H&E staining (Lagios)2
    1. Significance, in retrospect, of IHC pos. nodes: 6/2002 ASCO (abstract 146, Dr. Tan) report of retrospective analysis 368 ALNN mastect. 1976-78 @ Memorial S-K Hosp., ave. 17 nodes/patient, median follow up 17.6 years (22.5% increased yield): 2 more step levels (50 microns apart) H&E and IHC. Impact on DFS and breast cancer specific mortality (BCSM):
      Outcome neg. H&E
      neg. IHC
      (n=285)      		 neg. H&E
      pos. IHC
      (n=50)      		 pos. H&E
      pos. IHC
      (n=33)
      15 yr DFS 81% 66% 50%
      15 yr BCSM 16.1% 24.6% 45.3%
    2. general prognosis for pn1a H&E micrometastatic (<0.2 cm) disease is similar to those with pn0 disease (AJC's Cancer Staging Manual 1997:171-180)
    3. But, worse DFS @ 4 years (NSABP B-04) :
      • those pos. for micromets: 60% survival
      • those neg. for micromets: 90% survival
    4. 159 cases: only cases with occult mets = to or > 2 mm. by H&E were associated with a poorer 10 year recurrence-free survival and lesser mets similar to ALNN survival (Nasser, Human Path. 24:950-957, 1993)9
    5. Is it a true cancerous met. vs. benign inclusion vs. mechanical transport of benign or neoplastic cells? (AJCP 113:259-265, 2000 ):
      Situation Histology
      benign inclusion B9 nuclei and normal N/C ratio9
      no inflammatory cells associated with the epithelial cells & no desmoplasia; there are even cases of sinus mammary foci & even multiple nodes containing sclerosing adenosis29 foci.  
      mechanical transport
      (clinical implications uncertain)      		 mechanically dislodged epithelials (benign or malignant) are usually in the sinus spaces and associated with damaged RBCs and hemosiderin macrophages and negative for any "look" of growing in the node; invariably associated with either recent biopsies [LMC-04-5152, noninvasive & in 3 of 8 nodes] or significant26 tumor manipulation [S-02-6642]; benign groups cytologically benign.
      true biological metastasis looks like the primary and shows a "look" of growth in the node and not just sitting in sinus; and too large for mechanical transport (0.2 mm greatest dimension or larger)
      other nevus cells always in capsule and are S100 pos., ck neg & plasma cells can be ck pos.; and, rarely, "fibroblastic reticulum cells can be ck pos.9 ; dendritic node macrophages S100 pos. & ck neg.; anthracotic, melanosis, or siderotic macrophages can appear to be "marked" by the ck antibody; 

    6. IHC retrospectively increased yield in IDC & ILC (Cote, Lancet 354:896-900, 1/2000...736 cases of Trial V of Ludwig study):
      • IDC: IHC increased ALN+ status from 52 (8% of 672) to 148 (22%) cases of IDC out of 672 total IDC cases
      • ILC (or mixed): IHC increased ALN+ status from 2 (4%) to 25 (39%) of 64 cases of ILC (or mixed) out of 736 total cases
      • median follow-up of 12 yrs showed DFS and OS (for H&E or IHC micromets significantly poorer only in postmenopausals [so IHC all postmenopausal H&E neg.]
    7. IHC retrospective 203 cases in Queensland 1971-1983: 255 additional yield with stepcuts and IHC...and it is very significant16!
    8. IHC retrospective 96 cases in Houston, 1998-99, were routine neg. but stepcut H&Es and IHCs converted 22 cases (20% false neg.) to positive!17
  • Unless grossly suspicious for positivity, SLN frozen sections are bad idea (guard against sectioning induced false negativity by touch preps of the cut surface on pieces used for the FS):
    1. false neg. rate of 6% is lowest possible (Cancer 1999, 85:2433-38 )
    2. false negative rate of about 10% at P-BMC...where SLN FSs are liberally performed (longitudinal bisection of node and do FS on 1 half and perm. sect. on all else) 
    3. true occult positive rate at FS: and fairly rarely (at P-BMC) there will be a true positive FS that was not grossly positive
    4. but, many clinicians believe that an immediate touch prep or frozen section on the sentinel node (s) is such an advantage that they want it anyway so that they can do the axilla in the same anesthesia
    5. some feel that a positive SLN does not need axillary dissection (unless there is reason to believe that the rest of the axilla contains macroscopic disease) because standard treatments will be the same.
    6. others want to know the status of all level 1 and 2 nodes because clinical trial entry may depend on number of positive nodes, sizes and location of nodal metastases, etc., for variable dosing schedules, etc.
  • SLN breast injection technique6:
    1. if tumor largely intact: inject periareolar intradermal and peritumoral
    2. if post removal of all or most of tumor: inject periareolar intradermal only
  • SLN, probable contraindications:
    1. tumor is very high in UOQ
    2. breast has more than one cancer
    3. has clinically "positive" axillary nodes
    4. cytotoxic chemo has already been started
  • Treatment:
    1. bone met pain: Celebrex works great6.
    2. boost to axilla & supraclavicular when bulky mets or transcapsular invasion [LMC-01-3091]
    3. MammoSite baloon contained brachytherapy is poor for cosmesis & has about a 10% infection or fat necrosis problem & more or less reserved for those having great difficulty getting to the numerous daily series of external radiation, especially when age 60 or older.
References:
  1. F. A. Tavassoli, Pathology of the Breast, 2nd Ed., 1999, 874 pages.
  2. Lagios and others @ 6th Annual Breast Symposium, Columbia, SC, 18 May 2001
  3. 23rd annual San Antonio Breast Cancer Symposium, Dec. 6-9, 2000 (in Breast Cancer Research & treatment 64(1):1-151.
  4. F. A. Tavassoli, MD, or Daniel Sullivan, MD,  Medical College of Ga., Seminar, 21 April 2001
  5. Allred & Elledge, "Caution Concerning Micrometastatic Breast Carcinoma in SLNs", Cancer86:905-907, 9/1999.
  6. our LMC weekly breast conferences or personal communication from our oncologists.
  7. Rosen's Breast Pathology, text, 1997
  8. Rosen, May 2001 Annual SP CME, Pittsburgh
  9. Weidner, April 1995, ASCP Spring Meeting, CME, Orlando.
  10. check out ASCO current and archived meeting abstracts
  11. Fechner & Mills, Breast Pathology: Benign..., [atlas/text] 1990 [EBS's office]
  12. J. Clin. Oncol. 16:441-452, 1998
  13. Andrew Renshaw, Arch. Pathol. & Lab. Med., 126:39-41, Jan. 2002.
  14. Mascarel, Cancer, 94(8):2134-2142, 15 April 2002 [EBS office]
  15. The Doctors Company, 2002, "Breast Biopsy and Fine-Needle Aspiration", David B. Troxel, M. D., risk paper.
  16. Cummings MC, "Occult Ax. lymph Node Met. in Breast Cancer Do Matter...Results of a 10-year Survival Analysis", The American J. of Surgical Pathology 26(10):1286-1295, October 2002.
  17. Patrick Borgen, Management of the Axilla, 25th annual San Antonio Breast Symposium, 11-14 December, 2002.
  18. Hanna WM, et. al., Pathologic Characteristics..., Breast J.  5(2):105-111, March 1999.
  19. Yared MA, et. al., "Recommendations for Sentinel Lymph Node Staging in Breast Cancer", Am. J. Surg. Path. 26(3):377-382, 2002.
  20. Hansen NM, et. al., "Clinical Signif. of Axillary Micromets in Breast Ca.: How Small is Too Small?" Abstract 91, ASCO, 2001 (referred to in AJSP 26(3):384, 2002).
  21. Brogi E, et. al., Ductal Lavage in Patients Undergoing Mastectomy for Mammary Carcinoma, Cancer 98(10):2170-2176, 15 November 2003.
  22. Changsri C, et. al., Prediction of Additional Axillary Metastasis of Breast Cancer Following Sentinel Lymph Node Surgery, The Breast J., 10(5):392-397, Sept/Oct. 2004 (EBS's office)
  23. Van Zee KJ, A Nomogram..., Breast Diseases: A Yearbook Quarterly, 15(3): 300-302, Oct-Dec. 2004 (EBS's office).
  24. Van Zee KJ, Residual Disease in the Axilla: to Predict or Not Predict?, Breast Diseases: A Yearbook Quarterly, 15(3): 231-234, Oct-Dec. 2004 (EBS's office).
  25. Rody A, et. al., Androgen Receptor Expression in Ductal Ca. In Situ of the Breast..., Applied Immunohistochem. Mol. Morph. 13(1):25-29, March 2005 (WRA's journal).
  26. Diaz NM, et. al., Benign Mechanical Transport of Breast Epithelial Cells to Sentinel Lymph Nodes, Am. J. of Surgical Pathology 28(12):1641-1645, December 2004. (Much higher number of SLN pos. if massage breast after sentinel marker injection.).
  27. Chen C, et. al., "Paget Disease of the Breast: Changing Patterns of Incidence, Clinical Presentation, and Treatment in the U. S." , Cancer 107(7):1448-1458, 1 October 2006.
  28. Chao KK, et. al., Analysis of Treament Efficacy, Cosmesis, And Toxicity Using the MammoSite Breast Brachytherapy..., Int. J. Radiation Oncology 69(1):32-40, 2007.
  29. Rosen PP, et. al. "Sclerosing Adenosis in Sentinel,,,", Arch Path & Lab Med 132(9):1439-41, September 2008.
(posted Nov. 2000; latest addition 19 October 2008)
 
© Copyright 1999 - 2006, all rights reserved, Pathology Associates Of Lexington, P.A.