Lipoblastic nerve sheath tumors: report of a distinctive variant of neural soft tissue neoplasm with adipocytic differentiation

Benign nerve sheath tumors of soft tissue can occasionally adopt unusual or unfamiliar morphologic appearances that may introduce difficulties for diagnosis, such as multinucleation, bizarre nuclei, intranuclear vacuoles, and other degenerative changes. Tumor cells adopting a signet-ring or lipoblast-like configuration, however, are mostly associated with epithelial malignancies, liposarcoma and melanoma, and have been only rarely observed in spindle cell tumors of soft tissue. We report 5 cases of benign nerve sheath neoplasms that displayed prominent signet-ring cells with lipoblast-like features. The cases presented as solitary soft tissue masses in the groin, thigh, retroperitoneum, and shoulder in 4 men and 1 woman between the ages of 31 to 57 years. Four tumors predominantly showed features of schwannoma and one of neurofibroma; however, intimately admixed with the spindle cell population, there were also numerous scattered mature adipocytes as well as lipoblast-like cells displaying a signet-ring cell appearance. Immunohistochemical studies showed strong S-100 protein positivity in the spindle cells as well as in the signet-ring lipoblast-like cells and the mature adipocytes. The signet-ring cells were negative for mucin stains, cytokeratin, EMA, CEA, and several other differentiation markers. Ultrastructural examination was performed in 2 cases. The signet-ring cells contained large cytoplasmic lipid droplets that displaced the nuclei to the periphery, consistent with lipoblastic differentiation, whereas complex, interdigitating cytoplasmic processes covered by basal lamina material characteristic of nerve sheath differentiation could be identified in the spindle cells. Four patients for whom follow-up was available were alive and well with no evidence of recurrence over a period of 28 to 116 months (median follow-up, 50 months). The presence of mature fat and signet-ring lipoblast-like cells within a nerve sheath neoplasm is quite rare and may signify a process of aberrant differentiation. Neurogenic tumors should be added in the differential diagnosis of spindle cell tumors capable of displaying prominent signet-ring cell features.     

PTEN hamartoma of soft tissue: a distinctive lesion in PTEN syndromes

PTEN hamartoma tumor syndrome (PHTS) presents in a spectrum that encompasses the eponymous disorders Cowden and Bannayan-Riley-Ruvalcaba. Herein, we delineate the distinctive histopathology of a predominantly intramuscular lesion in PHTS, often called "arteriovenous malformation," because of certain imaging and histopathologic features. Cases were identified by review of lesions resected from patients with PHTS registered at our Vascular Anomalies Center and of unusual intramuscular vascular anomalies in our pathology database from 1985 to 2008. Thirty-four patients with this lesion were identified: 20 had a clinical diagnosis of, or were suspected to have, PHTS (genetically confirmed in 16). In 4 patients without clinical manifestations of PHTS, 2 had PTEN mutations, 1 did not, and in 1 the mutation was intronic. In the remaining 10, there was insufficient clinical information to fully assess whether they had manifestations of PHTS. Lesions manifested by 15 years of age, normally with pain and swelling, and were most often located in the lower extremity. The major mass was usually intramuscular, but often there were fascial and subcutaneous components and not infrequently a cutaneous vascular stain. Magnetic resonance imaging generally showed an infiltrative soft tissue lesion involving the muscle, fascia, and subcutis with frequently enlarged, serpiginous vessels, small arteriovenous fistulae with disproportionately dilated draining veins, and a prominent adipocytic component. Some lesions involved contiguous muscles, and 20% were multifocal. Resected specimens ranged in size from 1.2 to 25 cm; in 1 patient, amputation was necessary. Histopathologically, these unencapsulated masses, often with a nodular appearance at scanning magnification, consisted of: (1) a variable admixture of mature adipocytic and dense and/or myxoid fibrous tissues (50% to 90% of surface area); (2) a vascular component (10% to 50% of surface area) with: (a) clusters of venous channels, some with excessively and irregularly muscularized complex walls and lumens, and others with thin walls resembling pulmonary alveoli, (b) tortuous, thick-walled arteries with concentric muscular hyperplasia and relatively small lumens, (c) numerous small vessels (arteries, veins, and indeterminate channels), and (d) occasional arteriovenous communications; (3) lymphoid follicles (50%); (4) foci of bone (20%); and (5) hypertrophic nerves with "onion bulb" proliferation of periaxonal spindled cells (9%). We designate this disorganized overgrowth of essentially mesenchymal elements as PTEN hamartoma of soft tissue. It differs from other vascular and connective tissue lesions that occur in patients with PHTS. PTEN hamartoma of soft tissue is histopathologically distinctive, and its identification should prompt a thorough investigation for PHTS.     

Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm.

We report eight cases of epithelioid angiosarcoma arising in deep, usually intramuscular soft tissue. All the patients were men (mean age, 58). All the lesions arose in a limb or limb girdle. Cardinal morphologic features were the diffuse, sheetlike growth pattern, with only focally apparent vascular differentiation, and epithelioid tumor cells with a degree of intracytoplasmic vacuolation/lumen formation. Immunohistochemically, all eight cases coexpressed keratin as well as endothelial markers. In three cases, endothelial differentiation was confirmed ultrastructurally. Clinically, deep-seated epithelioid angiosarcomas are high-grade neoplasms that rapidly develop metastases. These findings expand the range of recognized epithelioid endothelial tumors and provide further evidence of keratin expression by such lesions. The presence of intracytoplasmic lumina/vacuoles (sometimes containing red blood cells) combined with the characteristic reticulin pattern and striking positivity for Factor VIII-RAg provide the clearest means of distinction from an epithelial metastasis.     

Angiofibroma of soft tissue: clinicopathologic characterization of a distinctive benign fibrovascular neoplasm in a series of 37 cases

Thirty-seven cases of a distinctive benign fibrovascular soft tissue tumor that may be mistaken for a low-grade sarcoma are described. There were 25 female and 12 male patients, ranging in age from 6 to 86 years (median, 49 y). The tumors presented most commonly as a slowly growing painless mass located in the soft tissues of the extremities, mainly the lower extremity, often in relationship to joints or fibrotendinous structures. Most lesions (29 cases) were well circumscribed, ranging in size from 1.2 to 12 cm (median, 3.5 cm). The microscopic appearance was remarkably consistent and was characterized by 2 components: a relatively uniform proliferation of bland, spindle-shaped cells with inconspicuous cytoplasm and ovoid-to-tapering nuclei set in a variably collagenous or myxoid stroma and a prominent vascular network composed of numerous small, branching, thin-walled blood vessels, often accompanied by medium-sized round or irregular and ectatic vessels. Mitoses (1-4/10 hpf) were occasionally observed (9 cases). Mild degenerative nuclear atypia was uncommon (5 cases). Tumor cells expressed epithelial membrane antigen at least focally in 16 of 36 cases (44%), CD34 and smooth muscle actin in 5 cases (14%), and desmin in 4 cases (11%); none expressed S100 protein. Five out of 6 cases analyzed cytogenetically showed a simple karyotype with a balanced t(5;8) chromosomal translocation. Treatment consisted of surgical resection: either simple excision (29 cases), wide excision (6 cases), or amputation (1 case). Follow-up information was available for 28 patients (range, 6 to 144 mo; mean, 51.9 mo). Most patients were alive with no evidence of disease, regardless of the status of surgical resection margins. Four patients developed local recurrence 9, 13, 36, and 120 months after the primary tumor was removed; only in 1 case was there an association with extensively positive surgical resection margins. One of these patients developed a second recurrence 2 months after the first one. None of the patients developed metastasis. The designation "angiofibroma of soft tissue" is proposed to reflect both the likely fibroblastic nature of the proliferating cells and the prominent vascularization of this benign soft tissue neoplasm.     

Myxoid leiomyosarcoma of soft tissue, an underrecognized variant

Myxoid leiomyosarcoma is an uncommon tumor which, although previously well described in the uterus, is recognized to a lesser extent at other sites. We describe 18 cases of soft tissue leiomyosarcoma in which myxoid stroma occupied >50% of the tissue examined. Patients ranged in age from 22 to 84 years old (median, 57.5 yrs) and female patients outnumbered male patients 14 to 4. Tumor locations included the limbs (6 cases), female external genitalia (4 cases), head and neck region (3 cases), chest (2 cases), nipple, paratesticular soft tissue, and perineum (one case each). The tumors had a grossly gelatinous appearance and adopted three major histologic architectures: fascicular, reticular/microcystic, and "myxofibrosarcoma-like." The tumor cells were predominantly spindled in all cases with typical features of smooth muscle differentiation; there was a mixture of spindle and epithelioid cells in one case. No cases with pure epithelioid cytology were seen. All tumors displayed immunoreactivity for smooth muscle markers (smooth muscle actin 16/17, desmin 8/18) and, in addition, four cases were positive for keratin CAM 5.2 and three for epithelial membrane antigen. The tumors had a tendency to be morphologically lower grade (9 tumors were grade I, 8 were grade II, and only 1 was grade III). Follow up was available in 13 patients with a duration of 8 months to 41 years (median, 39 mos), and revealed local recurrences (often repeated) in five cases and metastases in two cases. There were three tumor-related deaths, of which two were the result of uncontrolled local disease. The differential diagnosis of myxoid leiomyosarcoma is broad and encompasses both benign and malignant lesions. Accurate diagnosis is critical because therapies may differ widely for entities in the differential diagnosis of myxoid leiomyosarcoma.     

Expression of claudin-1, a recently described tight junction-associated protein,distinguishes soft tissue perineurioma from potential mimics

Perineuriomas are rare benign soft tissue tumors having an immunophenotype paralleling the normal perineurial cell [S-100 protein negative and epithelial membrane antigen (EMA) positive]. Because EMA expression in perineuriomas may be focal and/or faint, there is continued interest in the development of new markers of perineurial differentiation. Perineurial cells differ from almost all other mesenchymal cell types by virtue of their formation of tight junctions. In the course of evaluating a group of novel tight junction-associated proteins, we noted high levels of expression of claudin-1 by normal perineurial cells and have systematically extended these observations to perineuriomas. Twelve EMA-positive/S-100-negative perineuriomas were retrieved from our consultation archives and compared with 39 tumors in the differential diagnosis of perineurioma (seven dermatofibrosarcoma protuberans, eight low-grade fibromyxoid sarcomas, three desmoplastic fibroblastomas, seven fibromatoses, nine neurofibromas, and five schwannomas). All cases were immunostained for claudin-1 using standard avidin-biotin technique. Cases were scored as 3+ (>50% positive cells), 2+ (25-50% positive cells), and 1+ (5-24% positive cells). In all cases positive internal controls in the form of epithelium, normal perineurium, or endothelial cells were present. Positive staining for claudin-1 was visualized in a distinctly particulate pattern along the cell membrane. Cytoplasmic staining was infrequent and was not scored as positive. Claudin-1 expression was present in 11 of 12 (92%) perineuriomas studied (seven at 3+, three at 2+, and one at 1+). In all but two cases, the degree of claudin expression was equal to or greater than the corresponding EMA immunostain. Claudin-1 expression was not noted in any cases of dermatofibrosarcoma protuberans, low-grade fibromyxoid sarcoma, desmoplastic fibroblastoma, or fibromatosis. Six of nine cases of neurofibroma contained a significant number of claudin-1-positive cells that were thought to be perineurial in origin, based on the staining of long, delicate cytoplasmic processes. One of four schwannomas contained a subpopulation of perivascular, dendritic, claudin-1-positive cells of presumed perineurial lineage. This is the first study to document expression of claudin-1 in perineurial cells and suggests a role for claudin-1 immunohistochemistry in the diagnosis of perineuriomas. Although claudin-1 should not replace EMA in the diagnosis of perineurioma, we think that it may play a valuable adjunctive role in difficult cases. In particular, claudin-1 is often a more robust marker than EMA in a given perineurioma. Claudin-1 is not expressed within the lesional cells of the mesenchymal tumors that enter into the differential diagnosis of perineurioma.     

Plantar lentiginous melanoma: a distinctive variant of human cutaneous malignant melanoma

The neoplastic system of human cutaneous melanoma includes three generaly recognized variants: lentigo maligna, superficial spreading melanoma, and nodular melanoma. Lentiginous melanomas other than lentigo maligna constitute a fourth group, of which plantar lentiginous melanoma qualifies as an anatomic subgroup. Histologically and clinically, plantar lentiginous melanoma (PLM) is characterized by a period of radial growth and often by one or more foci of regression. In 27 of 33 plantar melanomas, a characteristic lentiginous, radial component of melanocytic proliferation was noted. In the remaining six cases, histological material failed to document a radial component. Eighteen of the 27 patients with PLM were blacks, and 18 patients died of distant metastasis. Tumors invasive to level II did not metastasize, but at levels IV and V and in tumors with a high mitotic rate, the prognosis was poor. The presence of lymph node metastases at the time of initial therapy correlated with a poor prognosis group.     

Chondroblastoma-like chondroma of soft tissue: an underrecognized variant and its differential diagnosis

Soft-tissue chondromas are usually composed entirely of mature hyaline cartilage. Infrequently, however, they may exhibit morphologic features that result in diagnostic difficulty. The authors report a series of eight hypercellular soft-tissue chondromas composed of enlarged chondrocytes within a variable amount of chondroid matrix that often demonstrated delicate calcifications and contained numerous osteoclast-like multinucleated giant cells. This histologic appearance closely resembles that of chondroblastoma of bone. However, its extraosseous location, dense cellularity, and poorly formed cartilage can cause confusion with more aggressive chondroid neoplasms of soft tissue. The clinicopathologic features of these chondroblastoma-like chondromas are discussed, emphasizing the characteristics that facilitate their accurate identification.     

Carcinoma cuniculatum: a distinctive variant of penile squamous cell carcinoma: report of 7 cases

We are reporting a peculiar variant of penile squamous cell carcinoma (SCC) characterized by its peculiar deeply penetrating and burrowing pattern of growth. This low grade, verruciform penile neoplasm is similar to the plantar epithelioma cuniculatum originally described by Ayrd in 1954. Clinical and pathologic features of 7 patients are presented. There were 7 partial penectomies and 4 bilateral inguinal node dissections. The mean patient's age was 77 years. Grossly, the tumors were white to gray, exo-endophytic, and papillomatous with a cobblestone or spiky appearance. All cases affected the glans and extended to coronal sulcus and foreskin (average size was 6.3 cm). The hallmark of the lesion was noted on cut surface where there were deep tumoral invaginations forming irregular, narrow, and elongated neoplastic sinus tracts connecting the surface of the neoplasm to deep anatomic structures. The neoplasm invaded through lamina propria and corpus spongiosum and grew along the loose connective tissue of Buck fascia to involve the tunica albuginea and corpora cavernosa (average depth was 32 mm). Deeply invasive keratin filled cysts or crypts, on serial sections, showed to be connected to the surface tumor. Fistulization to the skin was also noted. Microscopically, the lesions corresponded to well-differentiated carcinomas with bulbous front of invasion. There were focal areas of higher histologic grade and more infiltrative and jagged borders in 4 cases. Inguinal nodes were negative in 4 patients in which groin dissection was performed. Carcinoma cuniculatum is a variant of penile SCC with distinctive growth pattern and should be distinguished from other verruciform tumors such as the verrucous, papillary, and warty carcinomas. Unlike most subtypes of penile SCCs and despite the deep invasion, none of the tumors showed groin or systemic dissemination at time of diagnosis.     

Necrotizing soft tissue infections: a surgical disease

Despite advances in antibiotics and infection control practices necrotizing fasciitis is still a potentially lethal disease. We reviewed 37 patients with necrotizing fasciitis to identify prognostic factors indicating outcome. Overall mortality was 24 per cent. Mortality was significantly increased for elderly patients. Solid-organ transplant recipients also represented a subset of patients with increased mortality. Most infections were polymicrobial. There was no Clostridium perfringens cultured. Rapid diagnosis and treatment with surgical debridement remains the cornerstone of therapy.     

Overview: soft tissue augmentation

No single filler substance meets all of a clinician's expectations. There are, however, many substances currently available that are useful in the soft tissue armamentarium. This article reviews the many filler substances; their indications, shortcomings, complications, and approval status by the Federal Food and Drug Administration.     

Lymphoma presenting as a soft tissue mass. A soft tissue sarcoma simulator

Lymphoma presenting as a soft tissue mass is rare and thus may be confused with the more common soft tissue sarcoma. No previous analysis of the clinical and radiologic features of lymphomas presenting as soft tissue masses is available because most of the cases reviewed are from the pathology literature. Four patients with diagnoses of extranodal lymphomas of the soft tissues were reviewed retrospectively with respect to their clinical features, primary tumor characteristics, stage, radiographic characteristics, treatment, and followup. Mean age was 72.5 years (range, 52-85 years). The soft tissue mass occurred in the thigh (three cases) and shoulder (one case). The median size of the soft tissue mass was 6.7 cm (range, 2-15 cm) in the largest dimension, as measured on magnetic resonance imaging. These patients each had evidence of lymphadenopathy at the time of diagnosis. Lactate dehydrogenase was increased significantly in two cases and increased slightly in two other cases. One case was Stage II(E) at presentation, one was Stage III(E), and two were Stage IV. All were B cell immunophenotype. All patients died between 2 and 24 months after diagnosis, despite the use of Cytoxan, vincristine, adriamycin, and prednisone chemotherapy in each case. Clinical and radiographic features that favor extranodal soft tissue lymphoma over sarcoma include pain and tenderness, lymphadenopathy (particularly when confluent radiologically), ipsilateral extremity swelling, and elevated lactate dehydrogenase.     

Soft tissue perineurioma: clinicopathologic analysis of 81 cases including those with atypical histologic features

Perineuriomas are uncommon benign peripheral nerve sheath tumors that include soft tissue, sclerosing, and intraneural variants. Fewer than 50 soft tissue perineuriomas have been reported to date, and the clinical significance of atypical histologic features is unknown. To characterize these tumors further, 81 soft tissue perineuriomas received between 1994 and 2003 were retrieved from the authors' consult files. Hematoxylin and eosin sections were reexamined, immunohistochemistry was performed, and clinical details were obtained from referring physicians. Forty-three patients were female and 38 male (mean age, 46 years; range, 10-79 years). Tumor size ranged from 0.3 to 20 cm (mean, 4.1 cm) in greatest dimension. Most patients presented with a painless mass. The tumors arose in a wide anatomic distribution: 36 lower limb, 19 upper limb, 15 trunk, 7 head and neck, 3 retroperitoneum, and 1 paratesticular. Forty-two tumors were situated primarily in subcutis, 25 in deep soft tissue, and 9 were limited to the dermis. Nearly all cases were grossly well circumscribed; 12 showed focal microscopically infiltrative margins. Most tumors had a storiform and focally whorled growth pattern; 17 exhibited fascicular areas. Thirty-eight tumors were hypocellular, 15 were markedly hypercellular, and 7 showed alternating zones of hypocellularity and hypercellularity. Stroma was usually collagenous but in 17 tumors was predominantly myxoid, and in 16 was mixed collagenous and myxoid. Mitoses ranged from 0 to 13 per 30 high power fields (mean, 1); 53 tumors had no mitoses. Based on worrisome cytologic or architectural features, 14 cases were classified as atypical perineuriomas: 12 contained scattered pleomorphic cells, 1 showed an abrupt transition from typical morphology to a markedly hypercellular, fascicular area with cytologic atypia, and 1 exhibited diffuse infiltration of skeletal muscle. All tumors were reactive for epithelial membrane antigen; 50 of 78 (64%) expressed CD34, 22 of 76 (29%) claudin-1, 16 of 77 (21%) smooth muscle actin, and 4 of 81 (5%) S-100 protein. All tumors were negative for glial fibrillary acidic protein, neurofilament protein, and desmin. Clinical follow-up was available for 43 patients (mean, 41 months; range, 6-146 months). Among tumors for which the status of surgical margins was known, 52% were widely excised, 31% were marginally excised, and 18% had positive margins. Only two tumors recurred locally (one of which was atypical): one recurred 10 years following primary excision; and one recurred twice, 5 and 9 years following excision. No tumor metastasized. Soft tissue perineuriomas behave in a benign fashion and rarely recur. Atypical histologic features (including scattered pleomorphic cells and infiltrative margins) seem to have no clinical significance and appear to be akin to those seen in ancient schwannoma and atypical (bizarre) neurofibroma.     

Soft tissue perineurioma in a patient with neurofibromatosis type 2: a tumor not previously associated with the NF2 syndrome

Neoplasms that commonly affect patients with neurofibromatosis type 2 (NF2) include schwannomas, meningiomas, astrocytomas, ependymomas, and neurofibromas. Perineuriomas are rare tumors of the peripheral nerve sheath that share some characteristics with meningioma. As in both NF2-associated and sporadic cases of schwannoma and meningioma, perineuriomas often harbor mutations or deletions of the NF2 gene. However, perineuriomas have not previously been reported in the clinical setting of NF2. A 30-year-old man with a history of bilateral vestibular schwannomas, a parasagittal meningioma, an intraspinal ependymoma, and multiple other neoplasms involving both cranial and peripheral nerves (thereby fulfilling the diagnostic criteria for NF2) presented with an enlarging thigh mass. The diagnosis of cellular soft tissue perineurioma was confirmed by both immunohistochemical and ultrastructural analysis. This case represents the first report of a soft tissue perineurioma arising in the setting of NF2.     

Hamartoma of the scalp with ectopic meningothelial elements. A distinctive benign soft tissue lesion that may simulate angiosarcoma

Five cases of a distinctive benign soft tissue lesion of the scalp in patients ranging from 4 months to 40 years of age are described. Clinically, the lesions appeared as solitary, subcutaneous nodules suggestive of a cystic vascular malformation or other benign condition. Histologically, however, the lesions were characterized by a monotonous, pseudoinfiltrative proliferation of cuboidal epithelioid cells arranged in clusters within the dermis and subcutaneous tissue in intimate association with vessels, adipose tissue, and other connective tissue elements. A prominent feature in all cases was the presence of areas simulating freely anastomosing vascular channels lined by round to spindle-shaped, slightly hyperchromatic epithelioid cells reminiscent of angiosarcoma. Immunohistochemically, these cells were negative for factor VIII-related antigen and Ulex europaeus lectin but were strongly positive with vimentin and epithelial membrane antigen antibodies, this latter being in keeping with the immunohistochemical profile of meningothelial cells. The meningothelial nature of these cells was supported by the electron microscopic demonstration in one case of cells with complex, interdigitating cytoplasmic processes that were joined by scattered cell junctions and contained abundant intracytoplasmic intermediate filaments. The intimate admixture of meningothelial elements with haphazardly arranged connective tissue elements sets these lesions apart from cutaneous meningiomas and warrants their designation as hamartomas with an ectopic meningothelial component.