Ductal Carcinoma In Situ

Ductal Carcinoma In Situ
Key Facts
Etiology/Pathogenesis
  • Same molecular subtypes recognized in invasive carcinoma are also seen in DCIS
  • Transition to invasion is poorly understood
    • May involve loss of function of normal myoepithelial and stromal cell rather than gain of function of tumor cells
Clinical Issues
  • Incidence
    • Without mammographic screening: < 5% of carcinomas
    • With screening: 20-30% of carcinomas
  • Clinical presentations
    • Mammographic calcifications (85%)
    • Palpable mass or radiologic density (10%)
    • Nipple discharge (5%)
  • Natural history
    • If untreated, ˜ 1% of patients per year develop invasive carcinoma at same site
    • With treatment, rate of recurrence is < 10%
    • Some recurrences are biologically related to DCIS, and some are new primary carcinomas
    • Survival rate for women with DCIS is greater than that for women without breast cancer
Top Differential Diagnoses
  • Lobular carcinoma in situ
  • Atypical ductal hyperplasia
  • Invasive carcinoma
  • Lymph-vascular invasion
  • Collagenous spherulosis
  • Gynecomastoid hyperplasia
DCIS is most commonly diagnosed when clustered calcifications are detected by screening mammography. The calcifications are typically numerous and variable in size and shape.
Cribriform DCIS forms sharply demarcated round spaces image distributed evenly throughout the ducts and is frequently detected due to calcifications forming on intraluminal secretory material.
TERMINOLOGY
Abbreviations
  • Ductal carcinoma in situ (DCIS)
Synonyms
  • Intraductal carcinoma (IDC)
    • Not recommended since the abbreviation can be confused with invasive ductal carcinoma
  • Ductal intraepithelial neoplasia (DIN)
    • Only some subtypes of DIN are equivalent to DCIS
Definitions
  • Clonal proliferation of epithelial cells confined to ducts and lobules with a cohesive pattern and typically E-cadherin positive
ETIOLOGY/PATHOGENESIS
Biology of DCIS
  • Same molecular subtypes recognized in invasive carcinoma are also seen in DCIS
    • Luminal A (ER positive, HER2 negative): ˜ 70%
    • “Luminal B HER2 positive” (ER positive, HER2 positive): ˜ 10-20%
    • HER2 (ER negative, HER2 positive): ˜ 20-30%
    • Triple negative (ER/PR/HER2 negative): 5-10%
  • HER2 subtype is slightly more frequent and triple negative subtype less frequent in DCIS as compared to invasive carcinoma
  • More biologic heterogeneity is seen in DCIS than in invasive carcinoma
  • No specific differences in genetic alterations or gene expression have been found specific to invasive carcinoma that are not found in DCIS
  • Changes necessary for transition to invasive carcinoma are not yet understood
    • Not all DCIS progresses to invasive carcinoma
    • Possible that invasion occurs due to loss of function of normal myoepithelial and stromal cells, rather than gain of function by DCIS
CLINICAL ISSUES
Epidemiology
  • Incidence
    • DCIS comprises < 5% of breast carcinomas in populations without mammographic screening
    • With screening, 20-30% of carcinomas are detected as DCIS
      • Incidence of DCIS increased after introduction of screening (1980s)
      • Majority of DCIS is diagnosed due to formation of calcifications detectable by mammography
Presentation
  • Mammographic calcifications (85%)
    • Associated with either necrosis or secretory material in lumens
  • Palpable mass or radiologic density (10%)
    • Usually associated with extensive high-grade DCIS with periductal stromal fibrosis
  • Nipple discharge (5%)
    • Discharge is spontaneous and unilateral
    • Extensive micropapillary and papillary DCIS are the most common types
  • Paget disease of nipple (< 1%)
    • Patients present with eczematous scale crust of 1 nipple
    • DCIS traverses lactiferous ducts onto nipple skin without crossing contiguous basement membranes
    • DCIS is generally high grade, and most overexpress HER2
Treatment
  • Surgery is used to completely remove ductal system involved by DCIS
    • Risk of recurrence is lower if DCIS is ≥ 0.2 cm from margins
    • Risk of recurrence after mastectomy is < 5%
  • Radiation therapy reduces recurrence by ˜ 50%
  • Tamoxifen also reduces recurrence by ˜ 50%
    • Benefit may be greater, or restricted, to ER-positive DCIS
      • Data supporting this finding is only published in an abstract of a subset analysis of NSABP B-24
      • Possibility of small effect for ER-negative DCIS not excluded due to small number of cases
Prognosis
  • If untreated, approximately 1% of patients per year develop invasive carcinoma at same site
    • At 20-30 years, majority of patients remain disease free
  • If treated with complete excision with negative margins and possible addition of radiation therapy &/or hormonal therapy, risk of recurrence is < 10%
    • Approximately 1/2 of recurrences are DCIS and 1/2 are invasive carcinoma
  • Lymph node metastases are very rare in cases of DCIS that have been completely examined microscopically
    • When present, usually consist of isolated tumor cells that have not been shown to have an effect on prognosis
    • If a macrometastasis is present, there is usually an undetected area of invasive carcinoma
      • Sentinel node biopsy may be performed in patients with large areas of DCIS that are difficult to completely sample
  • If treated with mastectomy, risk of recurrence is < 5%
    • Local recurrence may be due to breast tissue left behind in chest wall
    • Nodal or distant recurrence may be due to undetected invasive carcinoma at time of surgery due to extensive DCIS
  • Risk of dying of breast cancer after recurrence in breast is very low; most cancers are detected early and are small and node negative
    • Survival rate for women with DCIS is greater than that for women without breast cancer
    • Majority of women with DCIS have access to medical care, which is not true of women in general population
  • Pathologic prognostic factors can predict likelihood of ipsilateral recurrence
    • Nuclear grade
    • Necrosis
    • Extent: Volume of breast tissue occupied by DCIS
    • Margin width
  • Some recurrences are true recurrences (related to the DCIS), and some are new primary carcinomas
    • Risk of contralateral invasive carcinoma is approximately 1/2 that of ipsilateral invasive carcinoma
    • Suggests that 1/2 of ipsilateral invasive carcinomas may be due to new primary carcinomas
      • May explain why surgery with wide margins without radiation therapy does not eliminate possibility of subsequent cancer in same breast
Core Needle Biopsy
  • DCIS is usually detected on core needle biopsies for calcifications
  • Presence of microinvasion may influence a decision to perform a lymph node biopsy and should be documented if present
  • Subsequent excisions infrequently reveal invasive carcinoma if large bore vacuum-assisted biopsies are performed and targeted lesion was calcifications and not a mass
IMAGE FINDINGS
Mammographic Findings
  • Calcifications are most common presenting feature for DCIS
    • Features correlated with DCIS
      • Clustered pattern
      • Linear and branching pattern
      • Large number of calcifications
      • Small size (large calcifications are more likely to be associated with benign lesions)
      • Irregular or pleomorphic shape
      • Increasing over time
    • 20-30% of biopsies for suspicious calcifications will reveal DCIS on excision
    • Extent of DCIS is generally greater than that suggested by distribution of calcifications
    • Grade of DCIS is not reliably predicted by shape or number of calcifications
      • However, linear and branching calcifications are often associated with comedo DCIS
    • Calcifications without a mass are rarely associated with invasive carcinoma
      • In majority of cases, if invasive carcinoma is present, then the calcifications are associated with DCIS
      • In unusual cases, calcifications are associated with secretions in tubules or with necrosis in invasive carcinoma
      • Invasive carcinoma is generally small (< 1 cm)
  • DCIS sometimes forms a circumscribed mass
    • Localized area of DCIS with surrounding fibrotic stromal response can form a rounded or lobulated mass
    • DCIS involving a fibroadenoma can be detected as a circumscribed mass
    • Solid, solid papillary, or papillary DCIS can form masses
MR Findings
  • Majority of cases of DCIS are associated with enhancement
    • Although sensitive, findings are not specific enough for MR to be used for screening general population
  • Most common pattern is linear clumped enhancement
  • DCIS is typically surrounded by collarette of small capillaries
  • Associated increased blood flow is detected by MR
MACROSCOPIC FEATURES
General Features
  • Most cases of DCIS cannot be seen or palpated grossly
  • Cases of high-grade DCIS (typically comedo type) often have associated stromal response
    • Masses are usually firm but not hard
    • Borders are ill defined as opposed to distinct edge of invasive carcinoma
    • Color may be gray and texture gritty
  • Comedo-type necrosis can be seen grossly as minute extruded plugs of necrotic cells when tissue is gently squeezed
MICROSCOPIC PATHOLOGY
Histologic Features
  • Architectural patterns
    • Important to recognize
      • Grade is more important for prognosis; high-grade DCIS can have any architectural pattern
      • Majority of cases of DCIS consist of > 1 architectural type
    • Cribriform DCIS
      • Cribriform lumens appear punched out and rounded in shape
      • In 3 dimensions, spaces are spherical
      • Cells should be oriented around lumen
      • Lumens are distributed evenly throughout involved duct
      • Spaces associated with hyperplasia are typically sinuous in shape and peripherally located
    • Papillary DCIS
      • Papillary fronds have a central fibrovascular core
      • Myoepithelial cells are present around periphery of spaces but not within papillary cores
      • Endothelial cells lining blood vessels can be apposed to base of tumor cells in thin fibrovascular cores
      • Can be difficult to distinguish endothelial cells from myoepithelial cells using IHC muscle-type markers
      • p63 is a better marker to confirm absence of myoepithelial cells in papillary lesions
    • Micropapillary DCIS
      • Papillae have narrow bases that expand to bulbous ends
      • Appearance has been compared to that of light bulb or drumstick
      • Papillae do not have fibrovascular cores
      • Surrounding duct usually lacks hyperplasia and is flat
    • Comedo DCIS
      • Central area of necrosis surrounded by rim of tumor cells
      • Strict definition of comedo DCIS requires both central necrosis and high nuclear grade
      • Calcifications are almost always present in necrotic material and are usually numerous
      • Associated mammographic finding: Clustered or linear and branching calcifications
      • Mammographic lesion is often close to actual extent of comedo DCIS
      • Associated circumferential stromal fibrosis, often with lymphocytic infiltrate
      • Some cases form a clinically palpable mass or mammographic density and can sometimes be visible as foci of necrosis in an area of firm gray-white stroma
    • Solid DCIS
      • Cells completely fill ductal spaces
      • Some have solid papillary pattern, as fibrovascular cores may be present within cell proliferation
      • Solid DCIS may show some morphologic overlap with LCIS
    • Clinging DCIS
      • Cells line spaces and do not form architectural patterns
      • Difficult to diagnose in isolation unless cells are of high nuclear grade
      • In general, more easily diagnosed architectural patterns are also present
Cytologic Features
  • DCIS is a clonal population, which should be reflected in morphologic appearance
  • In contrast, hyperplasias consist of a mixture of luminal, myoepithelial, and intermediate-type cells
  • Metaplasia makes recognition of DCIS very difficult
    • Apocrine and clear cell metaplasia impart a very uniform appearance, even in benign lesions
    • Architectural features, high-grade nuclei, necrosis, or associated similar-appearing invasive carcinoma may be necessary for definitive diagnosis as DCIS
  • Nuclear grade is important feature to classify DCIS
    • Same nuclear grading system used for invasive carcinoma can be used for DCIS
    • Often a mixture of nuclear grades; highest grade present should be reported
  • Mucin production can be associated with cribriform, micropapillary, papillary, or clinging DCIS
    • Calcifications may be present in mucin
    • If duct rupture, can be difficult to distinguish extravasated mucin from small foci of invasion
    • Tumor cells should not be present in extravasated mucin
Necrosis
  • Presence of necrosis is often used to classify DCIS
  • Comedo necrosis should involve majority of central portion of involved duct
  • Focal necrosis may involve only small portion of duct
  • Single cell necrosis can also be seen
  • Necrosis is always associated with comedo DCIS, but varying degrees can be seen with other types
Extent of DCIS
  • “Extent” refers to volume of breast tissue occupied by DCIS
    • Extent can vary from 0.2 cm to > 20 cm or all 4 quadrants of breast
    • Average extent of DCIS is 2-3 cm
  • Measure of extent is useful clinically to determine
    • Likelihood of being able to achieve breast conservation with adequate margins
    • Likelihood of an area of invasion being present or being missed
  • Minimal extent required for a diagnosis of DCIS (rather than ADH) has been proposed
    • 0.2 cm or 2 completely involved ductal spaces have been suggested
    • No minimal extent required for DCIS with high-grade nuclei
  • Extent can only be estimated
    • Breast tissue is highly compressible
    • Shape of breast specimens changes (slumps) after excision
    • Specimen radiography also compresses and distorts shape (size) of excisions
    • Morphologic gaps in ductal involvement are reported to occur, particularly in lower grades of DCIS
    • DCIS is often removed in multiple specimens
  • Multiple methods to estimate extent
    • Measurement of DCIS on glass slide: Only accurate if DCIS is only present on 1 slide
    • Margins: If 2 opposing margins are positive or close to DCIS, extent can be estimated by using specimen size
    • Complete serial sequential sectioning (SSS) and mapping of sections with DCIS to give a linear measurement
    • Counting block method (CBM) multiplies number of blocks with DCIS by 0.4 cm (or average width of sliced tissue in cassettes, if known)
    • SSS correlates with CBM up to approximately 3 cm
    • Because CBM is related to volume as well as to linear dimension, it usually gives a larger estimate compared with SSS for very extensive DCIS
  • Sentinel node biopsy may be performed when DCIS is extensive, particularly as part of mastectomy
ANCILLARY TESTS
Immunohistochemistry
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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Ductal Carcinoma In Situ

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