—  SHORT COURSE #10  —

Pitfalls and Problems in Breast Pathology

Section 2 - Diagnostic Problems in Breast Pathology
How to avoid the pitfalls, new entities and controversial lesions

Ian O. Ellis and Sarah Pinder


Case Histories


Case 5 - Figure 1 - Atypical apocrine proliferation
Case 6 - Figure 1 - Columnar cell proliferation
Case 6 - Figure 2 - Columnar cell proliferation


Case 7 - Figure 1 - Unusual carcinomas 1
Case 8 - Figure 1 - Unusual carcinomas 2
Case 9 - Figure 1 - Unusual carcinomas 3


Case 10 - Figure 1 - Stromal lesion (H&E)
Case 10 - Figure 2 - Stromal lesion (smooth muscle actin)

Introduction
Almost any breast lesion may produce diagnostic difficulty and a degree of selectivity is therefore necessary in a seminar such as this. This has been achieved by reference to two main sources: data on consistency of diagnosis from External Quality Assessment schemes in the United Kingdom organised by the National Co-ordinating Group for Breast Screening Pathology and in Europe organised by the European Breast Screening Pathology Group; [1, 2, 3] an informed audit of cases sent for second opinion from other departments. It is, perhaps, not surprising that both routes produce similar problem cases which fit into a relatively restricted group of diagnostic categories which can be considered under the headings shown in Table 1:

Table 1 - Main categories of lesion that lead to diagnostic pitfalls in breast pathology

Sclerosing lesions
Papillary lesions
'Borderline' lesions
Fibroepithelial lesions
Effects of previous therapy
Pathological prognostic factors

In practice the pitfalls described below may be avoided or reduced by the application of sound general histopathological principles. These include the application of strict diagnostic protocols and in this respect there is good world-wide agreement for most lesions. Participants in the symposium are referred to the standard breast pathology texts in the reference list, including UK and European breast screening pathology guidelines. [4, 5, 6, 7, 8] It is interesting to note that many diagnostic difficulties arise with those lesions where complete agreement on diagnostic criteria has not yet been reached. The aim in this presentation is to emphasise practical points of distinction rather than to provide a comprehensive description of each lesion.

One further general point is pertinent. Experience has shown that in many cases difficulty in diagnosis is related to sub-optimal specimen preparation, mostly poor fixation or tissue processing. A comparatively minor investment of time and effort in improving the technical aspects of the diagnostic process will be rewarded by considerably better quality of preparations and a consequent decrease in unnecessary problem cases.

Sclerosing lesions
Some benign breast processes are characterised by a combination of epithelial proliferation, with or without a myoepithelial component, and stromal fibrosis and sclerosis that may result in formation of a mass lesion. The entities that can be placed within the umbrella of sclerosing lesions are sclerosing adenosis (SA), microglandular adenosis (MGA) and radial scar/complex sclerosing lesion (RS/CSL). They have many overlapping features and may all give rise to diagnostic problems clinically, on imaging (ultrasound and mammography) and histopathologically. Although they are frequently impalpable, both sclerosing adenosis and complex sclerosing lesion may produce palpable masses that can easily be mistaken for invasive carcinoma. Fine microcalcification is a common feature of all three entities and the appearances on mammography may be closely similar to those of low grade ductal carcinoma in situ (DCIS). [9] In addition both SA and RS/CSL may be identified on mammography or ultrasound as an architectural distortion or spiculate mass, which cannot be distinguished with confidence from carcinoma. In all these situations a tissue diagnosis must be established and increasingly this is obtained pre-operatively through needle core biopsy using one of the new spring loaded guns. [10, 11, 12] Diagnostic difficulty may be experienced histopathologically in interpreting such samples, and indeed in some circumstances excision biopsy specimens may also cause problems, the main differential diagnosis being invasive carcinoma, especially of tubular type.

The main morphological features of the sclerosing lesions and tubular carcinoma are shown in Table 2:

Table 2 - Differential diagnosis of sclerosing lesions
Tubular carcinoma Sclerosing adenosis Microglandular adenosis Radial scar
Infiltrative, often stellate architecture Lobulocentric architecture Infiltrative, disorderly architecture Complex, stellate architecture
Desmoplastic stroma. Central elastosis frequent Often central cellularity with sclerotic periphery Fibrotic stroma Variable stromal cellularity
Well formed angulated tubules Distorted, compressed tubules. Frequent obliterated lumina Uniform round tubules Distorted tubules
Abundant eosinophilic cytoplasm often with apical snouts Infrequent apical snouts Clear, vacuolated or granular epithelial cytoplasm. No apical snouts No apical snouts
Absent myoepithelial cells Prominent admixed myoepithelial cells Occasional myoepithelial cells described Myoepithelial cells seen
Patchy, incomplete basement membrane Uniform basement membrane Prominent basement membrane Basement membrane seen
Intraluminal secretion or microcalcification may be seen Intraluminal microcalcification may be seen Intraluminal colloid-like material which may be calcified Intraluminal secretion uncommon.Microcalcification may be seen
Frequent associated low grade cribriform or micropapillary DCIS May be associated apocrine metaplasia. Associated DCIS and lobular neoplasia rare but described Atypical features rarely described (see text) Associated cysts, sclerosing adenosis, epithelial hyperplasia and rarely in situ or invasive carcinoma

Reproduced with permission from Elston CW, Ellis IO. Systemic Pathology 3rd Ed - The Breast. London: Churchill Livingstone, 1998

Sclerosing adenosis is characterised by a disorderly proliferation of acinar and ductular epithelial cells, myoepithelial cells and intralobular stroma which results in expansion and distortion of lobules and an overall whorled appearance. Despite the apparent disorganisation of the cellular proliferation, a lobulocentric architecture is maintained. The epithelial component may form microtubular structures but the compressed acini frequently show obliteration of their lumina. Nuclei are small and regular without atypia and mitotic figures are infrequent. Fine foci of microcalcification are frequently found within the lumina of epithelial structures.

In microglandular adenosis there is a disorderly proliferation of small round acinar structures, apparently infiltrating between normal ducts and lobules and extending into adipose tissue. There is no spindle cell proliferation and the growth pattern is not lobulocentric. The acini appear to be lined by a single layer of epithelial cells and the lumina often contain PAS positive, diastase-resistant, eosinophilic material which may, rarely, be calcified.

Classically radial scar/complex sclerosing lesions are composed of a radial arrangement of ductular structures around a central fibroelastotic core. In early lesions the central connective tissue is cellular and includes numerous myofibroblasts. The entrapped ductular or tubular structures are lined by a two-layered epithelium although epithelial proliferation is commonly present. Atypical ductal hyperplasia or lobular neoplasia may also be seen. [13]

As noted above the most important differential diagnosis for all these lesions is invasive carcinoma, especially the tubular type. In excision specimens sclerosing adenosis can usually be distinguished by its circumscribed lobulocentric low power morphology in contrast with the infiltrative pattern and desmoplastic stroma of tubular carcinoma, but care should be taken with needle core and frozen section specimens in which this feature may not be apparent. Furthermore, the architectural distortion produced in both these techniques may result in a mistaken diagnosis of infiltrating lobular carcinoma due to compression of the epithelial structures. In rare cases of sclerosing adenosis extension of the glandular components into perineural and vascular spaces is seen, a finding that must not be regarded as indicative of malignancy in the absence of confirmatory features. The presence of apocrine atypia may also raise the question of malignancy [14] and this should be avoided by recognition of the benign features described above. Both ductal carcinoma in situ and lobular neoplasia have been recorded in the nodular form of sclerosing adenosis and may be mistaken for invasive carcinoma if the presence of myoepithelial cells is not recognised. [15] If the diagnosis is in doubt immunostaining with anti-smooth muscle actin will readily demonstrate their presence, thus excluding the diagnosis of invasion.

Microglandular adenosis can usually be distinguished from tubular carcinoma by its diffuse pattern and lack of central elastosis and desmoplastic stroma, although the sclerosing type of tubular carcinoma may provide a close mimic. A useful distinguishing feature is the fact that the glandular structures in MGA are usually uniform and rounded in contrast with the less regular, often angulated appearance in tubular carcinoma. Immunostaining for anti-smooth muscle actin is less helpful in MGA because in most recorded cases myoepithelial cells are said to be absent. [16, 17] MGA may also be confused with the tubulo-lobular variant of infiltrating lobular carcinoma. However, careful examination in the latter always reveals cords of cells typical of the classical lobular type in addition to microtubular structures.

In the great majority of cases of RS/CSL the distinction from tubular carcinoma is relatively straightforward. The dense, sclerotic, poorly cellular stroma and elongated flattened tubules are quite different from the desmoplastic stroma and well formed oval structures in tubular carcinoma. However, more complex lesions with an admixture of sclerosing adenosis and epithelial hyperplasia may cause problems; it must also be remembered that both in situ and invasive carcinoma may be encountered in association with RS/CSL. [13] If there is any doubt about the correct diagnosis immunostaining with anti-smooth muscle actin will help to clarify both these problems.

Great care should be taken in the interpretation of sclerosing lesions found on needle core biopsy because of the sampling problem. For example, the finding of part of a benign RS/CSL on core biopsy does not exclude the possibility of associated malignancy; it is, therefore, still our policy to excise all parenchymal distortions or architectural deformities.

Papillary lesions
These lesions cause diagnostic problems because papillary structures are found in benign and malignant processes and the differences between the two are often subtle and difficult to assess; the entities concerned are shown in Table 3.

Table 3 - Spectrum of papillary lesions of the breast

Single intraduct papilloma
Multiple duct papillomas
Complex sclerosing papillary lesion
Encysted papillary carcinoma (papillary carcinoma in situ)
Invasive papillary carcinoma

In practice few problems should be encountered with small single benign intraduct papillomas that are usually centrally placed under the nipple and removed by microdochectomy. However, potential pitfalls will be encountered with all of these processes on needle core biopsy, partly because of sampling error and partly related to architectural distortion due to crush artefact. Our early experience with pre-operative use of needle core biopsy, based on the manual Tru-Cut needle lead us to advice caution when benign papillary structures were identified, because of the risk of a false negative diagnosis. It is undoubtedly true that some invasive papillary carcinomas arise in a pre-existing benign papilloma, almost always of the multiple type. The finding of benign papillary structures on needle core biopsy does not necessarily mean, therefore, that malignant change is not present elsewhere in the lesion. It is our practice to issue a report with a non-specific conclusion of 'papillary lesion present', and local excision is advised. This would come into the B3 category - lesion of uncertain malignant potential - in the revised United Kingdom National Health Service Breast Screening Service (NHSBSP) Guidelines for Pathologists. It should also be noted that multiple duct papillomas are usually peripheral and often associated with florid epithelial proliferations, including usual and atypical ductal hyperplasia. In excision specimens, adequate sampling is required to exclude the presence of associated ductal carcinoma in situ (see also below – borderline lesions).

Some benign papillary lesions form relatively well defined solid masses with a dominantly sclerosed architecture. In the past the term ductal adenoma was applied to such lesions, but they are now believed to arise from sclerosis of duct papillomas and we prefer to use the term complex sclerosing papillary lesion. Epithelial proliferation is relatively common and a minor degree of nuclear atypia may be seen, especially if there is apocrine change. They are, in fact, entirely benign and care must be taken not to overdiagnose malignancy, especially if entrapped tubular structures are found. There is considerable morphological overlap with sclerosing adenosis and radial scar/complex sclerosing lesion and in some cases it may be impossible to make a firm distinction.

Encysted papillary carcinoma (papillary carcinoma in situ) may be confused with invasive papillary carcinoma, especially on needle core biopsy. This relatively uncommon lesion is now being detected with increasing frequency in mammographic screening. Because of their soft, cystic structure encysted papillary carcinomas are rarely palpable clinically, but are seen on mammography in older women as well circumscribed mass lesions. Astute radiologists quickly develop a suspicion of the correct diagnosis when they encounter an unusual degree of haemorrhage on needling the lesion. Using a multi-disciplinary team approach this information enables the pathologist to assess the papillary structures seen on needle core biopsy more accurately. The presence of multi-layering and genuine cytological atypia point towards a diagnosis of encysted papillary carcinoma rather than a benign intracystic papilloma but care must be taken not to overinterpret the presence of entrapped tubules as evidence of invasion. In any event all such circumscribed impalpable papillary lesions should be managed by complete local excision rather than mastectomy in the first instance. Attention must be paid to excision margins, since local recurrence is related both to the presence of ductal carcinoma in situ in adjacent ductal structures and completeness of excision. [18] As with needle core biopsy areas of possible invasion around the periphery of the excised lesion should be assessed with caution. There is usually a broad fibrous 'capsule' and 'pseudoinvasion' due to the presence of entrapped tubules is a frequent finding. Invasive carcinoma may, rarely, be associated with encysted papillary carcinoma, but should only be diagnosed when epithelial structures extend into adjacent breast or adipose tissue. Encysted papillary carcinoma has a good prognosis and complete excision appears to be curative. [18]

'Borderline' lesions
The language used in medicine is fascinating and it is interesting to observe how insidiously words such as 'borderline' creep into our vocabulary without due thought to their impact on clinical practice. It is difficult to establish when the term was first applied to breast lesions but it appears to have been in use for at least 25 years to encompass those lesions characterised by epithelial proliferation. The main problem with the term is that it implies a sharp division between entities and this is usually interpreted as providing a separation between benign and malignant lesions with a consequent effect on clinical management protocols. In reality such sharp distinctions rarely occur and certainly where breast epithelial lesions are concerned we are dealing with a spectrum of changes. This has been emphasised in recent years by molecular genetic studies which have shown loss of heterozygosity in usual epithelial hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ (DCIS); this data implies that even usual epithelial hyperplasia, in some cases, is a clonal, and therefore neoplastic, process. [19, 20, 21, 22, 22a] Nevertheless, from the practical viewpoint stratification is required so that individual patients receive appropriate treatment. The entities concerned are the epithelial hyperplasias of usual and atypical subtypes, in situ carcinoma and so-called 'minimal' invasive carcinoma. In my view it is more appropriate to regard these lesions as occupying a borderland between entities that are definitely benign and those that are unequivocally malignant. This concept now needs to be re-evaluated for two main reasons; there are definite problems in reproducibility of diagnosis of such entities as atypical ductal hyperplasia (ADH) and more appropriate cut-off points are required to stratify patients for clinical and therapeutic management. In addition there is mounting evidence that borderline lesions of the breast encompass a number of genetically different lesions that appear to have distinct lineage pathways to invasive carcinoma [22a, 22b, 22c] . These observations question the relevance of umbrella systems for classification such as MIN [22d, 22e] .

The debate concerning the utility of the term atypical ductal hyperplasia has continued for the past 20 years. Page and colleagues have promoted the view that epithelial proliferations which closely resemble DCIS of low grade type, but which do not exhibit all the precise morphological characteristics to make that diagnosis with confidence should be designated as ADH. [23, 24] Although this concept has received wide acceptance doubts remain. Some, [1, 3, 25] but not all, [26] reproducibility studies have shown poor agreement for the entity suggesting that there is a lack of agreement on the diagnostic criteria. It is therefore worth emphasising some key distinguishing features, as set out below:

a DCIS of low grade type has a population of evenly spaced, uniform cells with uniformly oval to rounded nuclear features, comprising without doubt the entire population of cells throughout at least two membrane-bound spaces (a measure of the extent of the lesion). Secondary spaces have smooth rounded 'punched out' borders of geometrical structure (cribriform architecture - cribrum - sieve - Latin) and rigid non-tapering bars can be found. Micropapillary structures are bulbous and regularly placed around the space.
NB Epithelial proliferations of high grade cytology, with or without comedo necrosis qualify as DCIS, regardless of lesional size.
b ADH exhibits partial involvement of the basement membrane-bound space by a cell population of the type defined above for DCIS of low grade type. A second cell population is usually present, consisting of columnar, polarised cells of the type seen in the ductal lamina positions immediately above the basement membrane. There is general agreement that lesions with these features, which measure more than 2-3 mm in diameter, are more likely to represent DCIS than ADH. ADH is, therefore, almost without exception, a tiny lesion.

In summary, we use the following rules of thumb.

1 We do not entertain a diagnosis of ADH unless low grade DCIS has been considered seriously in the differential diagnosis.
2 ADH is a very small, microfocal, process; the larger the lesion the more likely it is to be DCIS.
3 It follows that if there is any doubt about the differential diagnosis further levels and blocks should be examined. In our experience this usually resolves the problem, almost always by revealing evidence of low grade DCIS.
4 If changes resembling ADH are found in a needle core biopsy they should be regarded as either indicative of uncertain malignant potential or suspicious of malignancy. Excision biopsy is mandatory and usually reveals unequivocal low grade DCIS. [10, 12, 27]

In recent years there has been a proliferation of classifications for ductal carcinoma in situ. [7, 28, 29, 30] Despite differences in terminology all identify an aggressive comedo, poorly differentiated, high grade subtype and a relatively indolent subtype - non-comedo, well differentiated, low grade. In the United Kingdom it has been recommended that to avoid problems with the definitions of comedo necrosis and architectural pattern a simpler nuclear grading system is adopted for use in the National Health Service Breast Screening Programme (NHSBSP), and the same classification has been accepted by the European Commission Working Party on Breast Screening Pathology. [6, 7] However, problems with reproducibility still exist and only average agreement has been obtained in studies to date.

We are still left with the dilemma of correlating the morphology of these epithelial proliferative lesions and their management. Table 4 provides a somewhat speculative personal attempt to achieve this:

Table 4 - Current outline protocol for 'borderland' epithelial proliferative lesions, which correlates morphological structure with clinical management
Lesion Clinical significance
Epithelial hyperplasia Usual type Follow up not appropriate
Lobular neoplasia

Atypical ductal hyperplasia Low grade < 3 mm		Risk factor - follow-up only required - no
Ductal carcinoma in situ Excellent prognosis lesions - complete excision required
Low grade > 3 mm
Intermediate grad 		ħDXT
High grade (Microinvasive carcinoma)
'Small' invasive carcinomas <15 mm special type grade 1		ħaxillary dissection
ħlocal irradiation no systemic therapy
Invasive carcinoma Local and systemic therapy based on evaluation of prognostic factors

Epithelial hyperplasia of usual type, with its low relative risk factor of x2, needs no treatment or follow-up. The size rule should still be applied to define atypical ductal hyperplasia but, in my view, both ADH and low grade DCIS measuring less than 3 mm can be managed in the same way, by follow-up alone. There is no doubt that the prognosis for all types of ductal carcinoma in situ is excellent, provided that complete local excision is achieved. The same is true for so-called 'microinvasive carcinoma' (which will be referred to further below) and small invasive carcinomas. Note that the definition of "small" invasive tumour size has been raised to 15 mm from 10 mm because no difference in prognosis between the two was found in the Nottingham Tenovus Primary Breast Cancer Study. [4] This group of patients can therefore be treated by complete local excision, with or without axillary dissection. Local irradiation may be appropriate, but systemic therapy is not indicated.

Experience from both anecdotal consultation cases and early data from the UK NHSBSP indicate that microinvasion in DCIS is over-diagnosed by many general histopathologists. Because of this perception and the lack of consensus throughout the world on diagnostic criteria the definition recommended for use in the NHSBSP is very restrictive. [7] The lesion is composed predominantly of DCIS (almost always of high grade type), but with foci of definite invasion outside the specialised lobular stroma measuring not more than 1 mm in maximum diameter. There is no limit on the number of such foci. Care must be taken not to confuse as microinvasion extension of DCIS into lobules, branching of ducts containing DCIS, tangential cutting, crush and cautery artefact. Particular difficulty may be encountered in cases with marked periductal fibrosis and inflammation. In general terms the diagnosis of microinvasion should not be made unless there is convincing invasive carcinoma extending into interlobular stroma or adipose tissue. Multiple levels should be examined in suspicious cases and we have found in our laboratory that immunostaining for anti-smooth muscle actin may be helpful in distinguishing in situ from invasive elements. Immunostaining for basement membrane components (type IV collagen, laminin) is of less value. Pathologists are taught in general that when in doubt over a 'borderline' diagnosis to give the more malignant interpretation in order to avoid under treatment. It should always be borne in mind when considering a diagnosis of microinvasive carcinoma that some surgeons will carry out an axillary dissection or clearance in such cases but not, of course, for DCIS, and overdiagnosis therefore leads to unnecessary surgery. Furthermore, there is no evidence to date that has demonstrated that microinvasive carcinoma has a different prognosis from that of high grade DCIS. In my view, therefore, the diagnosis should only be made in those rare cases with unequivocal evidence of invasion.

Fibroepithelial lesions
Fibroepithelial lesions may give rise to a number of diagnostic problems but the most important concern phyllodes tumour. At the benign end of the diagnostic spectrum difficulty is occasionally encountered in distinguishing a cellular fibroadenoma from a benign phyllodes tumour. At the malignant end the criteria for the separation of benign and malignant phyllodes tumour are often misinterpreted with consequent overdiagnosis of malignant phyllodes tumour.

Classically fibroadenomas are usually encountered in women under the age of 30 years whilst phyllodes tumours are seen much more frequently in middle aged or older women. However, there is considerable overlap between the two entities at both ends of the age range and a significant minority of phyllodes tumours occurs in adolescents and young women. [31] Size alone is of no value as a distinguishing feature; although most fibroadenomas are small, measuring less then 20 mm in diameter and phyllodes tumours tend to be larger than this, there is marked variation in the size of both lesions. We have certainly encountered a number of phyllodes tumours measuring no more than 10 mm in diameter. Nevertheless, most problems are encountered with relatively large fibroadenomas in younger women when the presence of an intracanalicular pattern with leaf-like foci and cellular stroma raise the possibility of benign phyllodes tumour. Relative uniformity of stromal nuclei and a lack of mitoses favour a diagnosis of fibroadenoma. Further blocks should always be examined but it may be very difficult to make a clear distinction in some cases. It may be prudent to issue a cautious report in such cases, especially if the lesion extends to resection margins, since risk of local recurrence in phyllodes tumour is related to incomplete excision.

In the past phyllodes tumour gained an unwarranted aggressive reputation largely based on data from tertiary referral centres that, by their very nature, tend to acquire the more difficult cases for treatment. In addition there has been a general lack of agreement on the morphological criteria that should be used to designate malignancy in an individual tumour. As a result some pathologists, in an understandable attempt to avoid under-diagnosis, are inclined to err on the malignant side in assessing the histological appearances. It is now accepted that the majority of phyllodes tumours are, in fact, entirely benign; in our own community based study in Nottingham two thirds of the cases were classified as benign on morphological grounds and only 16 per cent had malignant features. [32] We therefore prefer to use the term 'phyllodes tumour' rather than cystosarcoma phyllodes and believe that the latter, with its innate implication of malignancy, should be abandoned.

Based on semiquantitative criteria [33, 34] we divide phyllodes tumour into three categories, benign, borderline and malignant. [32] Benign tumours have a pushing margin, minimal stromal overgrowth, cellularity and nuclear pleomorphism with stromal mitotic counts less than 10 per 10 fields (field diameter 0.152 mm2). In malignant lesions the margin is infiltrative, there is marked stromal overgrowth, cellularity and nuclear pleomorphism and mitotic counts are greater than 10 per 10 fields. Cases are placed in the borderline category if they fulfil some, but not all, of the criteria for malignancy, e.g., a pushing margin, but moderate nuclear pleomorphism and an intermediate mitotic count. Interestingly we found that none of these morphological features was useful in predicting local recurrence, which was strongly related to completeness of local excision. Metastasis is very uncommon in phyllodes tumour and only occurs in tumours with a malignant phenotype. It is our policy to excise benign phyllodes tumours with a clear margin of at least 10 mm; re-excision may be appropriate in some cases if completeness of excision is not achieved at the first operation. Mastectomy is advisable for patients with malignant phyllodes tumours and is also offered to women with very large benign lesions to avoid a poor cosmetic result. The borderline category is useful in preventing over-diagnosis of malignancy and therefore potential over-treatment. Optimum local therapy depends on the size of the tumour. Local excision is imperative, but only if this cannot be achieved with a satisfactory cosmetic result need mastectomy be considered.

Controversial Lesions / New Entities

Apocrine Lesions
The distinction between benign apocrine hyperplasia and low grade forms of apocrine DCIS is problematic and no simple solutions apply [35]. In addition forms of atypical apocrine proliferation can occur in association with sclerosing adenosis and in sclerosing lesions which can mimic invasive high grade carcinoma [36, 37] . Recognition of the problem in an individual case is key to avoiding error. We currently apply simple rules to these problems, adopting Pages groups stance on apocrine proliferation which uses cytomorphology and extent of lesion as the main arbiters between hyperplasia and DCIS. Use of immunocytochemical staining for myoepithelial cells is useful to recognise involvement of a sclerosing lesion.

Columnar cell alteration and Atypia
In recent years following introduction of mammographic screening and use of needle core biopsy to sample areas of microcalcification, forms of columnar cell alteration and atypia have been recognised [38, 39, 40] . These are often associated with mucin hypersecretion, microcyst formation and calcification. More exaggerated forms exhibit atypia merging with or indistinguishable from micropapillary types of DCIS. Coexisting invasive carcinoma of tubular or mucinous type have been described. We now consider these lesions to form a spectrum of epithelial proliferations analogous to the more conventional epithelial hyperplasia - ADH - low grade DCIS spectrum described above.

Low grade adenosquamous carcinoma and Sclerosing Lesions
We have recently recognised an association between radial scars/sclerosing lesions and a rare form of invasive tumour "low grade adenosquamous carcinoma" [41]. The significance of this observation remains uncertain at present.

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