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It is now a conventional concept that non-invasive carcinoma (CIS) of the breast originates in the TDLU (terminal duct lobular unit). The TDLUs hang like groups of 0.5-1.0 mm. grapes from the serpentine ducts which tend be very imperfectly radiated from the nipple in a somewhat radial-segmental fashion. All TDLUs, during lactation, produce milk which moves to the nipple through lumena. The key components of the TDLUs are ductal cells, lobular cells, and myoepithelial cells. Conservative breast surgery (CBS) has lead to studies producing some interesting clues for decision making in individual cases. IHC will be necessary to discern the difference between invasive and non-invasive carcinoma, particularly when CIS involves various types of adenosis [LMC-01-4299]. When nation-wide local pathologists of all backgrounds diagnosed cases go to clinical trial expert breast pathologists, there is about a 5-10% incidence of both underdiagnosis & overdiagnosis as to the following⁶. See breast DIN criteria

• types of CIS:
• lobular (l-CIS; LCIS): after 15 years, there is equal "laterallity" of any new cancers, 75% of which will be IDC⁶!
• ductal (d-CIS; DCIS)
• mixed (E-cadherin may give important information as to type or mixed or uniform small cells...next item below).
• ductal of small uniform cells and solid pattern (DCIS that looks like LCIS)
• indeterminate
• LCIS: the "eyeballing" criterion to go from LH to ALH to LCIS is highly subjective & having to do with whether the lobules are barely/mildly  lobular-hypercellular (LH) vs. filled & slightly/mildly distended with "normal" lobular cells (ALH) or definitely distended & overfilled ..."blown up"...with atypical lobular cells (LCIS). As with lobular neoplasia, ALH is a riskiness marker. But, see the precision criteria in "hyperplasia" section above. Old 1978 Haagensen division of " classical' LCIS was into usual small-cell type as "Type A" and larger cells & nuclei into "Type B" & with ER positive, low Ki67 & mitoses, and HER-2 negative⁶. If LCIS has what looks like comedo-DCIS but is of dyscohesive lobular cells with vacuoles(E-cad negative), it is referred to as "florid lobular CIS ²" or pleomorphic LCIS⁶ (PLCIS has nuclear 2-3x size variation...often with pink/apocrine cytoplasm [histiocytoid]), a lesion which often has microcalcification & is highly associated with microinvasive or invasive lobular carcinoma elsewhere in the lesion². If just Type A or B with comedonecrosis = "LCIS with necrosis"⁶. LCIS confers a 10x risk of future breast cancer @ about 1% per year; and it is both a marker of future risk (observe vs. observe & anti-hormonal Rx) & a precursor (remove it) of cancer and has treatment options ranging from observation to bilateral mastectomy; therefore, do not report margins because margins only pertinent to a pure precursor lesion)!⁶.
• DCIS:
• as to ADH: the minimal criteria to make a diagnosis of low grade DCIS are¹³:
• cytology: monotonous uniform round cells; round nuclei which are equidistant; maybe a subtle increase in N/C & maybe nuclear hyperchromia.
• architecture: solid; or, arcade/cribriform rigidity; or, micropapillary...see below.
• lesion size to make DX: 2 lumens to 5mm or larger defines DCIS (see "hyperplasia" above)⁶.
• true lesion size/extent vs. apparent size by mammography: (1) a discrepancy of 2CM or more is noted in in 44% of cribriform or micropapillary DCIS, 12% of comedo-DCIS, and 50% of cases containing a mixture of comedo-DCIS and either of the other two¹⁰! (2) in breast ending up with mastectomy, comed-DCIS is more likely to have extension to nipple than cribriform or micropapillary¹⁰. When lesions larger than 2-2.5 CM, odds are increased that the breast harbors multifocal DCIS¹⁰.
• architectural types:
  • solid: ductules filled with CIS cells.         
  • comedo: tubules solidly lined by CIS cells and lumens contain necrotic neoplastic debris (often calcified) in quantities that could be expressed grossly in the manner of a comedone. Other patterns can have central necrosis of DCIS cells in a manner resembling comedo-DCIS 7 situation should be noted as necrosis; but the necrosis does not change the basic DCIS pattern to comedo-DCIS.
  • cribriform: (can be predominantly tubules); but watch out for mimic by collagenous spherulosis. It is similar to "solid" but has many sublumens. Can be confused with micropapillary DCIS if the latter is a case with much cribriform-like Roman arche component [L09-14922].
  • papillary: lumenal paillations more bulky than "micropapillary" and even to the point of being "encysted" nodules/masses. If any component of a papillary DCIS lesion has any stroma in the papillations, best to call it "papillary DCIS"¹⁰. But, watch out for mimic by gynecomastoid hyperplasia (papillations taper toward lumen; CIS somewhat bulbous at lumen)⁶.
  • micropapillary: you must see papillations with microbulbous lumenad configurations (1) usual variant: microcalcifications don't match the lesion which tends to be multifocal and to extensively involve most of the duct segment at time of diagnosis, expressing as ductules lined by low papillaltions of d-CIS cells. But, watch out for mimic by gynecomastoid hyperplasia (papillations taper toward lumen; CIS somewhat bulbous at lumen)⁶. Lumpectomies of this variant have positive margins 90% of the time ⁵. (2) "clinging" variant³: minimally manifest papillations or Roman arches lining lumens lined by d-CIS cells. 
• alternate designation: some prefer to speak in terms of comedo-CIS vs. noncomedo-CIS (binary: low vs. high grades).
• cell variants:
  • biology not special: usual; apocrine (but ER & PR neg., below)²; signet ring; clear cell;
  • biology, special considerations: spindle cell may be problematic as to DDX vs. usual hyperplasia; small cell in solid pattern may look like lobular CIS.
• nuclear types (Bloom-Richardson; or 1997 consensus)¹⁰:
  • small (1.5-2 normal RBC diameters), regular (monomorphic), dispersed chromatin = grade 1.
  • intermediate nuclear size & not grades 1 or 3 = grade 2.
  • large (greater than 2.5 normal RBC diameters), pleomorphic, vesicular chromatin, & prominent nucleoli, maybe much mitotic = grade 3.
• extent of disease notes:
  • grade 3 d-CIS clinical extent tends to nicely match the imaging extent of microcalcification (Holland, Cancer 56:979-990, 1985).
  • micropapillary d-CIS tends to be widely segmental and multifocal (Patchefsky, Cancer 63:731-741, 1989).
  • non-high grade: 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], likely to be more widespread.
• grading notes: path report should always state the pattern, whether any DCIS necrosis, and some system of nuclear grading:
  • architectural type as a grade surrogate is poor.
  • Bloom-Richardson nuclear grade is the way to go
  • by whatever system of designating grade, high grade tends to recur short term and in high percentage (even with XRT⁴).
  • high grade nicely matches extent of mammographic microcalcification and less apt to have skip areas.
  • low/intermediate grades mismatch beyond mammographic extent of microcalcification.
  • radiation therapy (XRT) definitely helps reduce high grade recurrence rate.
• conservative breast surgery (CBS) surgical margin notes:
  • NSABP B17 def. of clear margin as one that does not transect tumor yields a recurrence rate of 22% @ 43 months (Fisher, NEJM 328:1581-1586, 1993).
  • 1 mm. margin as a clear margin yields 16% recurrence rate (Lagios, Breast J. 1:67-78, 1995).
  • if not to get XRT, you want a greater clear margin of maybe 5mm; if to get XRT, then 2mm or more is OK⁶.
• notes as to markers:
  • apocrine d-CIS is typically ER & PR neg. (androgen pos.)² [S-01-7806].
  • high molecular weight keratin (HMWK): using keratin 903 (K903) or ck5/6, ADH & low & intermediate grades DCIS tend negative and UDH positive and about a third high grade DCIS positive (usually focally)⁶.
• DCIS & micro-invasion:
  • artifacts: tangential at origin of a duct branch, involvement of a lobule, involvement of benign sclerosing lesions, distortion of involved spaces, tangential artifact, crush artifact, cautery effect, and specimen squeeze effect (toothpaste effect of some DCIS getting squeezed, wiped, or carried into a fatty or other space by manipulation artifact)⁶.
  • defined: 1977 AJCC = no focus greater than 1mm in size (don't sum up multiple foci)⁶.
  • where micro-invasion likely: palpable cases, large lesion (4-5 cm) cases (paper on determining the size of DCIS⁹), high grade cases with peri-epithelial chronic inflammation; at Beth Israel in 9/2009, these likely to get lumpectomy & sentinel node [& EBS guesses, especially if premenopausal]⁶.
  • sampling: even if you totally process the specimen to slides, you actually "see" less than 1% of it microscopically⁶!
  • burden of proof: it is the pathologist's burden to prove in his/her mind that a change is NOT microinvasion⁶.
• recurrence notes:
• of all grading schemes, only those based on nuclear grade stratify as to recurrence differences and Van Nuys was best (Badve, Human Path. 29:915-923, 1998)
• schemes based on nuclear grading can identify most of the cases likely for short-term local recurrence and invasive transformation (Sneige, Human Path. 30:257-262, 1998)
• d-CIS recurs as d-CIS or transformed to invasive ductal ca. in same breast in same segment, often at old scar (Holland, 1985; Faverly, Sem. Diag. Path.11:193-198, 1994)
• low 5-10 year recurrence in non-comedo, grade I & II but about 37% at 30 years and without risk diminishing after menopause (Page, Cancer 75:1219-1221, 1995)
• VNPI developed to predict risk of local recurrence after CBS
  • with margins of 10mm. or greater, high grade recurs in 10 years in up to 8% (taken to mean that 92% of recurrences are due to unresected residual d-CIS)
  • non-high grade is nearly 100% recurrence free
• radiation therapy notes:
  • radiation therapy (XRT) definitely helps reduce high grade recurrence rate
  • Van Nuys grouping scheme has greatest degree of inter-observer agreement (Bethwaite, J. Clin. Path. 51:450-454, 1998) while Lagios system study showed complete agreement between 6 pathologists in only 35% of cases. Therefore,
  • if grade goal is to exclude XRT in non-high-grade, there should be 100% agreement of grade among, say,  a cohort of no less than 3 pathology group members
• chemoprevention notes:
• Consensus Conference Recommendations as to Pathology:

1. 6th Annual Breast Symposium, Columbia, SC, 18 May 2001 (Dr. Lagios was key pathologist speaker)
2. Rosen's Breast Pathology, text book, 2nd Ed., 2001
3. Weidner N, The Difficult Diagnosis in S. P., 1996.
4. Page DL, Special Article (2002 A. P. Stout Society Symposium), Ductal Carcinoma In Situ of the Breast: Impact of Pathology on Therapeutic Decisions, A. J. S. P. 27(6):828-831, 2003.
5. Conferee statements, LMC weekly multidisciplinary Breast Conference.
6. Schnitt SJ, breast cancer topics, Gordon R. Hennigar Memorial Lecture, S. C. Society of Pathologists fall meeting, Grove Park Inn, Asheville, N. C. 12 Sept. 2009.
7. Foote & Stewart definition of LCIS, Am. J. Pathol. 17:491, 1941 has basically not changed!
8. Sneige, et. al. about PLCIS, Modern Pathology 2002 [here].
9. January 2009 issue of Archives of Pathology & Lab. Med.
10. Rosen PP, Rosen's Breast Pathology 3rd Ed, 1116 pages, 2009.