Pathology (August 2014) 46(5), pp. 402–410

ANATOMICAL PATHOLOGY

Adenosquamous proliferation of the breast and low grade adenosquamous carcinoma: a common precursor of an uncommon cancer? MARK JAMES WILSHER Douglass Hanly Moir Pathology, Macquarie Park, NSW, Australia

Summary Low grade adenosquamous carcinoma (LGASC) is rare but commonly reported to arise in association with benign proliferative and sclerosing breast lesions which themselves may show associated sclerosing or ‘adenosquamous proliferation’ (ASP) resembling LGASC, but are often derided as reactive mimics or attributed to earlier biopsy. Among other benign lesions, radial sclerosing lesion (RSL) may be associated with LGASC, yet attention is typically focused on its relationship to more common forms of mammary carcinoma. This study aimed to assess the presence and extent of ASP in the context of RSL in a small cohort of 20 cases and its similarity to LGASC. Twenty consecutive breast excisions that had a principal or incidental diagnosis of RSL were reviewed. RSLs that displayed foci of ASP were further examined with immunohistochemical markers for p63, calponin, cytokeratin 5/6, oestrogen and progesterone receptors. Sixty percent of excisions contained ASP either associated with a RSL or a concurrent papilloma, which morphologically and immunohistochemically were indistinguishable from the neoplastic ducts of LGASC. RSL with and without ASP broadly corresponded to accepted definitions for ‘early’ and ‘late’ lesions, respectively. ASP corresponded to the characteristic compact branching ducts of the core or nidus of a RSL. The morphological and immunophenotypic similarity of the ASP found in RSL and papillomata to LGASC warrants serious consideration that they are a potential precursor to LGASC, which may most commonly involute given the rarity of clinically apparent LGASC. Further study including micro-dissection of foci of ASP to compare its molecular genetic profile to that of LGASC is required. Key words: Adenosquamous proliferation, complex sclerosing lesion, low grade adenosquamous carcinoma, radial scar, radial sclerosing lesion. Received 1 December 2013, revised 16 January, accepted 17 March 2014

INTRODUCTION Adenosquamous proliferation (ASP) refers to proliferative elements in the breast with a dual glandular and squamous phenotype, typically within a variable spindle cell stroma, and often with a syringoid appearance. Its most developed form is low grade adenosquamous carcinoma (LGASC), originally described by Rosen and Ernsberger1 and later by Van Hoeven et al.2 LGASC is rare, but is often reported to arise in association with or from benign proliferative and sclerosing lesions such as radial sclerosing lesion (RSL), intraduct Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000115

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papilloma, sclerosing adenosis and adenomyoepithelioma.1–8 These lesions share in common an epi-myoepithelial phenotype.3 ASP associated with mass forming florid hyperplasia of usual type was termed ‘infiltrating epitheliosis’ by Azzopardi, but the ASP resembles if not equates to a small LGASC.9 Infiltrating epitheliosis has previously been equated with RSL in the literature, but they differ in several respects, particularly in their architecture (RSL is zonated), and degree of epithelial hyperplasia (epitheliosis).9 It is important to note that lesional size is not a diagnostic criterion for LGASC. Review of the descriptions of radial scar by Anderson and Battersby10,11 reveals that of the two forms they described, early and late, the core element or nidus of early radial scars appears to be that of an ASP. In late radial scars these are not described, the assumption being that they regress over time. Agrawal et al.6 regarded prominent ASP in a RSL configuration in a 19-year-old female as an example of LGASC. More recently, a case of bilateral RSL with prominent ASP regarded as multiple LGASC was also reported.8 These cases illustrate the fact that the distinction between RSL with prominent ASP and LGASC is subjective and, moreover, is probably artificial.8 Although metaplastic carcinoma including LGASC is described in association with RSL and papillomas, ASP in these benign proliferative and sclerosing lesions is often regarded as representing benign squamous metaplasia with reactive hypercellular stroma, perhaps related to infarction (in the instance of papilloma) or previous fine needle or core biopsy.5 Gobbi et al.5 stated that in a series of metaplastic carcinoma arising in RSL and papillomata that because RSL has ‘pseudoinfiltrative glands’ their distinction from associated metaplastic carcinoma was often not discernable. Along this theme, it has been stated that unlike LGASC, either the ductules of radial scars do not display a syringoid appearance12 or that their entrapped and compressed appearance merely imitates the syringomatoid glands of LGASC, with squamous metaplasia in occasional RSL further complicating their separation.7 Given the association of LGASC precisely with these aforementioned lesions, explaining the presence of similar adenosquamous proliferative elements as merely coincidental or reactive is unsatisfactory. Having increasingly observed the presence of ASP in RSL, sclerosing adenosis and nipple adenomata, and noting their striking similarity to the neoplastic ducts of LGASC unassociated with any previous biopsy, this resemblance seems less than coincidental and the line between the two very blurred. As RSL is a common lesion13–16 and seems especially difficult to separate from rarer LGASC,6,8 the frequency and extent of ASP in this setting was investigated in a series of 20 consecutive

2014 Royal College of Pathologists of Australasia

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RADIAL SCLEROSING LESION AND CARCINOMA

patients and its similarity to LGASC was assessed with immunohistochemical markers as described in that lesion.7,17,18

MATERIALS AND METHODS Twenty consecutive breast excision specimens (wide local excision or mastectomy) that had a diagnosis (principal or incidental) of RSL were collected to assess the frequency and extent of ASP (that are characteristic of LGASC) within them, as defined below. RSL was defined according to the generally accepted definition of a lesion with a stellate configuration of central ducts (nidus) with variable peripheral cyst formation and epithelial proliferation (corona) with also variable central fibroelastosis.14 ASP was itself defined by the presence of compact ducts with a variable squamous appearance and surrounding spindle cells within a pale stromal ‘cuff’, and by a characteristic immunohistochemical (IHC) pattern of expression as described in LGASC. Outer myoepithelial cells and variable luminal cells express p63, calponin expression is observed by outer myoepithelial cells and spindle cells of the lamellar cuff surrounding ducts, there is variable expression of high molecular weight cytokeratins such as cytokeratin 5/6 (CK 5/6), and a lack of oestrogen receptor (ER) and progesterone receptor (PR) expression.1,2,7,17–19 Histological sections were examined and if ASP was identified by H&E, the following immunohistochemical markers were performed: p63 (rabbit mono, pre-dilute; Ventana, USA), calponin (mouse mono, 1:50; Dako, Denmark), CK5/6 (mouse mono, 1:50; Dako), ER (rabbit mono, pre-dilute; Ventana) and PR (rabbit mono, pre-dilute; Ventana). Immunohistochemistry was performed on a Ventana Benchmark Ultra instrument, with antigen retrieval (CC1), using appropriate positive controls.

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21 mm (in which small lymphoid aggregates were also noted), such that the diagnosis of LGASC was considered on review (Fig. 1. C–F). The observed areas of ASP were consistently histologically and immunophenotypically identical to the ducts characteristic of LGASC. They characteristically showed mild cytological atypia and apoptosis, and occasional glandular and/or periductal stromal mitoses were frequently noted on careful examination. There was a variable p63 positive myoepithelial layer around the ducts of the ASP and calponin expression was ‘muddy’ and ‘blurred’ around them. The ducts also variably expressed p63 and CK5/6, and they generally lacked ER and PR expression. In the RSL, the degree of fibroelastosis was variable, but ASP was seen in lesions with nil to generally only mild fibroelastosis, with variable mild stromal myxoid change and a lymphocytic infiltrate and these were generally regarded as examples of ‘early’ RSL. In several cases with prominent fibroelastosis, only a few random foci of ASP were seen, which suggested involution/ regression of ASP in what were regarded as ‘late’ RSL. Absence of ASP in RSL might be explained by their involution, as RSL with no ASP generally showed prominent fibroelastosis and relatively spaced, sometimes atrophic, ducts and were each also regarded as corresponding to ‘late’ RSL as described by Anderson and Battersby.10,11 The presence or absence of ASP was unrelated to earlier diagnostic biopsy. In fact in several cases, ASP was present within the diagnostic cores.

RESULTS The patients (Table 1), all female, ranged in age from 28 to 75 years and the RSL were often multiple (five or more in several cases) and in some instances they coalesced. In two cases the lesion displayed features of both a RSL and complex papilloma. In 14 cases (70%), the RSL was the principal reason for excision, mostly radiologically screen detected, with an age range of 40–75 years (mean 57 years). The remaining were incidental findings in excision specimens for invasive ductal carcinoma (IDC) or ductal carcinoma in situ (DCIS) in five individuals and a malignant phyllodes tumour in one. In total, carcinoma was present in association within 11 cases (ages 28–71, mean 56 years), with DCIS present within the actual RSL in five cases (aged 54–71 years), and lobular neoplasia in a case from one 52-year-old individual (mean 62 years). Individuals with RSL not associated with malignancy were on average slightly younger (aged 40–75, mean 53 years). ASP was observed in 12 cases, including within multiple RSL in some cases (60%), the individuals aged 28–75 years (mean 61 years), with RSL ranging in size from 1.7 mm, to a case with multiple coalescing RSL over a 21 mm area. The remaining eight cases (40%) lacked ASP (aged 52–71, mean 58 years) with RSL similarly ranging in size from 2 to 20 mm. In 10 cases the ASP was associated with a RSL, generally with the appearance of a radial scar. In the remaining two cases the ASP was associated not with the RSL, but with an accompanying separate intraduct papilloma (‘sclerosing papilloma’). The amount of ASP varied. In both papillomata, the foci were only 1–2 mm and seen at their periphery. Associated with the RSL the foci of ASP ranged from only one or several ducts generally confined to the nidus of the RSL (Fig. 1 A,B), to more prominent foci with the ASP insinuating between ducts within the confines of the RSL. However, in several cases multiple foci of ASP were situated within the nidus and permeated between ducts beyond the corona of the RSL, and in one case extended between coalescing RSL over a distance of up to

DISCUSSION LGASC is a rare form of metaplastic breast carcinoma, first described by Rosen and Ernsberger1 and clarified in a follow-up report by Van Hoeven et al.2 who expanded and followed up on the original series. It is morphologically similar to syringomatous carcinoma of salivary glands and is strikingly similar to sclerosing sweat duct (syringomatous) carcinoma (microcystic adnexal carcinoma) of skin, a lesion that also has relatively indolent although locally aggressive behaviour, but is not associated with metastasis.1,2,19,20 A case of microcystic adnexal carcinoma arising in breast skin of 20-year duration, which invaded breast parenchyma, has previously also been reported.21 Syringomatous tumour, initially clarified by Rosen22 is a benign proliferating syringoma-like lesion usually confined to nipple and areolar skin, which also bears strong resemblance to LGASC, having a similar ASP. It lacks an intramammary location or potentially aggressive course.2 Suster et al.20 suggested that their four cases of ‘syringomatous squamous tumours of the breast‘ were perhaps benign precursors (or counterparts) of LGASC. LGASC is a diagnostic challenge radiologically as it lacks unique imaging features and its sonographic and mammographic appearance overlaps with benign and malignant neoplasms, so the diagnosis is firmly based on histology.23 However, the histological diagnosis is also not straightforward. Invasive ductal carcinoma with focal squamous metaplasia and the rare occurrence of mucoepidermoid carcinoma are also potential mimics of LGASC.2 The age at diagnosis of LGASC is reported from 19 to 85 years and presentation may be more often as a palpable mass than as an imaging detected lesion. Diagnosis is typically only suggested on FNA or core biopsy, but because of an accompanying atypical imaging appearance, excision biopsy is usually prompted.7 Their size generally ranges from 5 mm to 50 mm,19 but a lesion up to 80 mm has been recorded.2 Their

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47

65

46

28

45

67

54

55

52

62 40

54

75

55

52

64

61

71

44

2

3

4

5

6

7

8

9

10

11 12

13

14

15

16

17

18

19

20

F

F

F

F

F

F

F

F

F F

F

F

F

F

F

F

F

F

F

F

Screening

Screening

Screening

Screening

Left

Left

Left

Small irregularity on imaging

Screening

Screening

Right Screening, ?palpable lesion Left Screening

Right Screening

Left

WLE

WLE

WLE

WLE

WLE

WLE

WLE

WLE

Yes; core biopsy; DCIS Yes; FNA; nondiagnostic Yes; core biopsy; RSL with ASP

Yes; core biopsy; non-diagnostic

Yes; FNA; ‘Atypical’ Yes; FNA; ‘Atypicalpapillary’ No

No Yes; core biopsy; RSL with ASP No

Yes; core biopsy; LCIS

No

WLE WLE

Yes; core biopsy; RSL and ADH

No

Yes; fine needle; ‘atypical’

No

Yes; core biopsy; DCIS Yes; core biopsy; RSL Yes; core biopsy; RSL No

WLE

Mx

Incidental Mx Palpable lesion WLE

Right Screening

Left Left

Right Follow up imaging for papillomas Right Screening

Left

Mx

Mx

WLE

WLE

WLE

Palpable lesion WLE

Right Incidental

Left

Right Incidental

Right Incidental

Left

Left

Right Screening

5; 3–4mm

1; 3mm

Multiple RSL; accompanying intraduct papilloma (2mm), over area >20mm 1; 15mm

1; 20mm

Fibroelastotic

Fibroelastotic

Fibroelastotic

Stroma of RSL

Fibroelastosis

No

Yes (focal, but extending beyond corona) Yes (focal, nidus)

Malignant phyllodes tumour, 50mm –



Complex papilloma with DCIS also outside it, 27mm

Two tumours, MPC G3 and IDC G3 and DCIS 100mm Intermediate and high nuclear grade DCIS complicating RSL

IDC, G3, 50mm and I-HG DCIS 80mm IDC 3, G3, and HG DCIS, ERþ, PRþ, Her2 þ –

Epithelium suggestive of ADH within smallest RSL –

DCIS within largest RSL

Other/main pathology

Yes (variably prominent in all, within nidus and in some beyond corona)

Variable fibroelastosis and lymphocytic chronic inflammation

Fibroelastosis

Fibroelastosis

Low nuclear grade DCIS at periphery of RSL, 3mm –

DCIS within RSL and beyond

DCIS within RSL and beyond

Fibroelastosis in RSL No in RSL; yes from papilloma (focally at its immediate periphery) Yes (very focal, within and at periphery, ?regressing) No

Fibrocystic change and intraduct papillomata

Fibroelastosis

No

Mild fibroelastosis and mild IDC G2, 2, 6.3mm and 3mm lymphocytic chronic inflammation adjacent to RSL Minimal fibroelastosis and mild Proliferative change, small intraduct lymphocytic chronic inflammation papilloma Fibroelastosis Proliferative change

Yes (single focus, regressed?) Fibroelastosis Yes, (prominent but forming a nidus) Mild fibroelastosis

Fibroelastosis

No

Myxoid with mild lymphocytic inflammation Yes (focal, nidus) Myxoid with mild lymphocytic inflammation Yes (prominent in all and Lymphocytic chronic inflammation extending between RSL, ?LGASC) including lymphoid aggregates, and variable fibroelastosis Yes (within and at periphery) Lymphocytic chronic inflammation and focal elastosis No in RSL; yes from papilloma Fibroelastosis in RSL; myxoid (around its periphery) stroma around papilloma

Yes (focal in both, nidus)

No

No

No

1; papillomatous No change of corona; 10mm

1; 2.5mm

1; 4.5mm

RSL with lobular neoplasia (ALH) at its periphery 1; 4mm RSL; 4mm

1; RSL/complex papilloma; 3mm Large RSL >50mm; separate papilloma 1.7mm 1; 2mm

Multiple coalescing RSL over 21mm

RSL; 4mm

2 (at least); 10mm and 2mm 2; RSL/complex papilloma; largest 6mm 1; RSL and Bx site, up to 20mm 2; 2mm and 4mm

ASP present (and extent)

WILSHER

DCIS, ductal carcinoma in situ; F, female; FNA, fine needle aspiration; G, grade; IDC, invasive ductal carcinoma; Mx, mastectomy; RSL, radial sclerosing lesion; WLE, wide local excision.

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1

Presentation

Preoperative biopsy of RSL, method RSL number, features and size Operation and diagnosis

Details of 20 patients with radial sclerosing lesions

Age Case (years) Sex Side

Table 1

404 Pathology (2014), 46(5), August

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RADIAL SCLEROSING LESION AND CARCINOMA

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Fig. 1 RSL with ASP (’early RSL’). (A) Case 5. RSL, with lymphoid infiltrate and loose stroma (H&E). (B) Case 5. RSL, detail of ASP (H&E). (C) Case 6. RSL with prominent ASP (H&E). (D) Case 6. ASP with adjacent lymphoid aggregate (H&E). (E) Case 6. Lamellar cuff of calponin positive spindle cells surrounding ducts. (F) Case 6. ASP with focal expression of p63 by luminal cells and occasional myoepithelial cells.

behaviour is usually locally aggressive, but metastasis is rare.7 In the expanded series of Rosen and Ernsberger, reported by Van Hoeven et al.,2 of 32 cases, one also assessed by electron microscopy (EM), two patients aged 33 years and 40 years had metastasis at initial surgery from tumours larger than 30 mm. One had a nodal metastasis and the other had pulmonary metastasis. Recurrence occurred in five patients, and in one the tumour progressed to invade the hemithorax and brachial plexus and was ultimately fatal. Gobbi et al.5 recorded a case of LGASC in a 77-year-old woman with metastasis to an axillary lymph node as a solitary squamous cyst. The tumour size was not recorded, but there were two recurrences of the primary lesion over an 84-month period. In another paper,24 a case of LGASC which transformed to osteosarcoma and a spindle cell carcinoma in successive recurrences over a 5-year period, was associated with multiple pulmonary metastasis and eventual death. Lesions excised over the period were 20 mm, 23 mm and 15 mm in diameter, respectively. Histologically, LGASC has a distinctive appearance. It is composed of variably compressed tubules that may be lined by columnar or squamous cells with a variable outer layer of myoepithelial cells that may merge with squamous elements and may form tadpole-like extensions akin to syringoma,

within a variable spindle cell background that is often difficult to separate from periductal stroma. Stromal lymphoid aggregates are variably described.1,2,7,18,19,25 The pale staining of the stroma helps distinguish it from background benign breast tissue, a useful feature as tumours often show peripheral extension into normal breast tissue which makes determining the tumour outline difficult.7 Immunohistochemical markers show variable staining in lesional glands and stromal cells for cytokeratins and for myoepithelial markers. Myoepithelial cells are variably identified around neoplastic glands. A characteristic and diagnostically useful finding is lamellar staining with myosin heavy chain or calponin of stroma immediately surrounding neoplastic glands in a layered cuffing manner as opposed to a crisp ‘garland’ of myoepithelial cells around non-neoplastic ducts and lobules. Both the myoepithelial cells and squamous cells express p63, and the stromal cells generally do not express keratins.18 This outlines the importance of performing several myoepithelial markers to highlight the pattern of expression so that the presence of myoepithelial cells is not automatically interpreted as a sign of benignity. LGASC are ‘triple negative carcinomas’ that express basal keratins and have complex genetic profiles. A minority of the spindle cells, but particularly

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WILSHER

those near (or surrounding) the epithelial component, have been shown to be clonal and derived from the epithelial component.17 Although LGASC has a triple negative phenotype, only once has a BRCA1 germ-line mutation been recorded.26 Compounding the difficulty in diagnosis, LGASC is commonly reported in association with or emanating from benign proliferative and sclerosing lesions.2–5,7 LGASC can grow in a stellate, infiltrative fashion like a RSL and in this instance may be more commonly diagnosed as a RSL than the contrary, as RSL are more commonly encountered in routine practice.25 Twelve of 32 of the cases in the series of Van Hoeven et al.2 arose from an intraduct papilloma, three with an adenomyoepitheliomatous appearance. In another study,3 an additional three cases of LGASC arose in association with an adenomyoepithelioma, with a gradual transition between the two. Denley et al.4 described four cases of LGASC arising within complex sclerosing lesions (CSL). Subsequently, Gobbi et al.5 reported on metaplastic spindle cell breast tumours arising within papillomas, CSL and nipple adenomas. Eleven were cases of LGASC, five of which were not recognised in the initial biopsy and were diagnosed at the time of recurrence. They stated that it could be impossible to detect metaplastic carcinomas in some radial scars, CSL and papillomas because of the presence of spindle cells and compressed ducts in these lesions. Because LGASC is rare, the incidence of lesions without associated features of a RSL is unclear and Denley et al.4 suggested that rather than actually arising in a radial scar (RSL), LGASC might alternatively induce a stromal reaction including central sclerosis and elastosis that mimics a radial scar. Moreover, breast carcinoma in general has a radiating architecture with central fibroelastosis. In a report on ‘scar cancers’, Fisher et al.27 found that 38% of 1569 cases of invasive breast carcinoma were associated with a scar, which they classified into five different types. One type of scar, recorded in 14% of these cases, was regarded as morphologically identical to a radial scar. This was termed ‘type 1 scar cancer’ and seen as representing carcinoma arising in or associated with a radial scar. More recently, Agrawal et al.6 reported a case of a RSL with a prominent adenosquamous proliferation in a 19-year old woman that was thought sufficient for a diagnosis of LCASC. They stated that LGASC ‘should be considered in uncertain sclerosing lesions with an abundance of epithelial proliferation with signs of squamous differentiation in a predominant fibroblastic stroma’. A recent case of bilateral multiple RSL with prominent ASP sufficient to diagnose as bilateral multicentric LGASC, the index lesion a 25 mm tumour, further highlights the subjective distinction between cases of RSL with prominent ASP and LGASC, a distinction that seems probably artificial.8 Regarding spindle cell predominant lesions arising in association with sclerosing lesions, Gobbi et al.5 stressed that ‘to avoid over diagnosis of malignancy in the reactive process, the lesion should present increased cellularity and clumps of cytokeratin positive plump spindle cells, besides the ‘reactive’ spindle cells and squamous elements’. Rosen19 stated that because overt lymphoid aggregates are uncommon in ‘typical’ RSL their presence might indicate a LGASC. LGASC is said to differ from RSL by having non-elastotic fibrous or cellular stroma around glands, lymphoid aggregates and more frequent squamous differentiation.25 In LGASC, careful attention to the pattern of immunohistochemical staining, and as mentioned above, lamellar staining around ducts with heavy chain myosin or calponin is a particularly useful diagnostic clue.18 However,

Pathology (2014), 46(5), August

in the current study, no morphological or immunophenotypic difference was seen between the ASP associated with RSL and papillomata, and LGASC. Moreover, in one case of multiple coalescing RSL with prominent insinuating ASP, there were even small lymphoid aggregates. Soo and Tan7 recommended the use of the term ‘low grade sclerosing lesion’ for instances where there is uncertainty, at least on core biopsy, as to whether a lesion represents a benign fibrosclerosing lesion (including RSL) or LGASC. Although LGASC is reported in association with RSL, the latter is more typically associated with more common forms of carcinoma where the diagnosis is thankfully generally straightforward.28–37 RSL, a term proposed by Rosen38 encompassing the terms ‘radial scar’ and ‘complex sclerosing lesion’ for lesions 10 mm, respectively,10 is generally regarded as a benign lesion. RSL are commonly encountered breast lesions that may be found incidentally in breast excisions for other reasons, commonly carcinoma, or they may present as a radiological abnormality on imaging in their own right. They are reportedly uncommon under the age of 30 years and are most frequently diagnosed in women aged 40–60 years.38 The rate of detection has dramatically increased due to the introduction of population-based screening programs.39 RSL have clinical, radiological and histological features that overlap with carcinoma.38,39 RSL have a characteristic stellate, zonated configuration with a central nidus containing ducts within a variably fibroelastotic stroma and an outer corona comprising cysts with variable epithelial hyperplasia.14 They commonly occur on a background of proliferative breast disease.28,32,40 The pathogenesis of RSL has been debated with many theories over time including a reaction to unknown injury, duct or vascular obliteration, inflammation, and origin in sclerosing adenosis, with its stellate configuration perhaps the result of scarring contraction with associated elastosis.10,11,14,15,27,40 Fenoglio and Lattes41 described RSL in detail in 1974 under the term ‘sclerosing papillary proliferation’, although as early as 1928 Semb42 referred to the lesion as ‘rosette-like lesions’ and ‘proliferation centres’. The term radial scar is a translation for ‘strahlige narben’ (literally: radiating scars) from the paper in German by Hamperl in 1975.43 However, it has been also described under additional names including ‘non-encapsulated sclerosing lesion’13 and ‘indurative mastopathy’.44 In 1985, in histological and EM studies of radial scars, Anderson and Battersby10,11 proposed that radial scars were progressive lesions that could be divided into early and late forms. In what they regarded as ‘early lesions’, there were distorted branching ductal structures at their centre, which ‘could be distinctly atrophic’. Spindle cells were seen in the stroma particularly around these central ducts and ductules, with unclear delineation and there were chronic inflammatory cells and little fibroelastosis. In what they regarded as ‘late’ or ‘developed lesions’, there were isolated ‘well developed round or elongated tubular structures’ with an epithelial and myoepithelial bilayer, as well as ducts distended by hyperplastic epithelium, the stroma was elastotic and collagenised, and there was clear distinction between the ducts and stroma. The ducts in late lesions, being set within sclerotic scars (with elastosis) were regarded as ‘remnants’ persisting after the active phase. The spindle cells in early lesions were regarded as myofibroblasts and on EM stromal cells appeared to be continuous with and form part of the ductal structure, the stroma merging with the myoepithelium. They considered sporadic myofibroblastic

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RADIAL SCLEROSING LESION AND CARCINOMA

activity to be key to the causation of radial scars. The source of the myofibroblasts was thought likely to be from fibroblasts. However, they acknowledged that in view of the lack of cell type demarcation noted on EM, the myoepithelial cell could in fact explain their origin. The description and particularly the images provided of ‘early’ radial scars almost certainly equate to the ASP described in the current series and, moreover, are indistinguishable from a snapshot of a LGASC. The absence of these foci of ASP in late lesions implies their involution. In the current series, ASP seen in 10 cases with RSL with generally limited elastosis certainly supports this concept of a progressive lesion. Linell et al.14 had earlier considered the initial stage of radial scars to be sclerosis with early deposition of ‘elastoid material’ and that the centre (nidus) ‘always contains or has contained obliterated ducts’. Others share this concept of early RSL with branching and budding ductal structures in the core with intervening spindle cells distributed around those ductal structures and with a mild stromal lymphoplasmacytic inflammatory cell infiltrate, and a late phase of RSL with less abundant stromal cells and a collagenised stroma with more pronounced elastosis.38,45 Doyle et al.34 recorded that 57.6% of their cases had obliterated ducts centrally and 90% had cystically dilated peripheral ducts (the corona). They also noted perineural invasion by ‘benign glands’. Infiltrating epitheliosis has been confused with RSL in the past, but differs from RSL in that instead of hyperplasia being limited to a corona, it is a prominent component without zonation. Like ‘early’ RSL, it too has an ASP, which appears to ‘flow out’ of the epitheliosis (florid hyperplasia) and lie within desmoplastic stroma with a keloidal appearance and they may even show discontinuity from the main mass, closely resembling LGASC.9 Immunohistochemically, RSL have been described as being strongly positive for ER and PR,46 but D’Alfonso and Shin25 described only focal expression. Rosen38 states that myoepithelial cells may be easily demonstrated at the periphery of ducts at the outer aspect of the RSL, which often consists of cysts and hyperplastic ducts (the ‘corona’), but that in the central portion (core) the myoepithelium may be very attenuated or even undetectable. Similar to ducts involved by DCIS, the myoepithelial cells surrounding ‘entrapped glands’ within RSL have been shown to display phenotypic alterations compared to myoepithelial cells surrounding normal ducts and lobules in same sections, in that there was variable reduced expression of a number of myoepithelial markers: cytokeratin 5/6, smooth muscle myosin heavy chain, CD10, p63 and calponin.47 In another study,48 a myoepithelial cocktail of p63 and smooth muscle actin (SMA) was proposed to greater enable the demonstration of myoepithelial cells within sclerosing breast lesions (in four RSL and two sclerosing papillomata). Glands lacking expression of both markers were more likely to reside within the ‘core’ of the sclerosing lesions. Glands in the proximity of the core tended to express SMA alone. Both markers were expressed in the lesion’s periphery. In the current series, it was the ASP that showed patchy p63 expression of luminal, as well as outer myoepithelial cells, and calponin expression was often seen as a characteristic ‘muddy’ lamellar cuff of staining of the periductal spindle cells, but the epithelial cells also variably stained. The ASP typically lacked ER and PR expression. The immunoprofile of ASP in this setting and of the neoplastic elements of LGASC is essentially the same. In the current series there was a strong association of RSL with in situ and invasive ductal and lobular carcinoma.

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Traditionally, the main clinical significance of RSL is in the observed association with common forms of breast carcinoma and there remains controversy as to whether RSL is an incidental finding of no consequence, simply a marker for cancer, or is an intrinsically premalignant lesion and direct precursor of carcinoma, which also includes LGASC.4,5,29,36,39 In fact, Rosen38 states that the wide and overlapping range of frequency of RSL associated with benign and malignant breast lesions, suggests that they may arise with similar frequency in both circumstances. RSL is a common entity and an autopsy study has shown a frequency of 28% in unselected females,16 and of these cases, the lesion was multicentric in 67% cases and bilateral in 43%. Wellings and Alpers15 found radial scars in 14% of 83 breasts from a random autopsy series with an average of 7.7 per breast, whereas in breasts with carcinoma, 26% of 107 breasts contained radial scars with an average of 15.5 per breast. The average age was similar at 59 years. In an extensive study, Linell et al.14 detected RSL in 16% of mastectomy specimens, which were often multiple with up to 25 recorded in a single breast, with a mean age of 61 years. In a study of 400 cases of fibrocytic disease, Fisher et al.13 found RSL in 4% of cases. RSL itself is generally considered a benign sclerosing lesion which exhibits various secondary alterations in the epithelium from usual hyperplasia to atypical ductal hyperplasia and lobular neoplasia, and may be involved by DCIS or invasive carcinoma, the latter more often present at the lesion’s periphery.34,35 The reported incidence of atypia and carcinoma widely varies between studies. Jacobs et al.30 found a two-fold risk increase for breast carcinoma in women with radial scars, which increased with the size and number of radial scars. Sanders et al.32 demonstrated an increased rate of the development of carcinoma following biopsy of a RSL over an average follow-up time of 20.4 years with a relative risk of 1.82 at 10 years. The increased risk was stated to be largely due to the type of coexistent epithelial proliferative disease, and it was stated that if there was epithelial atypia, biopsy alone is insufficient management. This may potentially indicate that the occurrence of neoplasia in and associated with RSL is a reflection of the normal proliferative capability of breast epithelium.29 Sloane and Mayers28 found that as many as 43.3% of mammographically detected RSL harboured carcinoma. Fasih et al.31 showed a high incidence of atypia and carcinoma in RSL, with an incidence of atypical ductal hyperplasia of 18% and of either in situ or invasive carcinoma of 16%. Douglas-Jones et al.33 found that in only 3.9% of cases reported as RSL on core biopsy, carcinoma was present on excision. In another study, Doyle et al.34 demonstrated a high incidence of epithelial atypia and carcinoma in 22.4% and 24.8% in a series of 125 histologically confirmed RSL. Of these cases, 45.1% had a previous benign core biopsy, supporting the common belief that RSL should be excised and examined in their entirety. The invasive carcinomas were ductal, tubular, lobular or tubulolobular. After surgical excision of a RSL diagnosed on needle core biopsy, atypical hyperplasia (or papillary lesion) and in situ or invasive carcinoma was found in 22.4% and 5.9% of cases, respectively, in a recent study by Andacoglu et al.;37 malignancy was more frequent in older post-menopausal women. The relationship between the size of a RSL and presence of carcinoma is variably reported also. In Anderson and Battersby’s series,10 smaller radial scars (6–7 mm in size, and age >40 years. However, Bunting et al.36 found that size of a RSL (< or > 10 mm) had no association with the future development of carcinoma in patients after excision of the RSL. They stated that the more common occurrence of carcinoma with larger RSL is simply related to increased age of the patients, as each are more common with increasing age. The direct neoplastic precursor potential of RSL has been explored previously, but with reference to more common forms of breast carcinoma, particularly tubular carcinoma. Fisher et al.13 postulated that RSL (or as they called it ‘non-encapsulated sclerosing lesion’) might represent an incipient tubular carcinoma. Linell et al.14 subsequently postulated in a study of 555 mastectomies, that radial scars were the earliest recognisable stage of more than 50% of breast carcinomas, which begin as a small tubular carcinoma (that they thought always arose in a radial scar) and progress to less well differentiated subtypes. Their detailed manuscript contained images purported to show transitions between simple radial scars and tubular carcinomas. They stated that radial scars may remain dormant for a very long period and that development of a tubular carcinoma may also take a similarly long period and argued that as radial scars are common, either only some of them become malignant or (many more do but) they regress. They stated that because radial scars were far more common than carcinoma it was improbable that they all developed into carcinomas. Anderson and Battersby believed that it was inappropriate to imply a causal relationship between radial scar and carcinoma (including tubular carcinoma) based on a similar scar-like morphology.10 More recently, Manfrin et al.49 in noting an increase in the occurrence of atypical epithelial hyperplasia and carcinoma in RSL in patients of increasing age, interpreted this trend as evidence that RSL may represent a ‘natural model of

Pathology (2014), 46(5), August

carcinogenesis’ starting with a proliferative lesion in patients less than 50 years old, and over time developing epithelial atypia and subsequent carcinoma. As early as 1928, Semb42 also proposed that the proliferation centre of a RSL could give rise to carcinoma. The concept of regression of a neoplasm arising in/from a radial scar is interesting and, moreover, may indeed be more relevant to the origin of LGASC than to tubular carcinoma. Tot50 described ‘eccrine duct lobules’ at the periphery of a case of LGASC which were regarded as a possible precursor lesion. The image provided in that article resembles transversely sectioned insinuating ducts of LGASC including those seen at the periphery of the tumour (Fig. 2). Moreover, these ducts interpreted as a precursor lesion by Tot,50 also closely resemble the ASP seen within the RSL in the current series (Fig. 1), both histologically and immunohistochemically, which supports the notion that the compressed branching ducts with surrounding spindle cells seen in ‘early’ RSL are not simply mimics of the ‘syringomatous’ ducts seen in LGASC. In common, they show cytological atypia, apoptosis, infiltration, express high molecular weight cytokeratin (in this instance CK5/6) and p63, have a muddy lamellar cuff of staining with calponin, and lack ER and PR expression. They were unrelated to diagnostic biopsy in the current series. It is surprising that they have been previously dismissed as ducts merely compressed by fibroelastosis or reactive mimics. LGASC is most obvious when it is extensive, with prominent desmoplastic stroma containing lymphoid aggregates.19 However, its peripheral advancing edge comprises cords and nests that permeate between native benign breast ducts and lobules and it is these areas which too resemble the ductal structures seen in ‘early’ radial scar; indeed, LGASC may have a purely radiating RSL type pattern of growth.6,8,25 The occurrence of different types of carcinoma arising in/ from a RSL may theoretically depend upon whether they arise

Fig. 2 LGASC, from archive (25 mm lesion arising in and mimicking a RSL). (A) Overview. Note lymphoid aggregates (H&E). (B) Periphery of tumour with LGASC insinuating between benign ducts and lobules (H&E). (C) Dual immunohistochemistry: AE1/AE3 (red) and calponin (brown). Note the same lamellar cuff of staining by calponin. (D) Dual immunohistochemistry: AE1/AE3 (red) and p63 (brown).

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RADIAL SCLEROSING LESION AND CARCINOMA

from the nidus or corona of the RSL. Common forms of in situ or invasive carcinoma are reported to occur at the periphery of the RSL where there is often florid hyperplasia, and therefore may be attributable to the proliferative capability of that epithelium.29,34,35 LGASC carcinoma in contrast may arise from ASP at the nidus of the RSL potentially representing a precursor lesion. According to this scenario, ASP which seem characteristic of ‘early’ RSL may take several routes: involution, perhaps initiating or contributing to the characteristic prominent fibroelastosis characteristic of more longstanding ‘late’ RSL, or persistence and potential progression until it forms an easily recognisable LGASC, presumably accumulating genetic mutations along the way. By inference, ASP in the setting of sclerosing papilloma or associated with other benign proliferations such as sclerosing adenosis may theoretically also be precursor lesions. Using micro-dissection, radial scars have been shown to harbour areas that are clonal and neoplastic and a minority of radial scars have been shown to have molecular and genetic changes that occur more commonly in breast carcinoma and premalignant breast lesions, but without significant allelic imbalance compared to background breast tissue.51 Clonal differences were seen between different micro-dissected areas within the same radial scars. The areas sampled included those with hyperplasia of usual type, apocrine metaplasia, adenosis, sclerosing adenosis and papillary change. However, these may be only relevant to the more common forms of carcinoma. In another study of RSL and carcinoma (but invasive ductal carcinoma only), Jacobs et al.30 showed similarities in mRNA expression for several factors involved in vascular development, which they said suggested a similar disturbance in epithelial-stromal interaction is present in RSL and invasive breast carcinoma. Most recently, activating PIK3CA mutations, which are present in 25–30% of breast carcinomas (particularly if ER positive), were detected in 63.6% of radial scars. However, because tissue was macro-dissected from unstained sections, the material tested was an admixture of epithelial, myoepithelial and stromal components. The authors had previously demonstrated similar findings in other proliferative lesions and acknowledged that the results may reflect the morphology of the epithelium (e.g., usual epithelial hyperplasia) rather than its underlying architecture or context such as a radial scar or benign papilloma.52 Future micro-dissection studies should specifically concentrate on the ASP (or nidus) within RSL so as to assess their molecular genetic profiles with specific reference to any similarity or overlap with bonafide cases of LGASC. Clearly, because sclerosing breast lesions are by far more common than LGASC, if ASP is a precursor lesion it seems to be not very effective, as only a few may progress, or at least they grow very slowly and remain clinically insignificant. Alternatively, they may form a spectrum of the same histological process, which is traditionally recognised as carcinoma only when extensive. LGASC are reported to metastasise when over 30 mm,2 after multiple recurrences5 or after high grade transformation,24 so their under-diagnosis may not be clinically significant in most circumstances. Indeed, if they occur limited to RSL or papillomata they may in any event be often completely excised.5 Clearly, the majority of cases of LGASC show relatively indolent behaviour, remaining locally infiltrative. Due to a lack of definitive diagnostic criteria to separate RSL with prominent ASP from LGASC, the onus is on the pathologist not to over-diagnose LGASC, as it may initiate

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inappropriate treatment including systemic therapy by the unwary clinician following a diagnosis of ‘triple negative carcinoma’. In doubtful cases, it may be prudent to stress that complete local excision alone should be sufficient treatment. Microdissection studies with molecular genetic analysis of ASP in various settings are required to assess their relationship to bona fide examples of LGASC. If a link was established even in the smallest of examples, terminology for these lesions may require reconsideration. Acknowledgements: Enormous thanks are especially due to Allison Morgan, Elizabeth Sinclair, Fiona Bonar, Ivan Burchett and Olivier Dupon. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Dr M. J. Wilsher, Douglass Hanly Moir Pathology, 14 Giffnock Avenue, Macquarie Park, NSW 2113, Australia. E-mail: [email protected]

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Adenosquamous proliferation of the breast and low grade adenosquamous carcinoma: a common precursor of an uncommon cancer?

Low grade adenosquamous carcinoma (LGASC) is rare but commonly reported to arise in association with benign proliferative and sclerosing breast lesion...
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