Desman, Garrett T. MD; Ozerdem, Ugur MD; Shin, Sandra J. MD
Good clinical correlation is essential for pathologists to render accurate diagnoses. Lesions arising in the breast are no exception. However, in practice, the clinical information provided with the specimen can be minimal or incomplete. For example, the anatomic site from which the abnormal finding is found may seem straightforward when dealing with lesions of the breast. However, in some cases, “breast” as a location is loosely defined as it can also mean to include neighboring sites such as the breast skin, subcutis, or axilla. In other instances, the lesion is located near the interfaces of these areas with the breast proper in which case both mammary and nonmammary entities need to be considered in the differential diagnosis. Also important but not usually provided as clinical information is pertinent past medical/surgical history as well as medication use, all of which can be pivotal in arriving at the correct diagnosis in certain cases.
With the increasing direction of subspecialization in the field of pathology, the number of practicing pathologists who are equally versed in breast and dermatologic pathology are likely to dwindle. Consequently, those who practice breast pathology would benefit from reviewing the salient dermatologic entities that can arise in areas near the breast and in addition, share morphologic features with breast entities. Needless to say, this distinction is critical as the subsequent clinical management is vastly different between some lesions originating from within and outside the breast proper.
Even for those who are diagnostically comfortable in both areas, evaluating initial samplings which are invariably obtained through either needle core or skin punch biopsies can be challenging due to the limited amount of material obtained for interpretation. The diagnostic pitfalls of rendering diagnoses on material representing partially sampled lesions are well known and further augment the already elevated level of diagnostic difficulty.
In this paper, we review the clinical and histopathologic features of cutaneous neoplasms known to arise within the vicinity of the breast and discuss the various breast entities that may fall within the histopathologic differential diagnosis. In addition, distinguishing features either morphologically and/or immunohistochemically are highlighted among these similarly appearing lesions when present.
PSEUDONEOPLASTIC LESIONS OF SWEAT GLANDS
Occasionally, hamartomatous and reactive sweat gland proliferations may mimic neoplastic disease, which may pose a significant diagnostic dilemma when limited clinical history is provided.
The apocrine nevus is a rare hamartoma composed of excess normal apocrine sweat glands most often presenting as an axillary swelling. Hyperhidrosis is typically not a feature. Lesions present at birth or during early adulthood and may be bilateral. A case of apocrine carcinoma arising in association with an apocrine nevus in an elderly patient has been reported.1 In addition, an occasional association with syringocystadenoma papilliferum has been reported. Histopathologic features include excess mature apocrine glands within the deep dermis and often times extending into the subcutaneous fat.
Share Histologic Features With: Apocrine cysts or apocrine metaplasia. If the axillary site is known, the possibility of these changes arising in ectopic breast tissue should be excluded.
Distinguishing Features Include: Apocrine glands whether normal or forming a nevus are typically clustered together with lumens that are mildly to moderately cystic if at all. Apocrine cysts tend to be solitary and larger in comparison. Proximity to the dermis can be helpful which favors apocrine glands over apocrine cysts.
The eccrine nevus, also referred to as nevus sudiferous, is a rare hamartoma composed of excess eccrine sweat glands with heterogenous clinical features most commonly presenting on the upper extremity. Unlike the apocrine nevus, localized hyperhidrosis (often unilateral) is a common finding and may be the only clinically appreciable finding.2 Additional clinical presentations include solitary or linear grouped papules, nodules, and plaques with a frequent tan-brown discoloration.3–5 Like the apocrine nevus, they may occasionally be bilateral.5 Lesions present during early childhood or adolescence. Histopathologic features include increased numbers and/or enlarged eccrine secretory coils. Eccrine nevi are characterized by increased size or number of eccrine coils. Occasionally, the eccrine coils may be surrounded by abundant mucin, in which case they are referred to as mucinous eccrine nevus.
Share Histologic Features With: Mammary lobules with apocrine or clear cell change.
Distinguishing Features Include: It may be difficult to distinguish by morphologic features alone, but the mixture of clear cells and dark cells, both normal components of eccrine sweat glands, is helpful. In contrast, mammary lobules show a single morphologic cell populace.
Changes similar to that seen in hamartomatous eccrine and apocrine nevi have been reported in foci adjacent to neoplasms such as squamous cell carcinoma (SCC), basal cell carcinoma, and malignant melanoma, as well as chronic inflammatory conditions with resultant fibrosis and/or sclerosis such as scarring alopecia and infection.6 Bilateral lesions associated with various medications such as nonsteroidal anti-inflammatory and chemotherapeutic drugs (doxorubicin, tamoxifen) have been reported that exhibit syringoma-like features, occasionally exhibiting squamous metaplasia of eccrine and apocrine sweat ducts and mucin-producing glandular cells.7–9 Similar lesions have been reported in association with chronic radiation dermatitis. Idiopathic cases are rare but have been documented.10
TUMORS OF THE SURFACE EPITHELIUM
Basal Cell Carcinoma
Basal cell carcinoma is the most common malignant neoplasm in humans. It is strongly associated with chronic UV light exposure, however, tumors may arise essentially anywhere on the body including the breast and axilla.11 Clinically, tumors may present as red pearly papules or in some cases indurated plaques. Many dermatopathologists subclassify basal cell carcinomas based on their dominant growth pattern: superficial, nodular, infiltrative, micronodular, desmoplastic, and metatypical.12 The aggressive patterns (infiltrative, micronodular, desmoplastic, and metatypical) frequently invade into the deeper aspects of the dermis or subcutis where perineural invasion is common.13 Although there is a risk of locally aggressive disease, distant metastasis is extremely rare. One exception to this rule is the metatypical type of basal cell carcinoma, which has mixed basal and squamous differentiation and is frequently referred to in the literature as basosquamous carcinoma. The risk of metastatic spread is similar to that of primary cutaneous SCC.14 Histomorphologic features of basal cell carcinoma include nests or infiltrative cords of basaloid cells with frequent mitoses and single cell necrosis. The most characteristic features are peripheral palisading of tumor nuclei, tumor-stromal retraction artifact, and accumulations of dermal mucin within the tumor and retraction cleft. The desmoplastic pattern of growth typically lacks these characteristic features as the tumor cells are compressed within dense collagenous stroma, and hence is the form of basal cell carcinoma most likely to mimic a breast carcinoma on core needle biopsy (Fig. 1A). Immunohistochemical stains will reveal the tumor cells to express keratins associated with follicular epithelium of the hair bulge, namely BerEP4. Other positive markers include bcl-2, CD10, p53, AR, and p63.15–20
Share Histologic Features With: Invasive mammary carcinoma (Fig. 1B).
Distinguishing Features Include: Differences in immunohistochemical staining patterns can be helpful if morphologically ambiguous. Basal cell carcinomas are typically positive for p63 and negative for CK7 and estrogen receptor (ER), whereas invasive mammary carcinomas are CK7+/p63− and ER+/−.
Fibroepithelioma of Pinkus
Fibroepithelioma of Pinkus is an uncommon variant of basal cell carcinoma that most commonly arises on the trunk and thigh, however, cases involving the breast and nipple have been reported21,22 (Fig. 1C). Clinically, the tumors most often resemble a fibroepithelial polyp, however, multiple firm indurated nodular plaques may develop in sites treated with prior radiation. Histopathologic features include 2 to 3 layers of basaloid epithelial cell forming anastomosing strands that descend from the epidermis, compartmentalized by a fibrous spindle cell stroma. The tumors characteristically lack stromal retraction artifact and dermal mucin, but frequently exhibit single cell necrosis. Ductular elements are absent. Immunohistochemical stains reveal the tumor cells to express BerEP4 and AR, similar to basal cell carcinomas.23 Ki-67 reveals a low proliferation index and p53 expression is weak. CK20 staining reveals retention of intratumoral Merkel cells analogous to trichoblastoma (TBL).24
Share Histologic Features With: Fibroepithelial lesions (fibroadenoma, benign phyllodes tumor) (Fig. 1D).
Distinguishing Features Include: Immunohistochemical stains may be helpful. Basaloid epithelial cords are nonreactive for CK7 and ER, whereas the glandular component of fibroepithelial lesions arising in the breast are immunoreactive for CK7 and at a minimum, also show scattered ER positivity.
Squamous Cell Carcinoma
Cutaneous SCC is the second most common cutaneous malignancy. The majority of cases are associated with chronic UVB exposure and less commonly HPV infection.25 These tumors most commonly present as an indurated slow-growing plaque or nodule with occasional ulceration. The overall 5-year metastasis rate is 5.2%, however, the rate is much higher for the ear and lip (11% and 13.7%, respectively). Features that are associated with an aggressive clinical course include: tumor diameter >2 cm, tumor depth >0.4 cm, tumors arising within chronic ulcers or sites of prior radiation, neurotropism, and immunosuppression.26 Poorly differentiated, nonkeratinizing tumors generally have a worse prognosis than well-differentiated, keratinizing tumors. The vast majority of invasive SCCs arises from an epidermal in situ carcinoma and therefore would rarely be mistaken for mammary carcinoma. As a general rule, dermal nodules of SCC without an in situ component or connection with the overlying epidermal surface must be considered possible metastases. However, a few special types may arise as invasive SCC without an overlying in situ component or connection with the epidermal surface. Follicular SCCs are a rare variant of cutaneous SCC that most commonly arise in the head and neck region, however, other locations may be encountered. These tumors arise from the follicular outer root sheath epithelium and form nodules of invasive carcinoma in the dermis that may only reveal connection with a hair follicle after numerous deeper sections have been obtained.27 In addition, invasive SCC may arise within an epidermoid (epidermal inclusion) cyst.28 Finally, invasive SCC may arise in a background of lichen simplex chronicus or lichen sclerosus, in which case the tumors frequently exhibit an invasive growth pattern extending downward from an epidermis without overlying in situ carcinoma.29 The histopathologic features of SCC vary depending on the degree of differentiation. Well-differentiated tumors are easily recognizable with infiltrating cords and nests of large epithelioid cells containing abundant eosinophilic cytoplasm, intercellular bridges, mitoses, and mild nuclear pleomorphism. Poorly differentiated tumors may be difficult to distinguish from adenocarcinomas and are generally composed of cells with basophilic to amphophilic cytoplasm. The presence of intercellular bridges may be the only recognizable feature revealing squamous derivation. Occasionally, SCC may exhibit acantholysis producing intratumoral cleft-like spaces, which may mimic the luminal structures of adenocarcinomas. Immunohistochemistry will reveal the tumor cells to express K903, CK5/6, and p63.30 The acantholytic spaces will be negative for EMA and CEA.
Share Histologic Features With: Mammary squamous carcinoma, primary.
Metaplastic carcinoma, squamous type.
Distinguishing Features Include: The distinction between primary cutaneous and mammary squamous carcinoma may be impossible in a limited sampling if connection to the overlying epidermis or coexisting squamous carcinoma in situ are not seen. Primary mammary squamous carcinomas are exceedingly rare and evidence of its origin from a breast cyst is needed for diagnosis.
The vast majority of cases of metaplastic carcinoma with squamous differentiation show intertwining tumor cells of squamous and spindle cell morphologies which is less commonly seen in cutaneous SCCs. Concurrent in situ carcinoma is generally uncommon in metaplastic carcinomas.
Merkel Cell Carcinoma
Neuroendocrine carcinoma of the skin, also referred to as Merkel cell carcinoma, is a rare but highly aggressive tumor that most commonly arises in chronically sun damaged skin. Tumors most commonly arise in elderly white patients as a firm raised painless nodule that usually measures ≤2 cm in diameter and slowly increases in size on the head and neck and extremities, however, any location may be affected.31 Ulceration is uncommon. The local recurrence rate is approximately 40% and the overall 5-year survival rate for distant disease is 75%. Although a staging system has been proposed by the American Joint Committee on Cancer, the 5-year survival for stage I disease is only 81%. Wide local excision combined with adjuvant radiotherapy may improve locoregional control of the disease as well as relapse-free survival. Sentinel lymph node biopsy is recommended due to the high incidence of lymph node metastasis. The precise pathogenesis is unknown, however, there is a higher incidence in patients with chronic UV radiation exposure and immunosuppression.32 Recently, the presence of Merkel cell polyomavirus has been found in a significant subset of these tumors suggesting an infectious etiology.33 Histologic features consist of dermal, and less frequently subcutaneous nodules composed of basophilic cells with vesicular nuclei containing small nucleoli (Fig. 1E). Nuclear molding, crush artifact, numerous mitoses, and individual tumor cell necrosis are common. In addition to a nodular growth pattern, the tumor cells may exhibit a trabecular pattern in which tumor cells dissect in between collagen bundles. Intraepidermal colonization of tumor cells may be seen in up to 10% of cases. Immunohistochemistry reveals characteristic perinuclear staining of CAM5.2 and CK20 within tumor cells. Additional commonly positive markers include neuron-specific enolase, chromogranin, synaptophysin, CD56, CD57, and EMA. Vimentin and S-100 protein are negative. Rare cases may express CK7 and TTF-1, therefore making the distinction from metastatic small cell carcinoma of the lung difficult.34
Share Histologic Features With: Mammary small cell carcinoma (Fig. 1F).
Distinguishing Features Include: Mammary small cell carcinomas are not known to exhibit perinuclear staining with CK20. Also, adjacent in situ carcinoma may be present which supports a mammary origin. In situ carcinoma can be small cell type or solid type with high nuclear grade.
Trichoblastoma (TBL) is a biphasic follicular neoplasm composed of both basaloid germinative follicular epithelium and condensed perifollicular stroma reminiscent of the primitive hair papilla. TBL may arise in any location where the skin contains hair. The tumors clinically present as a nonspecific nodule.35,36 Occasional giant forms have been reported. Histopathologically, these tumors have a propensity to arise within the deep dermis or subcutis and are characterized by anastomosing cords, sheets, and clusters of basaloid epithelium surrounded by a cellular stroma (Fig. 2A). Focal hair differentiation is usually identified in which the masses of basaloid cells are indented by the stroma, recapitulating the hair bulb. Occasionally, the basaloid cells may contain melanin pigment.37
Share Histologic Features With: Invasive mammary carcinoma.
Mammary adenoid cystic carcinoma (ACC), solid variant with basaloid features (Fig. 2B).
Distinguishing Features Include: Clusters of basaloid epithelium in a polarized arrangement is a feature not seen in invasive mammary carcinoma. Although the basaloid appearance of the cells is reminiscent of the solid variant (with basaloid features) of ACC, the absence of other features such as marked nuclear atypia, mitoses, intercalated ducts, and false lumens with basement membrane material essentially excludes this possibility.
BENIGN AND MALIGNANT SEBACEOUS NEOPLASMS
Sebaceoma, Rippled Pattern
Benign sebaceous neoplasms are categorized based on the proportion of basaloid germinitive cells and clear sebocytes. Sebaceous adenomas consist of lobules of sebocytes surrounded by 2 or more peripheral layers of germinitive cells yet accounting for <50% of the total cell populace.38 Sebaceoma was first described by Troy and Ackerman39 as a distinct neoplastic entity separate from sebaceous adenoma, basal cell carcinoma with sebaceous differentiation, and sebaceous carcinoma. Although these tumors most commonly arise on the head and neck, involvement of the chest has been documented. Clinically, these tumors present as yellow to skin-colored nodules most commonly in females in their sixth to ninth decade of life. Like most sebaceous neoplasms, there is an association with Muir Torre syndrome and microsatellite instability. Histopathologic features consist of lobules composed of disorganized mixtures of sebocyte clusters and germinitive cells in excess of 50% of the total cell populace. The tumors are usually confined to the dermis and characteristically connect with the overlying epidermis, but may also extend into the subcutaneous fat. Peripheral palisading of nuclei and stromal retraction artifact are absent. Occasionally, the tumor cells may exhibit a reticulated growth pattern where aligned tumor cell nuclei simulate the Verocay bodies of schwannomas or carcinoid tumors40 (Fig. 2C). Immunohistochemical staining will reveal tumor cell staining for p63, D2-40, and EMA, as well as variable staining for CK7. Tumor cells are characteristically negative for BerEP4.16,41–43
Share Histologic Features With: Invasive duct carcinoma, poorly differentiated.
ACC, solid variant with basaloid features (and basement membrane deposition) (Fig. 2D).
Distinguishing Features Include: If morphologically ambiguous and lack of connection with the overlying epidermis cannot be confirmed, immunohistochemical stains may be helpful. Immunoreactivity for p63 and D2-40 is characteristic of sebaceomas but not invasive mammary carcinomas. The presence of in situ carcinoma is helpful in supporting a mammary origin.
Extraocular Sebaceous Carcinoma
Sebaceous carcinomas are generally divided into ocular and extraocular types, however, their biological behavior appears to be similar with a risk of 30% to 40% for local recurrence, 25% to 35% for distant metastasis, and 10% to 20% for death from disease. Extraocular sebaceous carcinomas are more rare than the ocular type and typically present as painful or rapidly growing nodules on the trunk, genitalia, and extremities that may ulcerate.44–48 Breast and nipple lesions are well documented in the literature.47,48 A significant percentage of these tumors, especially extraocular, are associated with microsatellite instability and Muir Torre syndrome.49–51 The histopathologic features include closely arranged aggregates of infiltrative lobules composed of polygonal cells with variable cytomorphology. Well-differentiated tumors exhibit vacuolated clear cytoplasm, hyperchromatic nuclei with discernible nuclei, and occasional mitoses. Poorly differentiated tumors exhibit marked nuclear pleomorphism, prominent nucleoli, numerous mitoses, and amphophilic to basophilic cytoplasm. Central comedo-like tumor necrosis is common (Fig. 2E). All sebaceous carcinoma have the ability to colonize the overlying epidermis mimicking mammary or extramammary Paget’s disease. Currently, no immunohistochemical stain specific for sebaceous differentiation exists. In general sebaceous carcinomas are characteristically negative for the common markers expressed in other sweat gland tumors and metastatic visceral malignancies, such as CEA, S-100 protein, GCDFP-15, CA-125, and CA-19. The tumor cells are positive for EMA and androgen receptor with variable BerEP4 expression.42,52,53 In addition, immunoreactivity for HER-2 has been reported.54
Share Histologic Features With: Ductal carcinoma in situ (DCIS), solid type with high nuclear grade, central necrosis, and focal clear cell features (Fig. 2F).
Paget’s disease if the overlying epidermis is involved.
Distinguishing Features Include: Morphologically, if the presence of sebaceous differentiation is obvious, this finding strongly favors extraocular sebaceous carcinoma as such changes are only rarely seen in cases of invasive carcinomas or malignant phyllodes tumor.
Immunoreactivity for GCDFP-15 in mammary Paget’s disease is helpful as sebaceous carcinomas are negative for this stain.
BENIGN APOCRINE NEOPLASMS
Apocrine hidrocystomas are cystic dilatations of apocrine sweat ducts with variable epithelial hyperplasia most commonly arising on the face, however, axillary involvement has been documented.55 Lesions with micropapillary intraluminal hyperplasia are referred to as cystadenomas.56 Clinically, these lesions present as skin-colored to bluish, translucent papules, or nodules. Histopathologic features include a cystic dilatation lined by 2 layers of cuboidal to columnar cells with apical decapitation secretion (snouts)57 (Fig. 3A). Cystadenomas frequently exhibit micropapillary projections into the cyst lumen.
Share Histologic Features With: Cystic apocrine metaplasia or cystic papillary apocrine hyperplasia (Fig. 3B).
Distinguishing Features Include: Morphologic distinction may be impossible. Identifying neighboring mammary glands to confirm the location of the lesion would be most important. If arising in the axilla, the presence of mammary glands would suggest apocrine metaplasia in ectopic breast tissue.
Syringocystadenoma papilliferum is a unique lesion that most commonly arises on the scalp in association with a nevus sebaceous of Jadassohn, however, numerous sporadic tumors arising in the breast and axilla have been reported.58,59 Rarely, an extracranial linear or agminated configuration may be encountered.60,61 The tumors are typically skin-colored papules or nodules that contain a central dell. The histopathologic features include duct or tubular structures extending downward from the epidermis ending in a cystic dilatation containing papillary structures whose fibrovascular cores contain numerous plasma cells (Fig. 3C). The tubules, cyst, and papillary structures are lined by cuboidal to low columnar glandular cells that often exhibit apical decapitation secretion (snouts) (Fig. 3D).
Share Histologic Features With: Sclerosing adenosis (if tubular proliferation component sampled).
Invasive duct carcinoma, well differentiated (if tubular proliferation component sampled).
Papilloma (if papillary component sampled) (Fig. 3D: inset).
Distinguishing Features Include: Like sclerosing adenosis, the tubular structures of syringocystadenoma papilliferum are lined by myoepithelium and therefore would be immunoreactive for p63 and other myoepithelial markers. Distinction between these 2 entities may be particularly difficult and would rely heavily on clinical correlation (ie, connection with the overlying epidermis) if sampling is scanty. Invasive duct carcinoma lacks a myoepithelial layer and therefore, differential staining using myoepithelial markers would be helpful. Also, identifying numerous plasma cells in the fibrovascular cores of syringocystadenoma papilliferum should be helpful as this is not typically seen in papillomas.
Mixed tumor of the skin, also referred to as chondroid syringoma, is a benign adnexal neoplasm that most commonly arises on the head and neck as a nondescript dermal or subcutaneous nodule, however, cases involving the breast and axilla are well documented.62–64 This tumor is the prototype for the frequent biphasic nature of benign cutaneous adnexal neoplasms, in which the tumor stem cells undergo divergent differentiation into dissimilar tissue types.65 The characteristic histopathologic features include a well-circumscribed dermal or subcutaneous nodule composed of benign epithelial cords, nests, and tubuloalveolar structures embedded in a variable stromal matrix of cartilaginous, fibroblastoid, myoid, myoepithelioid, lipoid, or even osteogenic appearance (Figs. 3E, F). The epithelial component may exhibit eccrine, apocrine, sebaceous, pilar, mucinous, clear cell, spindle cell, or simple glandular differentiation.66,67 Variable mixtures of these elements may be present within a single tumor. Most tumors are currently classified as apocrine type. The tubuloalveolar structures are believed to represent secretory coil differentiation and are lined by 2 layers of cells; basolateral myoepithelial cells and apical cuboidal to low columnar secretory cells with frequent decapitation secretion. Two interesting combinations of elements include: chondroid stroma with scattered solitary plasmacytoid myoepithelial cells and dense hyalinized stroma with compressed tubuloalveolar structures, resembling sclerosing adenosis of the breast.68 The overall features reassuring of benignity are the well-circumscribed tumor growth combined with the absence of nuclear pleomorphism, mitoses, and necrosis. Tumors with small trailing elements beyond the tumor capsule or foci with enhanced cytologic atypia, usually of the myoepthelial cells, are referred to as atypical mixed tumors, however, they display a benign clinical course.66 Immunohistochemical stains will frequently reveal the apical epithelial cell layer to express AE1/AE3, EMA, CEA, and GCDFP-15, CD117, CK7, and AR, whereas the myoepithelial layer will express p63, vimentin, S-100 protein, and sometimes SMA. Stromal cells are vimentin and S-100 protein positive. Typically, there is no immunoreactivity for GCDFP-15, ER, PR, or CK20.69,70
Share Histologic Features With: Benign mixed tumor of breast (pleomorphic adenoma).
Metaplastic carcinoma, matrix producing type.
Invasive mucinous carcinoma.
Sclerosing adenosis (some cases depending on sampling).
Distinguishing Features Include: Both benign mixed tumor of breast and matrix producing metaplastic carcinoma contain myxocartilaginous differentiation. In contrast with chondroid syringomas, examples of the former typically show relatively lower overall cellularity and in the latter, some degree of nuclear atypia is evident. The spatial arrangement of carcinoma cells and mucin in cases of invasive mucinous carcinoma is dissimilar to that seen in tumors with myxocartilaginous differentiation (including chondroid syringoma), however, this can be very difficult to discern in limited samplings. Also, invasive mucinous carcinomas are commonly positive for estrogen receptor unlike chondroid syringomas.
Papillary Eccrine Adenoma and Tubular Apocrine Adenoma
Papillary eccrine adenoma is a rare dome-shaped nodule or plaque that occurs most commonly in African American females and almost exclusively on the extremities. The histopathologic features include aggregated ductular structures within the dermis lined by uniform polygonal basaloid cells that frequently form intraluminal micropapillary structures without fibrovascular cores.71 The tumor may connect with the overlying epidermis via colonization of the eccrine duct or through neoplastic duct-like structures. By definition, apocrine decapitation secretion is absent. An equivalent lesion with apocrine differentiation, referred to as tubular apocrine adenoma or tubulopapillary adenoma, most commonly occurs on the scalp but has been well documented in the axilla. These tumors frequently arise within preexisting nevus sebaceous or syringocystadenoma papilliferum, and malignant degeneration into apocrine carcinoma has been reported.72 These tumors exhibit apocrine decapitation secretion. Rare cases of mixed apocrine and eccrine differentiation have been documented.73 In tubular apocrine adenoma, the tumor may also connect with the epidermal surface through columns of cells that superficially resemble the normal sweat duct. Ductal spaces in these structures may contain luminal eosinophilic cuticles. The cytologic features are benign (Fig. 3G).
Share Histologic Features With: Apocrine cysts or apocrine metaplasia.
Ductal hyperplasia, micropapillary pattern (Fig. 3H).
Distinguishing Features Include: It may be impossible to distinguish by morphologic features. Ascertaining the location of the lesion is very important in this case. If found to be arising in the axilla, the presence of uninvolved breast tissue may favor proliferative fibrocystic changes arising in ectopic breast tissue.
MALIGNANT APOCRINE TUMORS
Apocrine carcinomas are rare with most reported cases involving the axilla and occasionally the chest and nipple.74,75 They can occur in other locations including the scalp, eyelid, ear, anogenital region, and wrist. Tumors typically present as solitary or multiple slow-growing nodules or plaques that frequently ulcerate and have been reported to be present for 30 years before diagnosis.74 There is a wide age range and no predilection for race or sex. Cases of bilateral axillary carcinoma associated with apocrine hyperplasia have been reported, as well as carcinomas arising within tubular apocrine adenomas and syringocystadenoma papilliferum.76,77 Intralymphatic cutaneous metastatic disease similar to that of inflammatory breast carcinoma has also been described.78 In regards to the histopathology, apocrine carcinomas characteristically exhibit morphologic plasticity, often revealing foci with varying differentiation, making the distinction of primary cutaneous carcinoma versus cutaneous metastasis extremely difficult.
In general there are 5 types of apocrine carcinoma with reproducible histomorphology. Two forms may be reliably diagnosed as primary cutaneous malignancies: ductopapillary apocrine adenocarcinoma (DPAC) and the apocrine type of mammary or extramammary Paget’s disease. The other 3 forms closely mimic metastatic adenocarcinoma: ductal apocrine adenocarcinoma (DAA), primary cutaneous mucinous carcinoma, and primary signet-ring cell carcinoma of the skin.
Ductopapillary Apocrine Adenocarcinoma
DPAC is essentially histopathologically identical to aggressive digital papillary eccrine adenocarcinoma with infiltrative growth of tubules and perineural and intravascular invasion, however, the tumor cells contain eosinophilic cytoplasm, with or without apical decapitation “snouts.”79 Micropapillary structures protruding into the lumens are a characteristic feature. Cytologic atypia is usually obvious with frequent mitoses. In addition, unlike its eccrine digital counterpart, these tumors most frequently arise within the eyelids, axilla, and genitoperineal skin. Regional lymph node involvement followed by distant metastasis is seen in approximately 40% of cases.79 Histochemical stains that are helpful in establishing apocrine differentiation include Prussian, blue, which will reveal intracytoplasmic iron deposition in 40% to 50% of cases. Immunohistochemical stains reveal strong and diffuse expression of GCDFP-15. Unlike most primary cutaneous tumors, the tumor cells are frequently negative for p63.
Share Histologic Features With: Invasive duct carcinoma, apocrine features.
Ductal carcinoma in situ, papillary and apocrine.
Distinguishing Features Include: Well-formed tubular formation or micropapillary configuration coupled with marked cytologic atypia and frequent mitoses is a combination of morphologic features uncommon to most invasive duct carcinomas. With that said, this distinction is largely impossible and the main compartment where the tumor resides is the best clue.
Ductal Apocrine Adenocarcinoma
DAA shares many similarities with ductal eccrine adenocarcinoma in which the tumor is arranged in randomly oriented infiltrative nests and cords with or without luminal structures. The luminal structures may be solitary or in a cribriform arrangement (Fig. 4A). Invasion into the subcutis with perineural and lymphovascular invasion is a common finding. The tumor cells of DAA contain eosinophilic cytoplasm and decapitation secretion. Obvious cytologic atypia, mitotic activity, and spontaneous tumor cell necrosis are constant findings. The clinical, histochemical, and immunohistochemical features are identical to DPAC. In fact, the only distinguishing feature from DPAC is a more solid growth pattern and the absence of luminal micropapillary structures.74,80
Share Histologic Features With: ductal carcinoma in-situ, cribriform, apocrine (Fig. 4B).
Invasive mammary carcinoma.
Distinguishing Features Include: The distinction may be impossible, particularly in limited samplings, as they share similar morphologic as well as immunohistochemical profiles including negativity for estrogen receptor and progesterone receptor if apocrine appearing. Both entities can also be positive for androgen receptor.
MALIGNANT MUCINOUS CARCINOMA
Primary cutaneous mucinous carcinoma is a distinctive tumor most commonly occurring on the head and neck, however, cases arising in the axilla, chest wall, and breast are well documented. The tumors present as slightly discolored nodules that occasionally have a soft consistency with a high rate of local recurrence but relatively low rate of regional lymph node metastasis.81 These tumors arise de novo without an associated benign counterpart, making histopathologic distinction from mucinous carcinoma of the breast extremely difficult. Occasionally, connection with the overlying epidermis provides the evidence for primary cutaneous derivation. The typical histopathologic features include large extracellular pools of epithelial mucin in the dermis and occasionally the subcutis. The mucin pools typically dissect through the tissue and contain irregular nests and small clusters of amphophilic polygonal cells with oval nuclei and small nucleoli (Fig. 5A). Mitoses and perineural and lymphovascular invasion are rare. The mucin stains with mucicarmine, colloidal iron, alcian blue, and PAS with diastase. Immunohistochemistry reveals the tumor cells to express CK7, p63, GCDFP-15, ER, and PR.82,83 Similar to mucinous carcinomas of the breast, cutaneous mucinous carcinoma may show neuroendocrine differentiation with tumor expression of synaptophysin and chromogranin.84
Share Histologic Features With: Invasive mucinous carcinoma of the breast (Fig. 5B).
Distinguishing Features Include: Identifying the presence of coexisting ductal carcinoma in situ with mucin production would confirm a mammary origin. Alternatively, connection to overlying epidermis would confirm its cutaneous origin. Diffuse and strong immunoreactivity for p63 is typical of primary cutaneous mucinous carcinoma but not those arising in the breast.
BENIGN ECCRINE TUMORS
Syringoma is a benign proliferation of eccrine ducts that may be localized or generalized. There is debate as to whether they are hamartomatous versus neoplastic lesions. The localized form usually is multifocal presenting as small clustered white-yellow papules on the upper face (ie, lower eyelids), axilla, and genitalia. Solitary lesions do exist, in which case complete excision is required to rule out microcystic adnexal carcinoma (MAC). There is a generalized and eruptive form, which most commonly presents on the chest, neck, and forearms.85 Familial inheritance has been documented. The histopathologic features include small, comma-shaped tubules, or cords embedded within a collagenous stroma (Fig. 6A). The tubules are lined by 2 or more layers of polygonal or flattened cells with clear to eosinophilic cytoplasm and monomorphic nuclei without nucleoli. Mitoses and infiltrative growth are absent.86 The tubules are internally lined by a bright eosinophilic cuticle and contain eosinophilic to amphophilic secretions. A clear cell variant associated with diabetes exists in which the cells are enlarged and contain clear glycogen-rich cytoplasm.87 Immunohistochemistry reveals antigen expression similar to that of normal eccrine ducts with EMA in peripheral cells, CK10 in intermediate cells, and CK6, CK19, and CEA in luminal cells. Expression of ER and PR is consistently negative.88
Share Histologic Features With: Low-grade adenosquamous carcinoma (Fig. 6B).
Distinguishing Features Include: Low-grade adenosquamous carcinomas are known to arise within mammary parenchyma (not superficially), therefore, the presence of adjacent uninvolved breast tissue would favor this diagnosis. Also, these tumors are typically associated with a chronic lymphocytic infiltrate (as aggregates or diffusely) which is not characteristic of syringomas. Syringomatous adenoma commonly arise in the nipple or retroareolar region; locations which should be discernible clinically from the superficial chest. Syringomatous adenoma and low-grade adenosquamous carcinoma are typically solitary lesions, whereas syringomas occur in a multifocal manner. Low-grade adenosquamous carcinoma characteristically have an infiltrative tumor border, however, this feature may not be readily appreciated in small samplings.
Poroma/Dermal Duct Tumor
Eccrine poroma encompasses benign tumors that arise within the eccrine sweat duct. Some authors have proposed occasional apocrine derivation, which seems to be much ado about nothing. Tumors that arise within acrosyringia, where the sweat duct enters the epidermis, are referred to as hidroacanthoma simplex, whereas tumors that arise within the dermal duct are referred to as dermal duct tumor. Frequently, both intraepidermal and dermal tumor nodules are present, in which case they are referred to simply as poroma.89 Clinically, the tumor typically presents as a brownish raised friable papule or plaque with sharp demarcation or peripheral moat-like change on skin with high concentration of sweat glands. The soles of the feet are most commonly affected, however, cases involving the chest and breast have been documented.90,91 Cases have been associated with chronic radiation dermatitis.92 The histopathologic features of hidroacanthoma simplex include intraepidermal “lakes” of compact, monotonous polygonal cells with bland nuclei and small amounts of amphophilic cytoplasm, resembling “mosaic tiles.” Peripheral palisading of the nuclei is not a feature. Small punched-out duct-like structures are randomly dispersed throughout the tumor. Mitoses are rare.93 The dermal duct tumors have a similar cytomorphology with large lobules containing duct-like structures in the dermis (Figs. 6C, D). The characteristic surrounding stroma is fibrovascular. Immunohistochemical stains reveal the tumor cells to express CK7 and p63 with EMA and CEA highlighting the duct-like foci.94,95
Share Histologic Features With: ductal carcinoma in-situ, solid papillary (Fig. 6E).
Distinguishing Features Include: Poromas/dermal duct tumors are diffusely and strongly positive for p63 (Fig. 6F), whereas DCIS demonstrate staining only along its perimeter (myoepithelial layer). Like DCIS, poromas/dermal duct tumors are also strongly positive for CK7 (Fig. 6G).
Eccrine cylindroma is a benign eccrine neoplasm that is most commonly encountered in the skin of the face, head, and neck of young adults as a solitary nodule. Multifocal disease is associated with the autosomal dominant Ancell-Spiegler syndrome, which has been mapped to the CYLD1 gene on chromosome 16q12-13.96,97 A rare form arising in the breast parenchyma is morphologically and immunohistochemically identical to the cutaneous counterpart.98 More recently, the recurrent t(6;9)(q22∼23;p23∼24) translocation resulting in a fusion of 2 transcription factor genes MYB and NFIB, which has been identified in ACC of the breast and head and neck has been demonstrated in several cases of cutaneous cylindromas by RT-PCR and/or immunohistochemistry (MYB).99 The histopathologic features consist of angular nests that are molded to one another in a “jigsaw puzzle” configuration (Fig. 6H). The nests are surrounded by dense eosinophilic basement membrane material. Globules of this material are frequently scattered within the nests. The nests are composed of 2 cell populations: compact basaloid cells and polygonal cells with amphophilic cytoplasm. Nucleoli are inconspicuous and mitotic activity is rare. Small buds of tumor trailing off from the main lesion are common and should not be interpreted as malignant transformation. In some cases, morphologic overlap with spiradenomas can be appreciated. Immunohistochemistry reveals the basaloid cells to express p63 and the amphophilic cells to express CK7. The tumor cells are consistently negative for ER, PR, and HER-2/neu.100
Share Histologic Features With: Mammary ACC, conventional type (Fig. 6I).
Distinguishing Features Include: Mammary ACCs exhibit cytologic atypia and mitoses, whereas cutaneous cylindromas are bland and without mitoses. If appreciated in a limited sampling, ACCs commonly show an invasive tumor border unlike cutaneous cylindromas which are well demarcated. Cylindromas arising in the skin and breast are morphologically indistinguishable, however, those occurring in the latter site are extremely rare (<10 cases reported in the literature). ACCs are typically positive for c-kit (CD117), whereas this stain has not been studied well in cylindromas (cutaneous or mammary).
Nodular Eccrine Hidradenoma/Clear Cell Hidradenoma
Hidradenoma (acrospiroma) is a benign tumor that most frequently presents as a solitary nodule or cystic lesion at essentially any location. The pathogenesis is uncertain, however, most cases exhibit evidence of eccrine differentiation.101 Occasional cases with apocrine, squamous, and mucinous differentiation have been reported.102,103 The tumor cells may have amphophilic or clear cytoplasm and are referred to as nodular hidradenoma and clear cell hidradenoma, respectively. The histopathologic features include well-circumscribed nodules surrounded by a fibrovascular or hyalinized stroma in the deep dermis or occasionally, the subcutis. Connection with the overlying epidermis may be seen. Approximately 50% of cases harbor the chromosomal translocation t(11:19); particularly the clear cell variant. An additional subset of tumors exhibit the chromosomal translocation t(6:22). Rare cases arising within the breast parenchyma with a t(11:19) translocation have been reported.104 The nodules may be solid, contain duct-like structures, or cystic. The tumor has a biphasic cellular population with round or polygonal cells with amphophilic cytoplasm and vesicular nuclei containing nuclear grooves and conspicuous nucleoli, and clear cells containing eccentric small hyperchromatic nuclei (Fig. 6J). The dominant cell type determines the adjectival modifier of “nodular” versus “clear cell” hidradenoma.105–107 Occasionally, the dense hyalinized stroma may result in angular arrangements of the tumor nodules, imparting a “pseudoinvasive” growth pattern (Figs. 6K, L). Mitoses are rare. Although local recurrence is rare, tumor nodules that exhibit budding or irregular peripheral cords, focal nuclear pleomorphism, and increased mitoses (1 to 2 per 10 high-power fields) should be reexcised to exclude well-differentiated hidradenocarcinoma.108 Immunohistochemical stains reveal the tumor cells to express p63 and AE1/AE3 with luminal staining for EMA and CEA. A PAS stain will highlight the clear cells, consistent with glycogen accumulation.
Share Histologic Features With: Invasive mammary carcinoma with apocrine or clear cell features.
Distinguishing Features Include: In limited samplings, the distinction may be very difficult. However, hidroadenomas are typically diffusely positive for p63, a characteristic not seen in invasive mammary carcinomas.
MALIGNANT ECCRINE TUMORS
Microcystic Adnexal Carcinoma
MAC, also referred to as sclerosing sweat duct (syringomatous) carcinoma or malignant syringoma, is a rare locally aggressive adnexal carcinoma with both sweat duct and follicular differentiation typically involving the head (ie, nasolabial and periorbital regions), but may rarely involve the axilla and breast.109 The tumor is clinically characterized as a slow-growing, flesh-colored, hard plaque, or nodule with an occasional central dell. Most cases are asymptomatic, however, pain may be an indicator of perineural invasion. The margins are typically difficult to delineate with palpation and local recurrence is common after wide excision. Distant metastasis is extremely rare.110 There is an increased incidence in women and cases have been reported to arise after radiation therapy.111 The histopathologic features of the superficial portions of the tumor are similar to syringoma with round cystic and comma-shaped structures embedded within fibrous stroma (Fig. 7A). The cells frequently have a slight basaloid quality and rarely mitoses and necrotic cells may be seen. The cystic structures may contain either keratinous or amphophilic secretions. The most distinguishing feature is that the tumor cells descend into the deep dermis, subcutaneous fat, and sometime skeletal muscle as tiny cell clusters and cords with focal lumen formation. Perineural invasion is common. Immunohistochemistry reveals tumor expression of AE1/AE3, p63, and EMA with luminal expression of CEA. Rarely, the tumor cells may also express CK15 and BerEP4. Ki-67 will reveal a low mitotic index.112,113
Share Histologic Features With: Syringomatous adenoma.
Low-grade adenosquamous carcinoma (Fig. 7B).
Distinguishing Features Include: Syringomatous adenoma most commonly occur in the nipple or retroareolar region and therefore confirming that the nipple/retroareolar region of the lesion would highly favor this diagnosis.
Syringomatous adenoma is well-demarcated despite individual invasive-appearing glands, whereas MAC is infiltrative throughout and commonly demonstrate perineural invasion.
Like MAC, low-grade adenosquamous carcinomas are infiltrative but lack perineural invasion and occur deep in the breast parenchyma. With that said, the tumor border of lesions may be variably sampled in needle core/punch biopsies.
Eccrine porocarcinoma is one of the more common adnexal malignancies that preferentially occurs in the elderly and may present anywhere eccrine sweat glands are highly concentrated. The common locations include the distal extremities, head and neck, and trunk.114 Tumors of the breast have been reported, some of which have arisen in the setting of chronic radiation dermatitis or lymphedema after lymph node dissection. These tumors may arise de novo, but most commonly arise within preexisting poromas and typically present as rapidly enlarging verrucous plaques or nodules that may ulcerate. Local recurrence, lymph node involvement, and distant metastasis and death have been reported in 17%, 19%, and 11% of cases, respectively. Multiple epidermotropic metastases have been documented. Because of this aggressive behavior, some advocate sentinel lymph node biopsy. Eccrine porocarcinoma is closely related clinically and histopathologically to ordinary eccrine poroma, however, porocarcinoma exhibits an infiltrative growth pattern, desmoplastic stroma, tumor cell necrosis, nuclear pleomorphism, numerous mitoses, and frequent perineural and lymphovascular invasion. Porocarcinomas more frequently exhibit enhanced squamous differentiation compared with benign poromas (G.T.D., unpublished personal observation). The nests and lobules of tumor cells contain luminal structures, which is the most reliable feature distinguishing these tumors from SCCs. Just like eccrine poroma, these tumors may arise anywhere within the eccrine duct and hence may connect to the epidermal surface (referred to as malignant hidroacanthoma simplex), be confined to the dermis (malignant dermal duct tumor), or both. Immunohistochemical stains will reveal the tumor cells to express CK7, p63, EMA, and CEA, with preferential staining of the luminal structures.115
Share Histologic Features With: Invasive mammary carcinoma, poorly differentiated, high grade.
Distinguishing Features Include: May be impossible to distinguish, particularly in limited material. Evidence of a preexisting poroma would strongly favor a cutaneous origin. In addition, porocarcinomas diffusely express p63, whereas invasive mammary carcinomas are negative.
Adenoid Cystic Carcinoma of the Skin
Primary cutaneous ACC is an extremely rare neoplasm most commonly arising on the scalp or chest with a slow-growing yet locally aggressive behavior. Perineural invasion is common. The tumor has counterparts in other organ systems such as the salivary gland, breast, respiratory tract, and genitourinary tract.116,117 Unlike salivary gland tumors, the primary cutaneous tumors have a local recurrence rate of 50%, but rare distant metastasis. The histopathologic features consist of clusters of basaloid cells arranged as tubules, elongated cribriform nests, or solid nests and cords situated in the dermis or subcutis without epidermal attachment. The tumor cells are believed to be of eccrine derivation and lack peripheral nuclear palisading and stromal retraction artifact. Mitoses are rare. Cribriform nests are the most common growth pattern encountered and are the most diagnostically distinctive. The nests and individual tumor cells are surrounded by PASd positive basement membrane material with small globules scattered within the nests. The cystic spaces are actually pseudolumina and contain hyaluronic acid and sulfated acid mucin that stains with Alcian blue. Immunohistochemistry reveals the tumor cells to express cytokeratin and c-kit (CD117) with variable luminal staining for EMA, CEA, SMA, and S-100 protein.118
Share Histologic Features With: Mammary ACC.
Distinguishing Features Include: Morphologically, these 2 entities are indistinguishable. Ascertaining the tumor’s location is particularly important in this case. Very rarely, mammary ACC will have a coexisting in situ component which may or may not be represented in the initial biopsy material.
Malignant hidradenoma is a rare neoplasm that most frequently arises on the face and extremities, however, lesions of the chest wall and breast have been reported.119 Malignant degeneration within preexisting benign hidradenomas have been reported with the chromosomal translocation t(11:19) but not t(6:22).120 De novo carcinomas also occur. There appears to be a high rate of local recurrence as well as mortality.121 The histopathologic features are similar to hidradenoma but with enhanced cytologic atypia, infiltrative pattern of growth, tumor necrosis, and high mitotic activity. Cases with central comedo necrosis have been documented and cytologic atypia may range from mild to anaplastic.122 Immunohistochemical stains reveal tumor expression for AE1/AE3, CK5, CK7, p53, p63, CEA (focal), AR, EGFR, ER, MUC5AC, and strong/diffuse membranous staining for HER-2.119 Ki-67 staining of >10% of tumor nuclei warrants classification as adenocarcinoma and not as an “atypical” hidradenoma. Although immunohistochemical staining for HER-2 is frequently positive, amplification of the oncogene demonstrated by FISH is rare suggesting a limited therapeutic importance.119
Share Histologic Features With: Invasive mammary carcinoma.
Distinguishing Features Include: Immunoreactivity for p63 in malignant hidradenomas may be helpful in distinguishing them from invasive mammary carcinomas which are negative for this stain.
De Novo Eccrine Carcinomas Which are Morphologically Dissimilar to their Benign Counterparts
Although some eccrine carcinomas may arise within preexisting benign eccrine neoplasms, other de novo malignancies exist that may not resemble a benign counterpart. In many cases, the histopathologic distinction from visceral metastasis may be impossible. In general, these eccrine carcinomas most commonly arise on the head and neck as well as the extremities. The only 2 distinct de novo eccrine adenocarcinomas that have been reported to arise within the breast or axilla are ductal eccrine adenocarcinoma (DEA) and primary cutaneous signet-ring cell carcinoma, the latter which is additionally, extremely rare with a strong predilection to occur in males (5:1).
Ductal Eccrine Adenocarcinoma
DEA is perhaps the most common of the de novo eccrine carcinomas and always presents as a solitary, slow-growing mass that has been present for months to years before clinical detection. Several cases involving the breast have been reported.123 Its histopathologic features are virtually identical to invasive ductal carcinoma of the breast, however, metastatic breast carcinoma typically presents as rapidly enlarging crops of multiple nodules.124 DEA is characterized by an aggressive clinical course with a relatively high rate of local recurrence (70%), distant metastasis (50%), and disease-related mortality (70%).125 The histopathologic features include infiltrative solid nests and cords or tubules composed of atypical basaloid polygonal cells embedded within a desmoplastic stroma (Fig. 7C). Involvement of eccrine ducts and colonization of the overlying epidermis have been reported and are a helpful finding in distinguishing these tumors from metastatic disease. The tumor cells may frequently contain small intracytoplasmic vacuoles. Numerous mitoses are usually present. Areas with squamous differentiation may resemble SCC and are referred to as squamoid eccrine ductal carcinoma and have a markedly improved clinical outcome.126 Immunohistochemical stains will reveal the tumor cells to express EMA, cytokeratin, p63, luminal CEA, and variable expression of ER, PR, HER-2, S-100 protein, and GCDFP-15.127,128
Share Histologic Features With: Invasive duct carcinoma, poorly differentiated (Fig. 7D).
Distinguishing Features Include: Morphologically, it may be very difficult if not impossible to make this distinction. However, immunoreactivity for p63 in DEAs is not seen in invasive duct carcinomas.
Keloids are a common reactive lesion composed of exuberant scar tissue. They most commonly arise after trauma; however, spontaneous lesions may form on the chest. They typically present as well-circumscribed, raised, plaques, and nodules that slowly enlarge over time.129 Microscopically, there is a nodule composed of thick hyalinized collagen bundles surrounded by scattered fibroblasts (Fig. 8A).
Share Histologic Features With: Scar secondary to prior breast biopsy.
Fibromatosis (Fig. 8B).
Myofibroblastoma, collagenized and infiltrative variants (Fig. 8C).
Spindle cell metaplastic carcinoma, fibromatosis-like variant (Fig. 8D).
Distinguishing Features Include: In limited samplings, the distinction on morphologic grounds may be extremely challenging. Immunohistochemical stains for CD34, β-catenin, p63, and a cytokeratin panel would be helpful to distinguish keloid from mammary proliferations. The distinction between keloid and a scar from a prior breast procedure (or localized trauma) would largely rest on pertinent clinical history.
Dermatofibromas are the most common soft tissue tumor of the skin. These tumors most frequently present as firm papules on the extremities and trunk of middle-aged women.129 There is an association with trauma. Microscopically, there is an ill-defined dermal proliferation of spindled cells that may extend into the subcutaneous fat. The cells are arranged in a storiform pattern and may be admixed with focal foamy macrophages, dilated vessels, and scattered hemosiderin pigment (Fig. 9A). The most specific feature is found at the periphery of the tumors where the cells wrap their dendritic processes around collagen bundles. Immunohistochemistry will reveal the tumor cells to positively express factor XIIIa and D2-40. Occasionally, SMA expression may be seen. There is no staining for CD34 or desmin.130,131
Share Histologic Features With: Myofibroblastoma, cellular variant (Fig. 9B).
Pseudoangiomatous stromal hyperplasia, fascicular variant.
Distinguishing Features Include: Due to the significant morphologic overlap of these entities, immunohistochemical stains can be diagnostically very useful. Myofibroblastoma and pseudoangiomatous stromal hyperplasia are immunoreactive for CD34, whereas dermatofibromas are negative. Most mammary fibromatoses will express nuclear localization of β-catenin which is not characteristic of dermatofibromas. Moreover, none of these mammary lesions are known to express factor XIIIa and D2-40 to the extent seen in dermatofibromas.
Dermatofibrosarcoma protuberans is a locally aggressive malignant fibroblastic tumor that most commonly arises on the upper back of middle-aged patients, however, involvement of the breast has been well documented.132,133 Occurrence at sites of previous trauma, such as scars, injection sites, and infection has been documented.134 The tumor typically presents as a slow-growing firm indurated plaque with ill-defined palpable borders. Occasional nodularity may occur in later stages. Rapid growth during pregnancy has been reported.135 The local recurrence rate is relatively high (20% to 50%) when treated with wide excision; however, distant metastasis is extremely rare. Removal via Moh’s micrographic surgery has been shown to have lower recurrence rates.136 These tumors exhibit chromosomal translocations for t(17;22), creating a specific gene fusion of COL1A1 and PDGFB. Microscopically, there is a deep dermal spindle cell proliferation with a storiform and fascicular growth pattern (Fig. 10A). Vertical infiltration into the subcutis with entrapment of adipocytes is characteristic. Mitotic activity is typically low, usually not exceeding 5 per 10 high-power fields. Immunohistochemistry will reveal positive tumor cell expression of CD34, but negative expression of factor XIIIa, S-100 protein, desmin, actin, c-kit (CD117), stromelysin, and D2-40.130,137–139
Share Histologic Features With: Spindle cell metaplastic carcinoma (Fig. 10B).
Myofibroblastoma, infiltrative variant.
Distinguishing Features Include: See the Dermatofibroma section.
Dermatologic mimickers of breast lesions are underappreciated and should be considered in the differential diagnosis, particularly in small samplings with limited clinical information. Clinical correlation, especially the precise location of the lesion in question is of paramount importance and in some cases, the stated site as “breast” should be questioned and further clarified.
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