Nerve Sheath Tumor With Degenerative Atypia and Multivacuolated Lipoblasts

Introduction

Although “lipoblast-like” cells with single or multiple vacuoles have been described in many neoplastic and nonneoplastic conditions, bona fide lipoblastic differentiation is ordinarily restricted to purely adipocytic neoplasms. ¹ Nonadipocytic mesenchymal neoplasms with a minor lipomatous component have, however, been exceptionally noted to harbor lipoblasts. Examples of this unusual phenomenon include uterine lipoleiomyoma, lipomatous hemangiopericytoma, and so-called lipoblastoma-like tumor of the vulva.^2-5 Aberrant lipoblastic differentiation was most recently reported in 2006 by Plaza et al, ⁶ who described 5 benign nerve sheath tumors that included a variably conspicuous population of signet-ring lipoblasts, coining the term “lipoblastic nerve sheath tumor.” A single additional nerve sheath tumor with signet-ring lipoblasts has been reported since. ⁷

Despite these rare occurrences, the association between lipoblasts and liposarcoma is often spontaneous, which may potentially lead to an erroneously malignant diagnosis. In this brief report, we describe the seventh case of so-called lipoblastic nerve sheath tumor, and the first one, to our knowledge, to harbor both multivacuolated lipoblasts and degenerative nuclear atypia. Awareness of this potentially misleading, histologically atypical variant of nerve sheath tumors may help prevent a diagnosis of sarcoma in a benign soft tissue tumor containing lipoblasts.

Case Report

The patient is a 52-year-old healthy man who presented with a 2 cm subcutaneous mass on his right thigh. The mass was conservatively excised based on a preoperative impression of lipoma. Grossly, the tumor was round and well-delineated, with a tan homogeneous unremarkable cut surface. Microscopically, the lesion consisted of an unencapsulated, loosely cellular spindle cell proliferation with wavy, occasionally atypical nuclei, lying in a collagenous, variably myxoid background. Numerous mast cells as well as a spattering of chronic inflammatory cells were noted. In addition, there were few predominantly multivacuolated lipoblasts scattered evenly within the lesion without preferential peripheral localization. These lacked significant nuclear atypia or hyperchromatism (Figure 1A). An immunohistochemical panel comprising S-100 protein, CD34, smooth muscle actin, p16, Ki-67, MDM2, and CDK4 was performed. It showed strong and diffuse marking for S-100 and CD34, focal p16 positivity and lack of staining for smooth muscle actin, MDM2, and CDK4. S-100 highlighted both spindle cells and lipoblasts (Figure 1B), whereas CD34 decorated few spindle cells, staining mostly an intricate dendritic cell network involving the entire lesion. All lipoblasts were negative for CD34 (Figure 1C).

OPEN IN VIEWER

Figure 1.

(A) Hematoxylin and eosin stain showing several lipoblasts in a background of neural/schwannian type stroma with nuclear atypia (100×). (B) Immunohistochemical stain for S-100 protein showing nuclear and cytoplasmic staining in lipoblasts and stromal cells. (C) Immunohistochemical stain for CD34 highlighting the background dendritic cell network, with positivity in rare tumor cells. Note that the lipoblasts are negative

The lesion’s fibromyxoid mast cell–rich neural-type background, its spindle cells with wavy nuclei, and its strong S-100 positivity established the diagnosis of benign nerve sheath tumor, probably of the neurofibroma variety. The atypia was considered degenerative in nature, as is frequently the case in benign nerve sheath tumors. The additional and peculiar presence of lipoblasts further classified this lesion as lipoblastic nerve sheath tumor.

Discussion

Part of the challenge when encountering a lesion containing lipoblast-like cells is to recognize whether these represent genuine lipoblasts or pseudolipoblasts. The most commonly listed mimickers of lipoblasts are histiocytes in silicone granulomas, vacuolated carcinoma cells, signet ring lymphomas, and signet ring melanomas. Short of definitive confirmation by electron microscopy, the distinction is usually possible using morphologic and immunohistochemical means. For instance, true lipoblasts show variably sized vacuoles and characteristic indentation of the nucleus, with or without atypia, unlike histiocytes that show no nuclear indentation, and other nonhistiocytic mimickers that typically show signet ring rather than multivacuolated morphology. Immunohistochemically, lipoblasts are positive for S-100 protein and negative for histiocytic, epithelial, lymphoid, and melanocytic markers. ⁸

Only a handful of neoplastic proliferations are normally expected to harbor lipoblasts. Save for the benign childhood lipoblastoma, ⁹ the large majority of these lipoblastic tumors are liposarcomas. The resulting intuitive mental association of lipoblast with liposarcoma is, however, not always justified. First, as illustrated in this case, a lipoblast does not a liposarcoma make, even when exhibiting sufficient nuclear atypia.^2,10 Second, apart from the rare pleomorphic liposarcoma, ¹¹ the presence of lipoblasts is not considered necessary for a diagnosis of liposarcoma. Interpreting the lipoblast—or its absence—in a precise histologic context remains the single most important ingredient in either confirming or excluding the diagnosis of liposarcoma.

The present case mainly illustrates two confounding features that may obscure the diagnosis of benign nerve sheath tumor. First, the presence of multivacuolated lipoblasts, even without significant atypia, is potentially alarming to the unsuspecting pathologist. Second, the focal atypical cytology occasionally present in otherwise ordinary nerve sheath tumors (ancient change) can also be a cause of malignant overdiagnosis. ⁸ When faced with the above features, the main differential diagnosis is the spindle cell variant of well-differentiated liposarcoma (WDSCL). Distinguishing lipoblastic nerve sheath tumors from WDSCL is clinically relevant because WDSCL is a low-grade sarcoma with a potential for local aggressive behavior and recurrence and at least a theoretical capacity for dedifferentiation. ¹²

Initially described by Dei Tos et al ¹³ in 1994, WDSCL is a tumor of subcutaneous and soft tissues composed of spindle cells, adipocytes, and scattered lipoblasts with occasional nuclear atypia. Immunohistochemically, WDSCL has been shown to express both CD34 and S-100 protein, though S-100 is normally limited to the adipocytic/lipoblastic component.^12,13 WDSCL can be distinguished from lipoblastic nerve sheath tumor primarily by its higher cellularity, more pronounced adipocytic component, and lipoblastic atypia. When the latter findings are not definitive, strong and diffuse S-100 positivity in all tumor constituents should be helpful in excluding WDSCL, as it is an exceptional finding in atypical/malignant adipocytic neoplasms. Staining for S-100 protein should readily be prompted by this lesion’s distinct fibromyxoid and neural/schwannian character, and should confirms its nerve sheath identity. Intense positivity for CD34, highlighting the lesion’s prominent dendritic cell network, is often present in neural-derived tumors but does not exclude well-differentiated spindle cell liposarcoma.^12,14 Of note is that CD34 staining was not present in the series of Plaza et al. ⁶

In conclusion, we have discussed the first lipoblastic nerve sheath tumor demonstrating multivacuolated lipoblasts, and its potential mimicry of well-differentiated spindle cell liposarcoma. Realizing that multivacuolated lipoblasts and degenerative nuclear atypia can be present in an otherwise benign tumor can help the practicing pathologist avert an erroneous diagnosis of liposarcoma.