Breast Pathology

Histiocytoid Invasive Lobular Carcinoma

Puay Hoon Tan
Singapore General Hospital
Singapore


Clinical History
55 year old Chinese female underwent an ultrasound guided core biopsy of a left breast lesion at the 0300-0400 location, radiologically described as an 'ill-defined, predominantly hypoechoic area approximately 7x6 mm with dense shadowing - possible malignancy'.


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Figure 1
Low magnification of the breast cores showing fibroadipose stroma with sparsely scattered lobules.
Figure 2
Pale histiocyte-like cells are seen within the fibroadipose tissue.
Figure 3
A benign lobule with a few acini/ductules containing several plump rounded cells.
Figure 4
Pale histiocyte-like cells juxtaposed to benign ducts.

Figure 5
The abnormal cells show ample pale, sometimes finely vacuolated cytoplasm. An occasional cell shows an intracytoplasmic vacuole. Atypical lobular hyperplasia is noted.
Figure 6
The abnormal cells show central and eccentric, dark to sometimes vesicular nuclei, with mild to moderate pleomorphism. Percolation into fat is present.
Figure 7
The histiocyte-like cells stream around a lobule in a vaguely targetoid fashion. Atypical lobular hyperplasia is present.
Figure 8
Cytoplasmic outlines appear indistinct in some of the cells that seemingly fade into the background stroma. Cytoplasmic vacuoles are again discerned in occasional cells.

Figure 11
Immunohistochemistry for AE1/3 shows positive reactivity in the histiocytoid cells, confirming an epithelial origin of the histiocytoid cells.
Figure 12
E-cadherin is negative in the abnormal cells within the stroma supporting a lobular phenotype, while adjacent benign ductal epithelial and myoepithelial cells are positively highlighted. Lobular neoplastic cells within ductules are also negative for E-cadherin.
Figure 13
GCDFP15 is positively expressed in the abnormal histiocytoid cells.

Introduction:
Clinical history 55 year old Chinese female underwent an ultrasound guided core biopsy of a left breast lesion at the 0300-0400 location, radiologically described as an 'ill-defined, predominantly hypoechoic area approximately 7x6 mm with dense shadowing - possible malignancy'.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The core biopsies showed fibroadipose breast tissue with several sparsely scattered benign lobules. There were sheets of pale histiocyte-like cells with ample, delicate, sometimes finely vacuolated cytoplasm and inconspicuous cell membranes percolating the breast parenchyma. Nuclei of these pale cells were dark to vesicular and were centrally as well as eccentrically placed. Small nucleoli were discernible in some nuclei. Mitoses were scarce. Nuclear pleomorphism was mild to moderate. Rare cytoplasmic vacuoles were discerned. The cells were disposed individually and in loose aggregates, without obvious glandular differentiation, and occasionally streamed as linear arrays around resident benign lobules. A significant accompanying lymphocytic infiltrate was absent. A few intact breast lobules contained rounded acini that seemed minimally distended by plump, slightly discohesive cells that were relatively uniform in appearance, features of atypical lobular hyperplasia. Immunohistochemistry revealed positive reactivity of the sheets of histiocyte-like cells for AE1/3 confirming an epithelial origin. CD68, the histiocyte marker, was negative. E-cadherin was also not reactive in the abnormal cell population, contrasting against the positive staining of benign ducts and ductules. GCDFP15 was diffusely reactive. Estrogen and progesterone receptors were not expressed, and cerbB2 (HER2) showed 2+ cytoplasmic membrane staining.

Differential Diagnoses:
1. Histiocytic inflammatory reaction The sheets of pale cells present in the core biopsies of the current case resemble histiocytes, with their abundant cytoplasm and relatively banal and sometimes eccentrically placed nuclei. An inflammatory histiocytic population is often seen in association with duct ectasia in which histiocytes occupy the dilated duct lumen as well as spill out into the duct walls, sometimes effacing the lining epithelium which can be obscured by the inflammatory process, such that only a collection of histiocytes remain, which can lead to the appearance observed in this current case. Sometimes, foreign body type giant cells and cholesterol clefts may be seen, and the term xanthogranulomatous mastitis may be used to refer to this histological finding [1]. Clues to a benign histiocytic inflammatory process are the presence of other accompanying inflammatory cells like lymphocytes and plasma cells, and the generally limited localization of inflammatory cells centred around a disrupted duct. Lobular neoplasia is not a usual association. Immunohistochemically, histiocytes are negative for epithelial markers and will react positively with CD68. An exceedingly rare histiocytic process that has been described in the breast is Erdheim-Chester disease, which is a non-Langerhans cell histiocytosis of unknown etiology that more commonly affects long bones, skin, orbit, pituitary and retroperitoneum [2]. Histologically, a xanthomatous infiltrate is punctuated by Touton-type giant cells and patchy lymphocytes which sometimes zone to a perivascular location. Immunohistochemically, CD68 decorates the histiocytes, with negative reactivity for S100, CD1a and cytokeratins.

2. Fat necrosis The microscopic appearances of fat necrosis include the presence of histiocytes in relation to necrotic adipocytes. A foreign body giant cell reaction and other inflammatory cells are frequently present. Fat necrosis in the breast is often encountered in association with reactive and reparative changes in the context of a prior needling/core or surgical biopsy procedure for which the history should be readily available. However, it can also present as a spontaneous breast lump in a woman, with or without a history of breast trauma. Fat necrosis can occur post-radiation treatment for breast carcinoma [3], and very rarely, lupus panniculitis has been reported in the breast of patients with systemic lupus erythematosus [4]. The histological confusion of fat necrosis with a malignant process is particularly problematic during intraoperative frozen sections whereby nuclear atypia of reactive histiocytes can appear accentuated. The correct diagnosis is aided by identifying accompanying inflammatory cells with reactive alterations and foreign body giant cells, as well as obtaining a proper clinical history.

3. Granular cell tumor The granular cell tumor is a rare, usually benign tumor of Schwann cell derivation that can be discovered in the breast [5]. Clinically and radiologically mimicking breast malignancy, the granular cell tumor consists of sheets and nests of polygonal to occasionally spindle cells with ample cytoplasm containing eosinophilic granules that are PAS positive and diastase resistant. Some vacuolised and clear cells may be identified. Nuclei are vesicular with modest pleomorphism. Occasional distinct nucleoli are found. Nerve twigs may be observed in association with the granular cells. Immunohistochemically, the cells are positive for S100 and CEA, and are negative for estrogen and progesterone receptors. They are usually negative for histiocyte associated antigens including alpha1-antitrypsin and alpha 1-antichymotrypsin, though some reactivity for CD68 has been described. While generally benign and cured by complete excision, less than 1% of granular cell tumors are reported to be malignant. Histologically, the malignant forms display mitoses, pleomorphism, necrosis and there may be metastases [6], but instances of malignant behavior have been observed even in the absence of these microscopic features [5].

4. Rosai-Dorfman disease Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy (SHML) is primarily a nodal-based, idiopathic, benign proliferative disorder of histiocytes with 43% of these cases also involving extranodal sites. The breast is an unusual site of occurrence of RDD and can clinicoradiologically mimic cancer [7]. Histology of RDD consists of sheets of characteristic large histiocytes displaying emperipolesis, a microscopic hallmark of this disease. The predominant histiocytic population is reminiscent of the appearances of the current case. Lymphoid aggregates with germinal centres and plasma cells are frequent accompaniments. Immunohistochemistry shows cytoplasmic staining of histiocytes for S-100, often with weak positivity for CD68, while electron microscopy confirms histiocytic engulfment of lymphocytes and plasma cells. The etiology and pathogenesis of RDD are obscure, with an infective or immune mediated origin being proposed. Excision is often curative. Spontaneous resolution has also been described, though a more persistent and aggressive course has been reported. RDD of the breast tends to be resected as malignancy is often clinically and radiologically suspected.

5. Histiocytoid invasive lobular carcinoma Invasive lobular carcinoma of the breast assumes several morphological forms, for which the histiocytoid variant is an unusual and uncommon subset that comprises histiocyte- like tumor cells that harbor ample pale cytoplasm permeating the parenchyma in sheets, or in targetoid and linear patterns as in the classic variety. Apocrine morphology, more traditional invasive lobular components, and lobular neoplasia, may be identified. Percolation into fat can mimic the appearance of fat necrosis [8]. Immunohistochemistry shows positive staining of tumor cells with epithelial markers, while CD68 is negative. E- cadherin negative reactivity confirms a lobular phenotype. The close relationship with apocrine differentiation is supported by the diffuse presence of GCDFP15 positivity.

6. Invasive apocrine carcinoma This histological variety is defined by the presence of apocrine cells in >90% of tumor cells [9]. Apocrine differentiation can be observed in any type and grade of breast carcinoma, and its recognition is of no current predictive value. Two cell types are described in apocrine cancer: Type A cells which are intensely eosinophilic and contain abundant granular cytoplasm (resembling conventional apocrine cells), and Type B cells which are foamy with ample finely vacuolated cytoplasm. The latter are histiocyte-like and would be histologically synonymous with histiocytoid breast carcinoma, affirming reports of its apocrine immunophenotypic expression [10, 11]. In the current case, traditional apocrine type cells with pink cytoplasm are not an overriding feature, though it could be argued that the histiocyte-like nature of tumor cells together with GCDFP15 expression could qualify it as an apocrine cancer. The absence of E-cadherin staining in this case is consistent with a lobular phenotype.

7. Metastasis to the breast Unusually, the breast can be the site of metastatic disease [12]. Examples of metastases to the breast that can histologically display plump polygonal cells resembling the current case are renal cell carcinoma, melanoma and alveolar soft part sarcoma. Correlation with clinical history and radiological findings, together with adjunctive immunohistochemistry, can lead to the correct diagnosis.

Final Diagnosis:
Histiocytoid Invasive Lobular Carcinoma

Case Discussion:
Histiocytoid breast carcinoma was first described by Hood et al in 1973, in which 13 cases of tumor metastatic to the eyelid were documented, and where 8 of these metastases featured histiocytoid appearances that caused interpretive challenges [13]. It has since been variously ascribed to lobular or apocrine carcinoma, as well as linked to lipid-rich carcinoma. Eusebi et al noted the association of histiocytoid invasive breast carcinoma with apocrine lobular carcinoma in situ [10], and concluded that these histiocytoid cells manifested apocrine differentiation from their immunohistochemical reactivity with GCDFP15. He and co- workers later described a series of 10 aggressive pleomorphic invasive lobular cancers of which 5 included histiocytoid cells with granular foamy cytoplasm [14], and commented that apocrine differentiation in lobular carcinoma could assume typical apocrine, histiocytoid and pleomorphic appearances. In another paper describing 13 histiocytoid breast cancers, he demonstrated apocrine differentiation in all using immunohistochemistry and in situ hybridization, and cautioned about potential misdiagnoses of these cases as benign conditions [11]. Precise prognostic judgements could not be made for this group of histiocytoid breast carcinomas. Kasashima et al concurred with the controversial prognosis of lobular carcinoma with histiocytoid features, but found more frequent lymph node metastasis, shorter disease free survival and higher mortality in their 8 cases when compared with 14 age and tumor size matched examples of classic invasive lobular cancer [15]. They suggested that expression of MUC2 and MUC5AC in histiocytoid tumors augured a worse outcome. Gupta et al reported a series of 11 histiocytoid breast tumors, all of which had an invasive lobular pattern, with 8 cases showing accompanying lobular carcinoma in situ [16]. E-cadherin immunohistochemistry was negative in 8 cases, but disclosed moderate to strong membrane reactivity in the remaining 3 tumors, though the figure depicted in their paper showed incomplete membrane staining in some cells suggesting aberrant E-cadherin expression. GCDFP15 was present in all cases. Based on the presumed ductal differentiation with positive E- cadherin staining in 3 of their cases, the authors concluded that histiocytoid breast carcinoma did not belong to a specific phenotype and that both lobular and ductal origins were possible. Apart from the debate regarding the biologic affinity of histiocytoid breast carcinoma, of greater pathologic concern is its mimicry of benign and other conditions. The relatively bland cytomorphology resembles histiocytes, and especially in limited material such as core biopsies or fine needle aspirates, these tumor cells can potentially be dismissed as being of inflammatory histiocytic origin [17]. Metastases to lymph nodes and skin can also be overlooked as benign sinus histiocytes and xanthomatous dermal lesions respectively [13]. Hints to the correct diagnosis include the presence of accompanying tumor cells that are more pleomorphic and mitotically active, cells with cytoplasmic vacuoles and targetoid secretions, architectural patterns resembling those of invasive lobular cancer with linear files and concentric encirclement of lobules, associated classical invasive lobular carcinoma or lobular neoplasia, and use of adjunctive immunohistochemistry to verify the epithelial origin of lesional cells. Close clinicoradiological correlation is critical, as discordant findings on core biopsy or cytology should prompt histologic pursuit of a conclusive diagnosis on open excision. In the presence of a prior breast carcinoma, development of skin nodules comprising histiocyte-like cells should also be diligently assessed to rule out metastasis. Other differential diagnoses as described above can be excluded through close attention to microscopic findings aided by immunohistochemistry and supported by relevant clinical information.

Conclusion(s):
Histiocytoid invasive breast carcinoma is an unusual form of breast cancer, most often regarded as a variant of invasive lobular carcinoma. In this current case, the morphological appearances and lack of E-cadherin expression support its classification as a lobular cancer. Its resemblance to benign entities is a pitfall, and awareness of these mimics is needed in order to arrive at a correct diagnosis for appropriate patient management.

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