Despite the prevalence of DCIS there is no uniformly accepted classification system, however, a growing consensus of opinion recognises the importance of grade over morphology [8
5.1. Grading of DCIS
There are three commonly referenced grading schemes for DCIS, all of which employ the assessment of nuclear grade and presence/type of necrosis with some additionally utilising cellular polarity to ascribe an overall grade [9
]. No one system has been endorsed; however, a consensus conference and the College of American Pathologists recommend that a pathology report should include a description of nuclear
grade, presence and type of necrosis, and the architectural patterns present [8
]. Thus when we discuss the “grade” of DCIS this is now generally accepted to refer to the nuclear
grade of the lesion.
Three nuclear grades are identifiable low (1), intermediate (2), and high (3).
Grade 1 (Low Grade)
The nuclei are monomorphous and 1.5 to 2 times the diameter of a RBC with inconspicuous nucleoli and diffuse chromatin. The nuclei are usually orientated (polarized) toward the lumen ().
Low-grade DCIS. The neoplastic cells show small uniform nuclei with fine chromatin and are polarized around secondary lumina.
Grade 2 (Intermediate Grade)
The nuclei are neither 1 nor 3.
Grade 3 (High Grade)
The nuclei are large and pleomorphic, >2.5 times the diameter of a RBC with more than one nucleolus per cell, and contain irregular chromatin. The nuclear orientation is usually irregular (nonpolarized) ().
High-grade DCIS. The neoplastic cells demonstrate markedly enlarged nuclei, with significant pleomorphism, coarse chromatin, and lack of polarity.
Two types of necrosis are identifiable.
Central areas of necrosis, ghost outlines of cells and cellular debris ().
High-grade DCIS with central comedo-type necrosis.
Individual cell necrosis usually in the form of apoptotic cells.
In reality most substantive cases of DCIS show a variety of grades within the same lesion. Allred and colleagues have shown in a series of 120 cases of pure DCIS that 45.8% of cases showed areas of diversity with regard to nuclear grade (NG); 30% of cases contained areas of NG 1 and 2, 6.6% had an admixture of NG 2 and 3, and 9.2% had a mixture of NG 1, 2, and 3 [13
]. While there are no clear guidelines on how to manage this scenario, in general one should grade to the “highest” grade within the lesion, if it composes a significant component (>10%) of the case. Interobserver agreement in assigning a grade is moderate at best.
An alternate grading system for all atypical and malignant intraductal proliferations to include DCIS has been proposed by Tavassoli [14
]. Using this system the term ductal intraepithelial neoplasia (DIN) replaces descriptive terms commonly used for atypical and malignant intraductal proliferations and a graduated numerical and alphabetical designation is employed to assign lesion severity; as such low-grade DCIS is termed DIN 1C, intermediated grade DCIS is termed DIN II, and high-grade DCIS is referred to as DIN III. While this system has many merits it has not been widely adopted to date in the clinical community.
5.2. Morphological Variants of DCIS
There are many morphological variants of DCIS including comedo, solid, clinging, cribriform, papillary, solid variant of papillary DCIS, micropapillary, neuroendocrine, apocrine, cystic secretory, and Pagets disease. A significant proportion of DCIS lesions will harbour more than one morphological variant and all variants should be mentioned in the final synoptic report. Most of these morphological variants are well known to practicing pathologists but some are sufficiently rare or have some caveats that deserve mention.
Solid Papillary Carcinoma and Encysted (Intracystic) Papillary Carcinoma
While these entities have traditionally been considered as variants of DCIS recent studies have shown that when immunohistochemical markers for myoepithelial cells are employed some lesions have been found to lack such cells around the periphery of the tumor; in such cases whether the lesion is truly DCIS or a low-grade invasive carcinoma with pushing tumor margins is unresolved. Rakha and colleagues have recommended considering those lesions with demonstrable myoepithelial cells as DCIS and those without as a special type of invasive carcinoma. In their study, these lesions were associated with a low incidence of stromal/skeletal muscle invasion, low frequency of lymph node metastasis (3%), and infrequent development of local or distant recurrence. Thus they conclude that these lesions are characterized by indolent behaviour and extremely favourable prognosis. They go on to stress that these lesions can be treated with adequate local therapy without the need for adjuvant chemotherapy [15
Micropapillary carcinoma is a variant of DCIS characterised by the presence of intraluminal tufts of malignant cells that lack a true fibrovascular core. When present in a “pure” form, that is, not admixed with other morphological variants, it has been shown in one study to be associated with extensive disease involving multiple quadrants [16
Apocrine DCIS (ADCIS)
Scott et al. recommended that apocrine DCIS be recognized as a special variant of DCIS given its rarity, the specific challenges in distinguishing it from atypical apocrine proliferations, and the difficulties with assigning an accurate grade [11
]. Many morphological variants of apocrine DCIS have been described including solid, cribriform, and comedo subtypes but it is the characteristic cellular features of large cells with abundant eosinophilic cytoplasm with enlarged nuclei and prominent nucleoli that define this entity.
Nuclear grading of apocrine DCIS is particularly difficult as classic apocrine cells are enlarged with prominent nucleoli relative to normal breast epithelium leading some authors to suggest that the diagnosis and grading of apocrine DCIS specifically should rely not only on nuclear grade and the presence/type of necrosis but also on the size of the lesion such that low-grade apocrine DCIS is present when the apocrine cells are 3-4X the size of benign apocrine cells, necrosis is absent, and the size of the proliferation of concern is at least 4–8
High-grade apocrine DCIS is present when the apocrine cells are ≥5 times the size of benign apocrine cells and comedo-type necrosis is present. And when these two criteria are satisfied a minimum size criterion is not necessary.
Intermediate-grade apocrine DCIS describes those lesions that have nuclei in the size range of low-grade ADCIS that is, 3-4X a benign apocrine cell but have comedo-type necrosis or those lesions with apocrine cells typical of high-grade disease (≥5 times the size of a normal apocrine cell) but comedo-type necrosis is not
Given the rarity of these lesions in clinical practice a consensus opinion or expert referral may be warranted.
Cystic Hypersecretory DCIS
This is an extremely rare variant of DCIS characterised by cystically dilated ducts line by a mixture of benign, hyperplasic and malignant epithelium with micropapillary, and cribriform-type arrangements. The cells may have vacuolated cytoplasm reminiscent of lactating epithelium and stain positively for mucin. The cyst lumens often contain a viscous colloid secretary-type material [20
Paget's disease of the nipple is characterized by the presence of malignant epithelial cells within the squamous epithelium of the nipple-areola complex. It often presents as an eczematous change in the nipple-areola area and is invariably associated with high-grade DCIS (+/− invasive disease) in the underlying lactiferous duct system. This variant of DCIS is frequently HER2 positive.