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Selected diagnostic problems in neoplastic dermatopathology.

* Context.--Selected cutaneous neoplasms share features with benign counterparts or have subtle morphologic features that could be overlooked by the pathologist.

Objective.--To present clues to the diagnosis of potentially deceptive malignancies, including desmoplastic malignant melanoma, nevoid malignant melanoma, subcutaneous lymphoma, metastatic breast carcinoma, and epithelioid sarcoma.

Data Sources.--Published literature and personal experience.

Conclusions.--Knowledge of commonly misdiagnosed cutaneous neoplasms will help the general surgical pathologist avoid these potential pitfalls in neoplastic dermatopathology.

(Arch Pathol Lab Med. 2007;131:434-439)

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Diagnostically difficult cutaneous neoplasms are a consistent problem in dermatopathology. They are typically examined closely and often shared with colleagues in order to arrive at a consensus. However, some of the most unsettling lesions are those malignant tumors that are so innocuous-looking histopathologically that they escape special scrutiny. In this review, we consider selected cases that closely simulate benign lesions. By virtue of their bland features, such "wolves in sheep's clothing" may not be recognized when examined at scanning magnification.

DESMOPLASTIC MALIGNANT MELANOMA

Desmoplastic malignant melanoma (DMM) is an uncommon variant that may have banal features both clinically and histopathologically. (1) In a recent review of malpractice claims centering on melanoma, unrecognized DMM accounted for a disproportionate number of diagnostic errors. (2) The typical clinical presentation is that of a firm papule, nodule, or plaque on sun-exposed areas of the head and neck in an elderly patient. (3-5) However, other anatomic sites may be involved, including oral or anogenital mucosa. (6-8) In some cases, DMM may arise in a preexisting malignant melanoma in situ of the lentiginous (so-called lentigo maligna) type. When DMM arises in malignant melanoma in situ, the pigmentation of the junctional component may provide a clinical clue as to the tumor's melanocytic lineage. On the other hand, when DMM occurs without an associated junctional melanocytic proliferation, the lesion appears nonpigmented and does not resemble the usual clinical image of melanoma. Instead, the clinical features may falsely suggest a cicatrix, dermatofibroma, nevus, basal cell carcinoma, or cyst. (3,9)

In DMM, histopathologic examination reveals a dermal proliferation of spindle cells associated with a variable fibrotic stromal response (Figure 1). The tumor cells may be dispersed individually and haphazardly between the collagen bundles or may be grouped in long fascicles. (5,10) A whorled or storiform pattern is seen in some cases. Deep dermal involvement and perineural invasion are common, but these findings are typically apparent only in rather large biopsy specimens. Constituent neoplastic cells have elongated fusiform nuclei, and the cytoplasm virtually always lacks pigment. The nuclear features of DMM may be bland, slightly atypical, or overtly aberrant. Bland-appearing (pseudobenign) lesions can resemble a variety of other spindle cell proliferations, particularly proliferating scars and sclerosing blue nevus (Table 1). Cases with atypical cytologic characteristics may simulate atypical fibroxanthoma, leiomyosarcoma, malignant peripheral nerve sheath tumors, other sarcomas, or sarcomatoid carcinomas.

[FIGURE 1 OMITTED]

Important clues to the recognition of DMM are summarized in Table 2. In most cases, mitotic figures are identifiable with careful scrutiny. (5,11) Moreover, most DMMs have at least focally atypical cytologic features, such as nuclear enlargement and hyperchromasia (Figure 2). Although those features are helpful, they may be inapparent on scanning microscopy or may be absent in small biopsy specimens. Additional morphologic hints, which are only variably present, can be especially important in limited samples of pseudobenign DMMs. Scattered lymphocytic aggregates are seen commonly in such lesions, especially at the periphery of the tumors. Hence, that finding in a banal spindle cell proliferation should prompt one to undertake meticulous microscopic examination and consider the application of adjunctive diagnostic methods. A concurrent, atypical, intraepidermal proliferation of melanocytes, another helpful clue, is present in some cases of DMM. (3-5,12) The intraepidermal component may be relatively inconspicuous on one hand, or it may have the image of obvious melanoma in situ.

[FIGURE 2 OMITTED]

In distinguishing DMMs from cicatrices, the orientation of dermal spindle cells should be noted. In most DMMs, the orientation is haphazard, in contrast to a parallel horizontal configuration of fibroblasts in proliferating scars. (9) Sclerosing and hypopigmented blue nevus is another potential simulator of DMM. The adventitial dermis typically is spared in sclerosing blue nevus, as opposed to its involvement by DMM. (3) Desmoplastic nevus also must be differentiated from DMM. Compared with DMM, desmoplastic nevi have greater architectural symmetry, fewer atypical dermal cells, fewer (absent or very rare) mitotic figures in the dermis, and a significantly lower number of Ki-67-positive cells. (9,13) Benign peripheral nerve sheath tumors and spindled forms of melanoma can be particularly similar pathologically; both share the potential for production of myxoid stroma, serpiginous nuclear contours, and interspersed mast cells, and are only imperfectly distinguished from one another morphologically. Despite the similarity, the spindle cells of neurofibroma usually can be distinguished by their lack of hyperchromatic nuclei. (9)

In many instances, immunohistochemistry is a valuable adjunct in the diagnosis of DMM. S100 is expressed in nearly all cases, whereas HMB-45, tyrosinase, Melan-A/ MART-1, and PNL2 are characteristically absent in DMM. (4,11,14-19) The usual lack of HMB-45 expression is especially helpful in distinguishing DMM from sclerosing blue nevus, which is consistently labeled for that marker. (13) Stains for S100 protein may have an additional role in determining the depth and overall size of DMM. (20) However, caution is needed in interpreting S100 stains in regard to re-excision specimens. Nonneoplastic, S100-reactive dendritic cells are relatively common in scars associated with prior biopsies or excisions. (21-23) Correlation with light microscopy findings is mandatory to avoid the incorrect diagnosis of DMM in this setting. Other potential pitfalls in the immunohistologic evaluation of DMM include the expression of smooth muscle actin, CD34, or procollagen 1 in a small proportion of cases. (24-26) Another melanocytic marker, microphthalmia transcription factor (MiTF), has been evaluated for possible use in the differential diagnosis of DMM and other spindle cell proliferations of the skin. (27,28) Although there is no unanimity of opinion on its value, our own experience has mirrored that of Granter et al, (29) who found that MiTF was neither specific nor sensitive for DMM. Fewer than 30% of cases expressed that marker in their series, and 33% of nonmelanocytic cutaneous spindle cell lesions did so. Finally, the p75 neurotrophin receptor is expressed strongly in most cases of DMM. (14,30-32) In the rare instance of S100-negative DMM, p75 is stated to be particularly useful in supporting the diagnosis. (33)

NEVOID MALIGNANT MELANOMA

The term nevoid malignant melanoma (NMM) is used to describe an uncommon variant that closely resembles a nevus on scanning microscopy. Descriptions of the clinical features vary widely (10,34,35); however, in many cases the clinical impression is that of a benign lesion, such as a melanocytic nevus, seborrheic keratosis, fibroepithelial papilloma, or cyst. (35,36) Despite that fact, NMM has biologic behavior that is similar to other melanoma types. (37)

Potentially misleading histopathologic features of NMM include a symmetrical silhouette, sharp lateral demarcation, an inconspicuous junctional component, and the absence of pagetoid spread (36-40); overall lesional architecture is typically dome-shaped or verrucous. Constituent tumor cells are monomorphic and bland and may resemble the cells of a conventional melanocytic nevus or the epithelioid elements of a Spitz nevus. A small-cell variant of NMM also has been described. (34,41)

Key features of NMM are summarized in Table 3 and demonstrated in Figures 3 through 6. Dermal mitotic figures are invariably present and, at least focally, the monomorphic cells assume a sheetlike growth pattern rather than the typical nesting of a conventional nevus. In addition, a subtle lack of gradient-related maturation may be evident at the base of the tumor. (36) Discernible nucleoli in the melanocytes at the base are a helpful diagnostic clue. (38)

[FIGURES 3-6 OMITTED]

Immunohistochemistry may occasionally be useful in the recognition of NMM. HMB-45 expression typically is strong throughout the tumor, even in its deep components. (38) That pattern differs from the profile of banal nevi, in which HMB-45 labeling usually lessens progressively as one compares the superficial and deep aspects of the tumors. Nevertheless, Spitz nevi have a pattern of HMB-45 reactivity that is similar to that of NMM. Ki-67 and cyclin-D1 immunostains have been reported to have potential utility in differentiating NMM from Spitz nevus. (38,42) According to published reports, NMM shows a homogeneous pattern of nuclear labeling with those markers throughout the lesion, whereas Spitz nevi often demonstrate a gradient in which the superficial dermal components are more proliferative than cells in the deeper corium. (38,42) In our experience, however, Ki-67 staining is variable in this setting, and its usefulness is unclear.

The aforementioned immunohistologic attributes are not always present in NMM, and this tumor type usually can be recognized successfully using morphologic features alone. The most significant pitfall in that process lies in the innocuous appearance of the lesion on low-power microscopy, and habitually examining large nevi at higher magnification may provide some additional assistance in detecting cases of NMM. As Wick and Patterson (43) have stated, "the key to a diagnosis of NMM is a high index of suspicion in reference to 'nevi' that are bulkier than usual or that otherwise capture special attention on scanning microscopy. Special attention is warranted for lesions with expansile growth, irregular infiltrative configurations, or unusual cytologic monotony."

PSEUDOPANNICULITIC CUTANEOUS LYMPHOMAS

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) may closely mimic panniculitis both clinically and histopathologically. SPTL manifests as solitary or multiple cutaneous plaques and deep nodules, which may spontaneously wax and wane (33,44,45); the legs are a common site of involvement. Patients of all ages are potentially affected, and an associated hemophagocytic syndrome occurs in some instances.

Particularly in the early phases of the disease, the histopathologic appearance of SPTL may overlap considerably with that of panniculitis seen in lupus erythematosus (lupus profundus; Figures 7 and 8). Shared features include dense dermal peri-appendageal and lobular subcutaneous lymphocytic infiltrates, variable nuclear atypia in the lymphoid cells, histiocytic cytophagocytosis, and fat necrosis. (46) Rimming of adipocytes by lymphocytes is characteristic of SPTL but may also be seen in lupus panniculitis. Germinal centers, clusters of B lymphocytes, numerous plasma cells, mucin deposition, and concurrent vacuolar interface changes have been suggested as helpful clues to the diagnosis of lupus panniculitis. (46,47) Although T-cell clonality is characteristic of SPTL in genotypic analyses, that feature may not be demonstrable in a proportion of cases, and clonality also has been reported in some examples of lupus panniculitis. (46) Although the inflammatory infiltrate in lupus panniculitis includes CD8-positive lymphocytes, most cells within the inflammatory infiltrate do not express that marker. This finding is in contrast to SPTL, in which the majority of cells usually express CD8. (47)

[FIGURES 7-8 OMITTED]

In view of the diagnostic difficulties mentioned here, it may be prudent to qualify the diagnosis of lupus panniculitis in surgical pathology reports in some cases, especially if one observes significant lymphoid atypia or if T-cell clonality is present. Prior clinical and laboratory documentation of lupus erythematosus obviously is important in this context as well. In cases that are felt to represent lupus panniculitis, additional biopsies are indicated over time if the disease does not follow the expected clinical course with appropriate therapy.

Other lymphomas of the skin also may imitate panniculitis. Cutaneous [gamma][delta] T-cell lymphoma (CGD-TCL) may be situated predominantly in the subcutaneous tissue in some cases. (45,48-50) CGD-TCL presents as disseminated plaques or ulcerated nodules, most frequently involving upper and lower extremities. Histologically, the infiltrate of CGD-TCL frequently involves the subcutis, the dermis, and the dermal-epidermal interface, whereas SPTL usually spares the corium. In CGD-TCL, dermal mucin, involvement of the dermal-epidermal interface, and subcutaneous infiltration may closely mimic lupus panniculitis. (51) The immunophenotype of CGD-TCL differs from SPTL; it typically exhibits reactivity for CD56 but lacks [beta]-F1, CD4, and CD8 expression. On the other hand, SPTL is nonreactive for CD56 but expresses [beta]-F1 and usually CD8. (45) SPTL frequently pursues relatively indolent and fluctuating clinical course, (45) but CGD-TCL is aggressive and rapidly fatal. Like SPTL, however, CGD-TCL must be considered in the differential diagnosis of a lymphocytic panniculitis. Another consideration, albeit rare, is that of peripheral T-cell lymphoma (not otherwise specified), presenting exclusively in the subcutis; it may also simulate panniculitis in that circumstance. (52,53)

METASTATIC BREAST CARCINOMA

In women, breast carcinoma is the most common metastatic malignancy in the skin. (54) The anterior chest is the most common site (55); however, other more distant sites also may be involved. Cutaneous metastases of breast carcinoma can demonstrate a variety of histopathologic patterns, including interstitial infiltration, intralymphatic spread, epidermotropism (resembling melanoma), or duct formation (resembling adnexal carcinoma). (55-59) In the interstitial pattern of lobular breast carcinoma, single tumor cells infiltrate between dermal collagen bundles (Figure 9). In instances in which the metastatic cells are cytologically bland, scanning microscopy may suggest a benign interstitial infiltrate of histiocytes or fibroblasts. (55) Accordingly, metastatic breast carcinoma occasionally may be mistaken for granuloma annulare or dermatofibroma. In cases where the eyelids are involved, xanthelasma is another potential differential diagnostic consideration. (60)

[FIGURE 9 OMITTED]

Microscopically, observation of a "busy" (hypercellular) dermis justifies careful scrutiny of the cellular infiltrate. One may find subtle cytologic atypia and, if single-file cellular arrays also are present in the corium (Figure 10), breast carcinoma should definitely be considered. Keratin immunostains are valuable in confirming that suspicion, and we routinely obtain them in skin biopsies from the chest if the patient has a known history of mammary cancer. Further support for an origin in the breast can be provided by immunoreactivity for gross cystic disease fluid protein-15, estrogen receptor protein, progesterone receptor protein, or mammaglobin. (61,62) Histochemical stains with the digested periodic acid-Schiff method also are sometimes helpful in demonstrating intracellular mucin in the tumor cells.

[FIGURE 10 OMITTED]

EPITHELIOID SARCOMA

In Enzinger's seminal description in 1970, epithelioid sarcoma (ES) was recognized as a histopathologic simulator of palisaded granulomatous disorders. (63) Indeed, his case series included a number of examples that had been originally mistaken for benign granulomatous reactions. Epithelioid sarcoma typically is represented by a nodule or ulcerated mass on a distal extremity of a young adult. The hands and forearms are most frequently affected. In some examples, the clinical appearance suggests a diagnosis of granuloma annulare. Despite its potentially misleading clinical blandness, ES is a potentially aggressive tumor with frequent recurrence and metastasis, and an overall 10-year mortality rate of greater than 80%. (64)

Scanning microscopy reveals a variably cellular dermal or subcutaneous nodule, often containing central necrosis (Figure 11). Polygonal epithelioid cells, often with a subpopulation of spindle cells, comprise the tumor in most cases (Figure 12). Scattered multinucleated cells may also be seen. The epithelioid elements typically have abundant eosinophilic or amphophilic cytoplasm and oval or round nuclei, and cellular pleomorphism frequently is minimal. (63,65) A variably hyalinized, desmoplastic stroma is often seen.

[FIGURES 11-12 OMITTED]

The pattern of central necrosis in ES mimics, but is not identical to, the silhouette of "necrobiosis" in a palisading granuloma. In the former, cell debris and amorphous granularity are evident, whereas granulomas less often demonstrate those features. The overall architecture and bland appearance of the neoplastic cells may lead to misdiagnosis of ES as granuloma annulare or rheumatoid nodule. (63,66,67) Mitotic activity or prominent nucleoli may raise suspicion for ES, (68) but occasional granulomatous lesions share those attributes as well. (69) Colloidal iron or Alcian blue stains may reveal mucin in the central necrobiotic foci of granuloma annulare, (70) but in our experience that finding is not typical of ES. Immunoreactivity for keratin is seen in nearly all cases of ES, and this finding is also helpful in excluding the possibility of a granulomatous disorder. (68,71) Epithelioid sarcoma usually expresses epithelial membrane antigen and vimentin as well and, in contrast to metastatic carcinomas, this neoplasm frequently labels for CD34. (72)

In summary, the possibility of ES should be considered when a cellular and granuloma-like lesion is seen in the dermis or subcutis, especially in cases that lack stromal mucin and fibrin. Subtle nuclear atypia and mitotic activity are additional potential clues to the diagnosis, which may be confirmed using immunohistochemical studies.

CONCLUSION

All of the selected malignancies in this review may closely mimic benign lesions. When encountering certain bland-appearing cutaneous infiltrates, the pathologist must have an appropriate index of suspicion. Recognition of subtle clues may be crucial in correctly diagnosing these "wolves in sheep's clothing."

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Accepted for publication November 6, 2006.

From the Departments of Dermatology and Pathology, Mayo Clinic Arizona, Scottsdale (Dr DiCaudo); the Departments of Pathology and Dermatology, University of California at San Francisco, UCSF Dermatopathology Service, San Francisco (Dr McCalmont); and the Department of Pathology, University of Virginia Medical Center, Charlottesville (Dr Wick).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: David J. DiCaudo, MD, Departments of Dermatology and Pathology, Mayo Clinic Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259 (e-mail: dicaudo.david@mayo.edu).

David J. DiCaudo, MD; Timothy H. McCalmont, MD; Mark R. Wick, MD
Table 1. Histopathologic Features Distinguishing
Benign Simulators From Desmoplastic Malignant
Melanoma (DMM)

Cicatrix Spindle cells oriented parallel to the epi-
 dermis
 Blood vessels oriented perpendicular to the
 epidermis
 Scattered [S100.sup.+] cells (S100 diffusely
 positive in DMM)

Sclerosing blue Central zone of fibrosis
 nevus [HMB-45.sup.+]

Neurofibroma Lack of cytologic atypia
 Mitoses absent or rare

Leiomyoma Smooth muscle actin(rarely positive in
 DMM)
 [Desmin.sup.+]
 [S100.sup.-]

Dermatofibroma Epidermal hyperplasia
 Peripheral collagen trapping
 Factor [13a.sup.+]
 [S100.sup.-]

Desmoplastic Architectural symmetry
 nevus Fewer atypical dermal cells
 Fewer mitotic figures in dermis
 Fewer Ki-67cells

Table 2. Histologic Clues to the Diagnosis of
Desmoplastic Melanoma

Mitotic figures
Cytologic atypia
Lymphocytic aggregates
Intraepidermal melanocytic proliferation
Mucinous stroma
Perineural invasion

Table 3. Histologic Clues to the Diagnosis of Nevoid
Malignant Melanoma

Mitotic figures in the lower dermis
Prominent nucleoli at the base of the lesion
Subtle lack of maturation by cells at the base
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Author:DiCaudo, David J.; McCalmont, Timothy H.; Wick, Mark R.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Clinical report
Geographic Code:1USA
Date:Mar 1, 2007
Words:4769
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