Histoparhology 1989, 14, 5 15-522

Histiocytoid breast carcinoma:

an apocrine variant of lobular carcinoma

N.WALFORD & J.TEN VELDEN

Depart men t of Pathology, A cademisch Medisch Cent rum,
University of Amsterdam, The Netherlands

Accepted for publication 2 September 1988

N. 8i TEN VELDENJ. (1989) Histoparhology 14, 515-522

WALFORD

Histiocytoid breast carcinoma: an apocrine variant of lobular carcinoma

Two cases of in siru and invasive histiocytoid breast carcinoma are described. The
invasive components of both tumours showed architectural and cytological similari-
ties lo lobular carcinoma. The in siru components showed areas of classical lobular
carcinoma in siru,areas of lobular carcinoma with apocrine features and areas with
transitional features. It is concluded that histiocytoid carcinoma represents an
apocrine variant of lobular carcinoma. Differentiation of this tumour from chronic
sclerosing inflammation may be difficult in both primary and secondary lesions.

Keywords: breast, carcinoma, histiocytoid, apocrine, lobular

Introduction

In 1973 Hood, Font & Zimmerman, from the Armed Forces Institute of Pathology
Registry of Ophthalmic Pathology, described 13 cases of metastatic carcinoma in
the eyelids of patients known to have had, or subscquently shown to have, primary
mammary carcinomas. Although these authors did not have the opportunity of
examining material from the primary tumours, the appearances of the metastatic
lesions were regarded as sufficiently distinctive to justify a separate appellation for
these tumours. The histiocyte-like morphology of individual infiltrating ceils-
many of the lesions were originally misdiagnosed as chronic sclerosing inflam-
mation-suggested the name histiocytoid breast carcinoma.
Subsequently occasional reports have appeared in the literature (reviewed by
Dabski, Milgrom & Stoll 1985), concentrating more on the bizarre pattern of
metastasis than on the histological appearances; indeed we have been unable to find
any comprehensive account of the histopathology of primary mammary, as
opposed to metastatic, histiocytoid carcinoma. We describe here the histological

Address for correspondence: Dr N.Walford, Department of Pathology, Academisch Medisch

Centrum, University of Amsterdam, Meibergdreef 9, 1 105 AZ Amsterdam, The Netherlands.

515
 Histiocytoid breast carcinoma 5 17

margins and slightly eosinophilic cytoplasm. The nuclei in some respects resembled
those of classical lobular carcinoma in their bland monotony, having smooth
rounded contours, a palely staining, uniform nuclear membrane and normo-
chromatic finely granular chromatin with a single, usually central, small eosino-
philic nucleolus (Figure 1). However, the nuclei differed in being larger and usually
oval; some nuclei were reniform, or else had a slight ‘cleavage’ in the long axis,
enhancing their resemblance to histiocyte nuclei. Mitotic figures were few (1-2/10
high power fields) in both cases. Intracytoplasmic lumina were numerous and
prominent, showing an alcian blue positive halo with an inner ring or crescent of
PAS positivity. In poorly-fixed material they were better demonstrated on
immunostaining with anti-epithelial membrane antigen. On H & E sections they
were easily overlooked or dismissed as processing artifacts. Often these lumina were

Figure 1. Case 1. Infiltrating tumour shows trabecular pattern and bland nuclear characteristics. PAS/
diastase. x 350.

Figure 2. Case 2. Targetoid pattern of infiltration around duct with Indian’filing. Cytokeratin. x 55.
5 18 N . Walford and J.ten Velden

Figure 3. Case 1. Hyalinized collagen, single histiocytoid cells and a lymphocytic infiltrate closely
simulate a chronic inflammation. H & E. x 230.
Figure 4. Case 2. Infiltration of single tumour cells between adipocytes. H & E. x 230.

sufficiently large to indent and displace the nuclei peripherally, producing an

appearance difficult to distinguish from signet-ring cells. Architecturally, the
arrangement of invasive tumour cells varied with clumps and trabeculae two to three
cells thick and ‘Indian file’ single non-cohesive cells. A ‘targetoid’pattern of growth
around pre-existing normal ducts was often seen (Figure 2).
A striking feature of both tumours was the presence of extensive hyaline fibrous
tissue. In central parts of the tumours the mixture of dense collagen, isolated
histiocytoid cells and lymphocytes was liable to be confused with a non-neoplastic,
inflammatory lesion (Figure 3). At the advancing edge of the tumours the cells
showed a solid, cohesive picture, whose neoplastic nature was more obvious.
Invasion of fat took the form of either broad fibrous septa with files of tumour cells
within them, or frequently of penetration of single tumour cells between adipocytes
with a fine pericellular deposition of collagen (Figure 4).
 Histiocyfoid breast carcinoma 5 19

Figure 5. Case 2. Breast lobule showing transition between classical in sifu lobular carcinoma (right)
and histiocytoid carcinoma (left). x 140.

Figure 6. Case 1. Pagetoid spread of carcinoma into a large duct; the epithelium survives as a single
flattened layer on the luminal surface (arrow); intracytoplasmic lumina simulate signet-ring cells.
H & E . x140.
520 N . Walford and J.ten Velden

Widespread in situ lobular carcinoma was present both within and around the
invasive tumour. This showed a complete spectrum of changes ranging between
classical lobular carcinoma in situ with acini filled by sheets of closely packed cells
with monotonously uniform rounded nuclei, to acini replaced by large ‘histiocytoid’
cells resembling those seen in the invasive tumour. Occasionally, transitions between
these two types could be seen within the same lobule (Figure 5). Intraductal tumour
spread was a prominent feature of case 1, sometimes taking the form of Pagetoid
spread, with a single layer of attenuated duct epithelium overlying the tumour cells
(Figure 6).
Sections from the eyelid lesion in case 2 showed extensive destruction of striated
muscle with deposition of collagen and a mixture of chronic inflammatory cells and
histiocytoid cells; sections from the skin lesion showed a scanty widely scattered
infiltrate of tumour cells throughout the dermis.

IMMUNOCY TOCHEMISTRY

Both tumours (and the eyelid deposit in case 2) stained strongly for cytokeratin, as
did normal ductal and lobular epithelium; anti-epithelial membrane antigen showed
weak diffuse cytoplasmic staining, with stronger staining of the intracytoplasmic
luminal membranes. In invasive tumour there was marked variability of membrane
staining from cell to cell, and some cells showed a polarization of staining to one
edge only. Normal ducts and lobules showed positive staining of luminal
membranes only, with no cytoplasmic staining. Staining for carcinoembryonic
antigen was uniformly negative.

Discussion

The original description of 13 cases of histiocytoid carcinoma (Hood et al. 1973)was

based entirely on histological examination of metastatic tumours in the eyelids.
These authors did not discuss the classification of the primary breast tumours,
material which they presumably had no opportunity of examining. Discussions of
the pathology (Filototico et al. 1983, Eusebi et al. 1984, Eisenberg, Bagnall &
Harding 1986, Allenby & Chowdery 1986) have usually reflected the view expressed
by Azzopardi (1979) who felt, on the basis of the illustrations and histochemical
findings of Hood er al. (1973), that these tumours probably represented a variant of
lobular carcinoma.
Our two cases support the view that histiocytoid carcinoma is indeed a variant of
lobular carcinoma. The evidence is summarized as follows. (1) The widespread
presence of in sirucarcinoma within lobules both in and around the invasive tumour.
Morphologically both tumours showed a complete spectrum of in silu changes
ranging from classical lobular carcinoma in siru through intermediate forms to a
floridly ‘histiocytoid’ appearance. (2) In situ carcinoma was also seen within ducts,
but less frequently. When present it was usually confined to a ribbon of cells
expanding the margin of the wall, and rarely filled the whole lumen in the manner
 Histiocytoid breast carcinoma 52 1

normally seen in in situ ductal carcinoma. The presence of Pagetoid spread in ducts
is another feature which, though not specific for lobular carcinoma, is highly
characteristic of it (Anopardi 1979). (3) The pattern of invasion of the invasive
components of these tumours showed features regarded as highly characteristic of
lobular carcinoma (Mqrtinez & Azzopardi 1979), with extensive ‘Indian filing’ and
‘targetoid’ growth. (4) The presence of intracytoplasmic lumina, seen in large
numbers in both the in situ and the invasive components of the tumour. Whilst not
specific for lobular carcinoma, or even for malignancy (Gad & Azzopardi 1975),
intracytoplasmic lumina are more typically seen in lobular than in ductal or other
types of breast carcinoma (Martinez & Azzopardi 1979). Furthermore, their
presence in both components of the tumour confirms the essential histogenetic
identity of the in situ and invasive components. ( 5 ) The nuclei showed many
characteristics of logular carcinoma, in respect of their bland, normochromic
appearance with finely dispersed chromatin, single eosinophilic nucleolus, and
smooth, finely contoured nuclear membrane; in addition mitotic activity was
minimal.
Some light has been shed on the nature of histiocytoid carcinoma by Eusebi and
his colleagues (1984). In three cases, one of which included an in situ component,
they demonstrated immunoreactivity of tumour cells with a monoclonal antibody
raised against GCDFP-15 protein. This protein is found in the fluid of apocrine cysts
in benign breast disease and is regarded as a marker for apocrine differentiation
(Mazoujian, Pinkus & Davis 1982). However, they reported an apparent discre-
pancy between the morphological features of the tumour and the presence of the
apocrine antigenic marker. In one of their cases, electron-dense membrane-bound
osmiophilic granules were demonstrated and were regarded as comparable to those
demonstrated in apocrine ductal carcinoma (Mossler et a/. 1980), although they
were smaller and had a different distribution.
Diagnosis of histiocytoid carcinoma in either primary or metastatic form may
present considerable difficulties. In the series of Hood eta/. (1973), at least six of the
13 eyelid metastases were originally misdiagnosed as non-malignant lesions, usually
either as sclerosing inflammatory lesions or as xanthomatous lesions, and in one
case as a granular cell tumour. When seen at an early stage even the recognition of
the malignant nature of the breast lesion can be problematical. In our case 1, in the
central part of the tumour, the presence of single, bland, histiocytoid nuclei with
inconspicuous cytoplasm, together with scattered lymphoid cells and a dense
hyalinized stroma gave an appearance easily confused with an inflammatory lesion.
Furthermore, obliteration of large ducts by fibrous plugs closely resembled the
appearance described in late stage chronic periductal mastitis (Azzopardi 1979).
However, the greatest source of confusion lay in the pattern of fat infiltration seen in
each case, where isolated tumour cells lying between adipocytes were almost
indistinguishable from inflammatory cells. It seems likely that histiocytoid car-
cinoma, either as a focal or a generalized change within lobular carcinoma, is more
common than currently thought and may be underdiagnosed. A better understand-
ing of its nature and morphology may lead to its more frequent recognition in future.
522 A? Warford and J.ten Velden

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