Eduardo Calonje

Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low grade variant

Myxofibrosarcoma is one of the most common sarcomas in the extremities of elderly patients. We analysed the clinicopathologic features in a series of 75 patients. All patients were adults (range, 22-91 years; median, 66 years) with an approximately equal incidence in men and women. Thirty-five tumors arose in the lower and 25 in the upper extremities, nine on the trunk, two each in the retroperitoneum and the head and neck region, and one each in the pelvis and penis. Forty-eight cases (69.5%) were located in dermal or subcutaneous tissues. Distinctive histologic features included the following: a commonly nodular growth pattern; a myxoid matrix containing elongated, curvilinear capillaries; and fusiform, round or stellate tumor cells with indistinct cell margins, slightly eosinophilic cytoplasm, and hyperchromatic atypical nuclei. These lesions varied from a hypocellular, mainly myxoid, and purely spindle-cell appearance (low-grade neoplasms) to high-grade, pleomorphic (malignant fibrous histiocytoma-like) lesions with multinucleated giant cells, high mitotic activity, and areas of necrosis. Immunohistochemistry in 44 cases revealed only vimentin and occasional actin positivity. Ultrastructurally, tumor cells had a fibroblastic phenotype. DNA flow cytometry and proliferation analysis showed an association between aneuploidy and histologic grade. An average follow-up of 45 months (range, 5-300 months) in 60 cases has revealed local recurrence in 33 cases (54%). Thirteen patients developed metastases, and 13 tumor-related deaths occurred. A short interval to first local recurrence was associated with poor clinical outcome. The rate of local recurrence was independent of histologic grade, but only intermediate and high-grade neoplasms metastasized. The depth of the primary lesion did not influence the incidence of local recurrence. However, in deep-seated neoplasms, the incidence of metastases was higher and the percentage of tumor-related deaths was twice as high as in superficially located lesions, reflecting the fact that deep-seated lesions tended to be higher-grade, larger tumors. Myxofibrosarcoma tends to become progressively higher grade in recurrences, as demonstrated in five cases in our series. The poorly recognized low-grade myxofibrosarcoma is emphasized, as proper diagnosis and treatment and scrupulous follow-up are mandatory to avoid local recurrence and gradual tumor progression to a higher-grade neoplasm that may then metastasize.

Survival Outcomes and Prognostic Factors in Mycosis Fungoides/Sézary Syndrome: Validation of the Revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer Staging Proposal

PURPOSE We have analyzed the outcome of mycosis fungoides (MF) and Sézary syndrome (SS) patients using the recent International Society for Cutaneous Lymphomas (ISCL)/European Organisation for Research and Treatment of Cancer (EORTC) revised staging proposal. PATIENTS AND METHODS Overall survival (OS), disease-specific survival (DSS), and risk of disease progression (RDP) were calculated for a cohort of 1,502 patients using univariate and multivariate models. RESULTS The mean age at diagnosis was 54 years, and 71% of patients presented with early-stage disease. Disease progression occurred in 34%, and 26% of patients died due to MF/SS. A significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Univariate analysis established that (1) advanced skin and overall clinical stage, increased age, male sex, increased lactate dehydrogenase (LDH), and large-cell transformation were associated with reduced survival and increased RDP; (2) hypopigmented MF, MF with lymphomatoid papulosis, and poikilodermatous MF were associated with improved survival and reduced RDP; and (3) folliculotropic MF was associated with an increased RDP. Multivariate analysis established that (1) advanced skin (T) stage, the presence in peripheral blood of the tumor clone without Sézary cells (B0b), increased LDH, and folliculotropic MF were independent predictors of poor survival and increased RDP; (2) large-cell transformation and tumor distribution were independent predictors of increased RDP only; and (3) N, M, and B stages; age; male sex; and poikilodermatous MF were only significant for survival. CONCLUSION This study has validated the recently proposed ISCL/EORTC staging system and identified new prognostic factors.

Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases.

Epithelioid hemangioendothelioma of soft tissues (EHE) represents a distinct entity with an unpredictable clinical course. We analyzed the clinicopathologic and immunohistochemical features in a series of 30 patients. Patient age range was 16-74 years (median 50); 18 of 30 patients were female. Eight tumors arose in the lower and two in the upper extremities, seven on the trunk, five each in the head/ neck and anogenital regions, two in the mediastinum, and one in the abdomen. Seventeen neoplasms were located in deep soft tissues, nine were subcutaneous or perifascial, and four were dermal; size ranged from 0.4 to 10 cm; in 11 cases the tumor was > 5 cm. Tumors with an infiltrative growth pattern were more common than entirely circumscribed lesions. The tumors were composed histologically of short strands, cords, or small clusters of epithelioid, round, to slightly spindled endothelial cells that formed at least focally, intracellular lumina and were set in a frequently myxohyaline stroma. Thirteen of 30 lesions showed angiocentric growth, which was occlusive in many cases. Immunohistochemically, all cases tested were positive for at least one endothelial marker (CD31, CD34, factor VIII, Ulex europaeus), six of 23 (26%) were positive for cytokeratin, and five of 11 (45%) were positive for alpha-smooth muscle actin. Median follow-up of 36 months (range 2-96) in 24 cases showed local recurrence in three cases and systemic metastases in five cases (21%); four patients (17%) died of tumor. Although more aggressive histologic features (striking nuclear atypia in eight cases, numerous spindled cells in 10, more than two mitoses per 10 high-power fields in nine, and small, more solid angiosarcomalike foci in four cases) tended to be related to poor clinical outcome, there was no clear correlation. Two metastasizing cases showed no histologically atypical features whatever. We suggest that EHE of soft tissue is better regarded as a fully malignant, rather than borderline, vascular neoplasm, albeit the prognosis is better than in conventional angiosarcoma.

Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases.

The clinicopathologic characteristics of 69 cases of eccrine porocarcinoma (EP) have been studied. Seven cases of purely in situ disease are included. Forty patients were female, 29 male with ages ranging from 29 to 91 years (mean 73 years). The lower extremity represented the single most common site (44%). Other common sites were the trunk (15 cases, 24%) and head (11 cases, 18%). The histologic diagnosis of EP was predicated on the basis of an irregular tumor at least partly formed of characteristic poromatous basaloid epithelial cells displaying ductal differentiation, and significant cytologic atypia. Forty-seven tumors (68%) contained mature well-formed eccrine ducts having an eosinophilic luminal cuticle, with the remaining tumors containing small ill-formed ducts and/or intracytoplasmic lumina. All ducts were discernible via light microscopy and in 49 cases were highlighted with DPAS stain and/or CEA/EMA immunocytochemistry. A variant with a broad pushing tumor margin and marked nuclear pleomorphism showed some resemblance to proliferative bowenoid dysplasia. In 11 cases (18%) the tumors appeared to arise in continuity with a benign preexistent poroma. A variety of histologic patterns were displayed including clear, squamous, and spindle cell differentiation, mucus cell metaplasia, and colonization by melanocytes. Lymphovascular invasion was present in 9 cases (15%). Three cases showed pagetoid extension of malignant cells (epidermotropism) and appeared to be multifocal. Follow-up was available in 54 patients (78%) with 9 (17%) experiencing local recurrence, 10 developing lymph node metastases (19%), and 6 (11%) experiencing distant metastases or death. Mitoses, the presence of lymphovascular invasion, and tumor depth >7 mm were associated with a poorer prognosis. Dividing tumors into those with a “pushing” or “infiltrating” advancing margin was also predictive of outcome with the latter having an increased risk of local recurrence. This report, the largest series of EP to date, suggests that the incidence of aggressive behavior is less than popularly believed. Furthermore, EP can display a wide variety of histologic patterns that may lead to diagnostic error in the unwary. The large number of cases in this series enables a reliable evaluation of prognostic parameters. A more aggressive clinical course may be indicated by more than 14 mitoses per high power field (hazard ratio [HR] for death 17.0, 95% confidence interval [CI] 2.71–107), lymphovascular invasion by tumor (HR 4.41, CI 1.13–17.2), and depth >7 mm (HR 5.49, CI 1.0–30.3). Thus, mitoses, lymphovascular invasion, and tumor depth should be evaluated in these tumors. We also suggest that tumors presenting an “infiltrative” advancing margin are particularly prone to local recurrence and require wide excision with close attention to the surgical margins by the reporting pathologist.

Mixed tumors and myoepitheliomas of soft tissue : A clinicopathologic study of 19 cases with a unifying concept

We report 19 unusual cases of mixed tumors and myoepitheliomas arising in soft tissues. The neoplasms occurred in 12 males and seven females. The age at diagnosis ranged from 2 to 83 years (mean 35, median 30). Eight tumors arose in the upper limb, six in the lower limb, three in the trunk, and two in the head and neck region. Three cases involved both dermis and subcutis; the remainder arose in subcutaneous (13 cases) or deep subfascial soft tissue (three cases). The most common presenting complaint was a painless swelling, with duration ranging from 2 weeks to 1 year (median 2.5 months). Microscopically, the tumors were predominantly well circumscribed and lobulated. Six cases showed a focally infiltrative margin. Cardinal morphologic features included nests, cords, and ductules of epithelioid cells and/or nests of spindled cells within a hyalinized to chondromyxoid stroma. One tumor was predominantly composed of myoepithelial cells and devoid of epithelial differentiation (i.e., ductules). Cytoplasmic hyaline inclusions were noted in two cases; squamous differentiation was seen in one case. Osteoid production and/or metaplastic bone was observed in three tumors. Chondroid differentiation (usually mature) was seen in four cases. Adipocytic differentiation was seen in two tumors. Mitotic activity was variable but generally scant; atypical mitotic figures were not identified. By immunohistochemistry, 16 of 16 cases expressed pan-keratin; 16 of 17 S-100 protein; six of 14 alpha smooth muscle actin (IA4); two of 10 muscle specific actin (HHF-35); two of 10 desmin; three of 11 glial fibrillary acidic protein; and three of 16 epithelial membrane antigen. Clinical follow-up was available in 10 patients and ranged from 6 months to 20 years (mean 4.25 years, median 2 years). Two patients developed local recurrence; metastasis to lung and lymph nodes were observed in two additional patients. Both of the latter patients died. We believe that these findings expand the concept of cutaneous mixed tumors to include neoplasms composed predominantly of myoepithelial cells and to include tumors arising in deeper subcutaneous and/or subfascial tissues. The clinical behavior of such neoplasms, when arising in soft tissues, may be difficult to predict but is most often benign; however, a minority of lesions metastasize. Until larger studies with longer follow-up are available, treatment and prognostication are probably best based on criteria used in comparable salivary gland tumors.

Cellular benign fibrous histiocytoma. Clinicopathologic analysis of 74 cases of a distinctive variant of cutaneous fibrous histiocytoma with frequent recurrence.

We report seventy-four cases of a distinctive variant of cutaneous fibrous histiocytoma, which is often mistaken histologically for sarcoma and which carries a high local recurrence rate. These tumors appeared most commonly in young or middle-aged adults, with a predominance in men (male/female ratio 1.9:11. Anatomic distribution was wide, with cases occurring mainly in the upper limb/limb girdle (34%), lower limb/limb girdle (27%), and head and neck region (20%). Most lesions had been present for only a few months, and their sizes ranged from 0.5 cm to 2.5 cm in maximum diameter. Twelve (26%) of 46 cases with follow-up (mean duration 3 years) recurred locally, in one case twice. Distinctive histologic features were a commonly fascicular growth pattern, predominance of eosinophilic spindle cells with tapering nuclei, a moderate mitotic rate (mean three per 10 high-power fields), and frequent extension into the subcutaneous fat (33% of cases). In addition, all cases showed at least focal cytologic polymorphism (inflammatory cells, foam cells, giant cells), and 58% showed associated epidermal alterations in common with usual cutanous fibrous histiocytomas. Nine cases (12%) showed foci of central necrosis. Immunohistochemical studies (ABC method) found only vimentin and very focal smooth muscle actin positivity. Tests for CD34, desmin, S-100, keratin, and Factor XIIIa were negative in all cases. These lesions should be distinguished from dermatofibrosarcoma protuberans and leiomyosarcoma, with which many of these cases were initially confused.

Infantile Hemangiopericytoma Versus Infantile Myofibromatosis Study of a Series Suggesting a Continuous Spectrum of Infantile Myofibroblastic Lesions

The clinicopathologic features of 11 tumors, originally diagnosed as infantile hemangiopericytomas and with a spectrum of morphologic findings, are described. The age of the patients ranged from 6 days to 7 years; seven patients were younger than 1 year (mean, 2.25 years; median, 10 months); six were boys and five were girls. Three neoplasms were situated in skin or subcutis and seven in deep soft tissue; in one case the depth was unstated. Seven lesions arose in the lower limbs, and one each in the lumbar region, clitoris, chest wall, and soft tissue of the zygomatic region. One patient later was found to have two additional dermal tumors, one each on the anterior abdominal wall and the chest wall. Follow-up information in eight patients revealed local recurrence 12 years later in one case only. Histologically, all tumors showed distinctive features of infantile hemangiopericytoma, including immature cytology, multilobulated growth pattern, focal necrosis, and mitotic activity in varying degrees. Vascular invasion was noted in seven cases. Additionally, a second tumor cell component, composed of spindleshaped myofibroblastic cells forming fascicles and micronodules, was evident at least focally. Both the spindle cells and more primitive round cells were positive for α-smooth muscle actin. Both cellular components showed a haphazard zoning arrangement. We discuss the clinicopathologic similarities between infantile hemangiopericytoma and infantile myofibromatosis and point out the differences between infantile and adult hemangiopericytoma. Our study suggests that there exists a broad spectrum of benign infantile myofibroblastic lesions containing an immature-appearing cellular component with a distinctive, hemangiopericytoma-like vascular pattern. Infantile myofibromatosis and so-called infantile hemangiopericytoma almost certainly represent different stages of maturation of the same (single) entity.

Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases.

Fifteen cases of a distinctive type of low-grade angiosarcoma of the skin are described. Most tumors presented in the second to fourth decades of life, the youngest patient being 9 years old and the oldest 78 (mean age, 36 years). There was no sex predilection. Six tumors arose on the lower limb, four on the upper limb, three on the trunk, and one each on the penis and the scalp. One case arose in the setting of chronic lymphedema and another following radiotherapy for carcinoma of the uterine cervix. Distinctive morphologic features were the presence of long arborizing blood vessels arranged in a retiform pattern (reminiscent of normal rete testis) lined by monomorphic hobnail endothelial cells, a very prominent lymphocytic infiltrate in most cases, and the focal presence of papillae with hyaline collagenous cores, similar to those seen in malignant endovascular papillary angioendothelioma (Dabskas tumor). With a median follow-up of 7.25 years in 14 cases, retiform hemangioendothelioma has proved to be a low-grade neoplasm that recurs frequently but has a very low metastatic rate. The single regional lymph node metastasis in this series was from a case with a biphasic pattern in which only the spindle cell component was represented in the metastasis. There have been no tumor-related deaths, underlining the importance of accurate distinction from conventional angiosarcoma. This distinction is facilitated principally by the absence of dissection between individual collagen bundles and the absence of endothelial atypia or mitotic activity. The precise relationship between retiform hemangioendothelioma and Dabskas tumor is uncertain, possibly because cases of the latter may not be homogeneous.

Superficial angiomyxoma: clinicopathologic analysis of a series of distinctive but poorly recognized cutaneous tumors with tendency for recurrence.

Despite being first described in 1988, superficial angiomyxoma is still a poorly recognized cutaneous tumor. Although its histologic features are distinctive, its existence seems not to be widely accepted. We analyzed the clinicopathologic and immunohistochemical features in a series of 39 cases. Twenty-five patients were males; age range was birth to 82 years (median, 45.5 years). Most cases presented as cutaneous papules, nodules, or polypoid lesions. Seventeen tumors arose on the trunk, 14 on the head and neck, and seven on the lower limbs. All cases were treated by local excision, and eight recurred locally. In four of the latter cases, there were two recurrences. Histologically, the lesions were dermal with variable involvement of the subcutis. Tumors were poorly circumscribed, but a focal lobular outline was always identified. Distinctive histologic features included extensive myxoid stroma, numerous small blood vessels, varying cellularity, acellular mucin pools, stellate or bipolar fibroblastic cells, muciphages, a sparse, mixed inflammatory cell infiltrate with notable neutrophils, and occasional plumper cells with eosinophilic cytoplasm. Cytologic atypia was mild at most, and mitotic figures were rare. In approximately 20% of cases, the primary lesion or its recurrence contained epithelial structures, including epidermoid cysts, thin strands of squamous epithelium, and small buds of basaloid cells. Immunohistochemically, tumor cells were negative for S-100 protein, smooth muscle actin, and pan-keratin. We support the concept of superficial angiomyxoma as a distinctive clinicopathologic entity that should be included in the differential diagnosis of other myxoid cutaneous tumors, including dermal nerve sheath myxoma, trichodiscoma and trichofolliculoma, and low-grade myxofibrosarcoma.

Lipoblastoma and lipoblastomatosis : a clinicopathological study of 14 cases

The clinicopathological features of 14 cases of lipoblastoma and lipoblastomatosis are presented. The age of the patients at presentation ranged from 5 days to 6 years (mean 2.7 years); nine patients were male. Histologically, six cases were circumscribed (lipoblastoma) while eight were diffuse and ill‐defined (lipoblastomatosis). In both groups and in individual cases there was distinct lobulation, as well as a spectrum of adipocytic maturation. Cytologically, the 10 most mature lesions were composed of uniform adipocytes intermixed with only scattered lipoblasts and primitive mesenchymal cells. A notable feature in the other four cases was a prominent myxoid stroma producing a very close resemblance to myxoid liposarcoma. Mitotic figures were rare and always normal in appearance. Atypical nuclei were not evident. Follow‐up in eight patients revealed local recurrence in two. Liposarcoma in patients under 10 years is exceedingly rare, and, in myxoid form, may be almost impossible to distinguish histologically from lipoblastoma. Helpful clues are the lack of lobulation, variable growth pattern and increased nuclear atypia in liposarcoma.