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[Back to Breast Cancer
Index]
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 |
| Hyperplasia2: Minor degrees
of duct cell proliferation are commonly seen as part of fibrocystic
mastopathy, as forms of adenosis (excessive ductular profiles), or as
intraductal hyperplasia (usual duct hyperplasia [UDH]excessive ductal epithelium...epitheliosis).
Any degree of non-lactational proliferation of lobular cells
falls broadly into a category of "noninvasive lobular neoplasia"...a "marker" of increased breast future "riskiness". Duct adenosis
and/or hyperplasia can be very florid. The diagnosis of CIS
requires the right combination of the criteria of (1) size or extent , (2) architectural, change plus (2)
cytological change plus . And ductal CIS must be from 2 ductal cross-sections (Page 1985) to 2-3mm (Page 1998 in Dr. Ellis breast text) to maybe even 5mm in 2009
(Page to Schnitt, personal); and, lobular CIS must fill greater than 50% of TDLUs of a lobule; less is atypical lobular hyperplasia (Page)6. As to ductal CIS, any cases with only partial
fulfillment of the two criteria are "atypical duct hyperplasia" (d-AH
or ADH). That is, ADH approximates...but does not unequivocally
satisfy...the criteria for d-CIS (Fisher). "Severe ADH" may be
used when the process seems more widespread (less focal) in a biopsy. Cytological CIS-type "atypicalities" include:
nuclear enlargement that reduces the N/C ratio, nuclear hyperchromasia,
irregular chromatin pattern &/or nucleoli, distinct cell borders, easily identified mitotic figures, intercellular dyscohesion, and mucin-containing
intracytoplasmic lumens. Ductal CIS-type architectural change
includes: loss of cell polarity, loss of cell-heterogenic streaming
of nuclei (as birds in flight or fish in a school), tapering & non-rigid cell bridges around non-sharp fenestrationsloss of uneven lumen
spacing...becoming a more even cribriform lumen spacing. Columnar
cell hyperplasia2 (CCH) is a separate situation of
hyperplastic TDUs on a spectrum from columnar cell change (CCC),
to CCH, to flat epithelial atypia (FEA). CCH can be multifocal
and bilateral and often microcalcifies: it is a cystic increase in enlarged
crowded columnar epithelium which has apocrine change
with snouts. Because the entity has been previously thought to be
associated with tubular carcinoma [LMC-05-8748] or
lobular neoplasia, then (as with ADH) excisional biopsy is warranted when there is a
core biopsy diagnosis. |
ADH vs. DCIS: Why Do We Care?6
| |
ADH |
DCIS |
| risk of subsequent cancer |
3-5x age-matched normal |
8-10x age-matched normal |
| likely laterality of subsequent cancer |
either...marker of riskiness |
same site as current lesion ...precursor |
| type of subsequent cancer |
any type |
usually low grade ductal |
| management of subsequent cancer |
observation & anti-hormonal Rx |
complete local resection |
|
- 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:
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References:
-
6th Annual Breast Symposium, Columbia, SC,
18 May 2001 (Dr. Lagios was key pathologist speaker)
-
Rosen's Breast Pathology, text book, 2nd Ed.,
2001
-
Weidner N, The Difficult Diagnosis in S. P.,
1996.
-
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.
-
Conferee statements, LMC weekly multidisciplinary
Breast Conference.
- 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.
- Foote & Stewart definition of LCIS, Am. J. Pathol. 17:491, 1941 has basically not changed!
- Sneige, et. al. about PLCIS, Modern Pathology 2002 [here].
- January 2009 issue of Archives of Pathology & Lab. Med.
- Rosen PP, Rosen's Breast Pathology 3rd Ed, 1116 pages, 2009.
(posted June 2001;
latest addition/update, 16 January 2010) |
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