Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy: an update

The fibrohistiocytic tumors of intermediate malignancy are uncommon mesenchymal tumors, which typically occur in the skin and subcutis and which may pose significant problems for the dermatopathologist. This article reviews the clinical, histopathologic, and genetic features of dermatofibrosarcoma protuberans, giant cell fibroblastoma, angiomatoid (malignant) fibrous histiocytoma, plexiform fibrous histiocytoma, and soft tissue giant cell tumor (of low malignant potential). The differential diagnosis of these tumors with a variety of benign and fully malignant cutaneous soft tissue neoplasms is discussed.     

Nucleolar organizer regions in fibrohistiocytic tumors of the skin

Nucleolar organizer regions (NORs) are loops of DNA which are present within the nucleoli of cells that possess ribosomal RNA (rRNA) genes. NORs are associated with proteins which can be visualized by a simple silver staining technique. As the number of NORs appears to reflect cell and nuclear activity its determination in benign, intermediate and malignant conditions could be of help in their differential diagnosis. In this study, we investigated 35 fibrohistiocytic tumors of the skin of benign, intermediate and malignant potential from 32 patients: 15 fibrous histiocytomas (FH), 5 FH with atypia (AFH), 7 atypical fibroxanthomas (AFX), 5 dermatofibrosarcoma protuberans (DFSP) and 3 malignant FH (MFH). A one-step silver technique was used on formalin or Bouin fixed specimens. Ag-NOR counts from benign conditions (FH, AFH) significantly differed from that of their intermediate-risk (AFX, DFSP) and malignant (MFH) counterparts. Furthermore, in 2 cases (one AFX; one MFH) which twice recurred, Ag-NOR counts steadily increased with time. However, a distinction could not be achieved between AFX and MFH. Although Ag-NOR is a simple and valuable technique, it does not allow a definite distinction between malignant and intermediate processes, at least as far as fibrohistiocytic tumors of the skin are concerned.     

Flow-cytometric DNA analysis in cutaneous fibrohistiocytic tumors

BACKGROUND: Fibrohistiocytic tumors are rare skin tumors. There are many kinds of fibrohistiocytic tumors. It is often difficult to differentiate dermatofibrosarcoma protuberans (DFSP) and malignant fibrous histiocytoma (MFH) from dermatofibroma (DF) and other benign tumors. OBJECTIVE: In this study, the possible usefulness of DNA ploidy for the differentiation was studied. METHODS: Five MFH, 9 DFSP, 3 DF, 2 lipofibromas and 2 scars were studied for DNA ploidy using a flow cytometer. RESULTS: All the 7 benign tumors showed a diploid pattern. Of 14 malignant fibrohistiocytic tumors, 8 cases (57.1%) showed an aneuploid and 6 a diploid pattern. Two of 5 MFH (40.0%) and 6 of 9 DFSP (66.7%) showed an aneuploid pattern. These results showed that fibrohistiocytic tumors with an aneuploid pattern are malignant, though those with a diploid pattern may be benign or malignant. CONCLUSION: Analysis of DNA ploidy using flow cytometry was concluded to be useful for the differentiation of malignant fibrohistiocytic tumors from benign ones.     

Fibroblastic/myofibroblastic sarcoma of the skin: a report of five cases

BACKGROUND: A number of malignant soft tissue tumors, particularly those of fibroblastic and fibrohistiocytic derivation, have been found to display myofibroblastic differentiation focally. The term myofibroblastic sarcoma, a controversial presumably distinctive entity, defines a malignant soft tissue tumor in which myofibroblasts are quantitatively the predominant cell type. METHODS: Five cases of cutaneous spindle-cell sarcomas showing fibroblastic-myofibroblastic differentiation with predominance of fibroblasts were retrieved from the files of three large centers of dermatopathology. Tumors were analyzed histopathologically, immunophenotypically, and, in two cases, ultrastructurally. Results were compared with those previously reported in fibrosarcoma, malignant fibrous histiocytoma, and myofibroblastic sarcoma. RESULTS: Immunophenotypic and ultrastructural profiles of the cases analyzed in this series were closer to fibrosarcoma and to malignant fibrous histiocytoma than to myofibroblastic sarcoma by virtue of quantitative predominance of fibroblasts over myofibroblasts. On the other hand, histopathologic findings were in keeping with those reported in myofibroblastic sarcoma. CONCLUSIONS: Our series highlights the intrinsic problems in attaching certain cutaneous sarcomas with fibroblastic-myofibroblastic differentiation to one of the recognized entities and gives support to the hypothesis that fibrosarcoma, malignant fibrous histiocytoma, and myofibroblastic sarcoma are related histogenetically.     

Multiple cutaneous fibrous histiocytomas in association with systemic lupus erythematosus

Cutaneous fibrous histiocytomas are usually regarded as superficial lesions and commonly known as dermatofibromas; however, unusual cases histologically showing fibrohistiocytic proliferation extending into the deeper dermis or subcutaneous tissues are occasionally experienced. Some authors propose this type as benign fibrous histiocytoma of the skin, distinct from dermatofibroma. We describe herein a case of systemic lupus erythematosus (SLE) who developed multiple nodules on the face, trunk and extremities. The nodule on the forehead did not present a typical clinical appearance of dermatofibroma, and histopathological examination showed fibrohistiocytic proliferation with a storiform pattern extending into the deep dermis and subcutaneous tissues. By contrast, histology of the nodule on the abdomen showed fibrohistiocytic proliferation confined to the dermis and compatible with dermatofibroma. Although multiple dermatofibromas are occasionally seen in patients with SLE, benign fibrous histiocytoma of the skin showing deeper invasion than dermatofibroma is rarely associated with SLE.     

Benign cellular fibrous histiocytoma with erosion of the phalanx

Fibrohistiocytic tumors are characterized by the presence of fibroblast like spindle cells and histiocytes. The benign fibrous histiocytoma (dermatofibroma, BFH) as well as the malignant dermatofibrosarcoma protuberans (DFSP) and the malignant fibrous histiocytoma (MFH) belong to this group. A recurrent painful, hard 2 cm tumor on the left hallux of a 54-year-old woman led to an erosion of the underlying phalanx. The patient had suffered from ingrown toenails for more than 10 years. Histologically there was a deep penetrating fibrohistiocytic tumor that grew in a storiform pattern with interspersed foam cells. The tumor was CD34 negative and mitoses were scarce. The diagnosis was benign cellular fibrous histiocytoma (BZFH). BZFH belong to the group of BFH with a high recurrence rate especially after incomplete removal. Damage to the underlying bone has not been reported so far.     

Atypical fibrous histiocytoma of the skin and subcutis in childhood and adolescence

The authors have observed 15 examples of a distinctive fibrohistiocytic lesion in children and adolescents which they chose to designate as "atypical fibrous histiocytoma" (AFH). Patient ages ranged from 1 to 19 years (mean 9.3 yr.). Only two cases were encountered in the first year of life, but 7 were seen in children under the age of 10 yr. The anatomic distribution of AFH showed a tendency for a truncal origin (66%), and none was located in the skin of the face, neck, or scalp. Tumor sizes ranged from 1 to 3 cm, and one-third were 2 cm or greater in maximum dimension. Histologically, AFH was characterized by a multinodular, dermal or dermal-subcuticular proliferation of spindle cells, with tapered, cytologically bland nuclei. However, nucleocytoplasmic ratios were increased when compared with those of normal fibroblasts. Nuclear chromatin was dispersed or vesicular; nucleoli were seen in a minority of cases, but mitotic activity was regularly present. Admixed giant cells were present but infrequent, cellularity was dense, and a storiform growth pattern was consistently seen. Mean followup in this group of cases averaged 75 mo. Seven patients (47%) had tumor recurrences after initial excision; in two of these, tissue margins had been free of involvement. The authors conclude that AFH of childhood is analogous to a lesion that has previously been reported as "benign fibrous histiocytoma" in adults. Complete excision and regular postoperative surveillance are recommended for these tumors.     

S100A6 expression in fibrohistiocytic lesions

BACKGROUND: S100A6, an S100 calcium-binding protein, has been found in a variety of cutaneous and extracutaneous lesions including: melanocytic nevi, melanoma, some salivary gland and epithelial tumors, and malignant fibrous histiocytoma (MFH). Dermal dendrocytes (DD) in the papillary dermis of skin also express S100A6 protein. We evaluated a variety of cutaneous fibrohistiocytic lesions to determine if the immunophenotype of S100A6 positivity can be expanded to include some or all of these lesions. METHODS: Formalin-fixed, paraffin-embedded tissues from fibrous papules (FP, 20), dermatofibromas (DF, 20), dermatofibrosarcoma protuberans (DFSP, 5), atypical fibroxanthomas (AFX, 5), oral fibromas (3), digital fibroma (1), and dermatomyofibroma (1) were evaluated with antibodies to S100A6, S100B, factor XIIIa, and MAC387 using a one-hour capillary action-based immunohistochemical procedure. RESULTS: DD in 20/20 FP, 19/20 DF, and 4/4 fibromas stained positively with anti-S100A6 in a pattern similar to anti-factor XIIIa. No DFSP cases stained with anti-S100A6. Anti-S100A6 showed superior staining to anti-factor XIIIa in 4/5 AFX cases. CONCLUSIONS: The immunophenotypes of some fibrohistiocytic lesions can be expanded to include S100A6 protein. With the exception of AFX, the use of anti-S100A6 does not appear to offer added benefit over anti-factor XIIIa in the differential diagnosis of fibrohistiocytic lesions.     

The value of immunohistochemistry in atypical cutaneous fibrous histiocytoma

Atypical cutaneous fibrous histiocytoma is a rare variant of dermatofibroma/fibrous histiocytoma characterized by striking atypia, thus resembling atypical fibroxanthoma. We studied 9 examples of ACFH histopathologically and immunohistochemically to investigate the nature of these atypical cells. Histology revealed ill-defined skin nodules, which were polypoid in 6 cases. A minority of mononuclear and giant cells (< 5%) revealed striking pleomorphism and showed large nuclei with prominent nucleoli. Immunohistologically, the atypical cells expressed vimentin, but were negative for S-100 protein, the keratin marker MNF116, alpha smooth muscle actin, CD34, factor XIIIa, and monocyte/macrophage markers Ki-M1p, KP1 (CD68), and MAC387. Positivity for MiB1 was very modest (< 1%) and limited to small- and medium-sized, inconspicuous cells. Multinucleate giant cells proved to be heterogenous, on one hand cells with differentiation toward macrophages with positivity for Ki-M1p and KP1, on the other toward fibroblasts positive for vimentin only. These immuno-histochemical results for differentiation markers in atypical cutaneous fibrous histiocytoma are similar to our previous findings and data in atypical fibroxanthoma; MiB1 helps to separate these entities from each other as the latter shows a very high proportion of proliferative atypical cells corresponding to the numerous mitoses seen in routine sections.     

Dermatofibrosarcoma protuberans – An Update

Dermatofibrosarcoma protuberans (DFSP) is a rare fibroblastic skin tumor of intermediate malignancy. Its pathogenesis has not yet been fully clarified. Recent basic genetic research has shown chromosomal translocations, generally termed “ring chromosomes”, in DFSP. These arise from a fusion of chromosome regions 17q22 and 22q13, the gene loci which code the alpha chain of type I collagen. The diagnosis is made histologically. Differentiation from atypical dermatofibroma and dermatomyofibroma, as well as from malignant fibrous histiocytoma, whose prognosis is usually much less favorable, can be improved by immunostaining for CD 34 and Factor XIIIa. The extent of the tumors can be estimated by CT and more precisely with MRI. All these techniques fail to detect the fine tumor fascicles extending into the adjacent connective tissue and fat. Surgery is the therapy of choice for DFSP. The locally infiltrative growth pattern features clinically inapparent extensions which often extend for long distances in a horizontal direction. These tumor extensions are best detected by uninterrupted histological check of all margins, including the base (3‐D‐histology), with paraffin sections. Re‐excision of tumor‐positive areas until tumor‐free margins are obtained (“histographic surgery”) insures a high cure rate (97 %) while preserving normal tissue.     

A Case of Cutaneous Malignant Fibrous Histiocytoma

A 54-year-old Japanese man with cutaneous malignant fibrous histiocytoma on the back is reported. He not only had a past history of thyroid cancer 1 year prior to the onset of the skin tumor, but also had simultaneous bladder cancer. Despite the early, wide resection, the prognosis was rapid and progressive. Histologically, the primary lesion of the skin tumor was difficult to differentiate from dermatofibrosarcoma protuberans; however, the recurrent and the metastatic lesions changed in appearance.     

Atypical fibrous histiocytoma of the skin with CD30 and p80/ALK1 positivity and ALK gene rearrangement

We report the case of a two patients who presented with a solitary, asymptomatic, angiomatoid nodule on the right thigh. Histopathological finding showed a poorly circumscribed lesion, located in the dermis. The morphological aspect strongly suggested the diagnosis of atypical fibrous histiocytoma (AFH), but surprisingly, the neoplastic cells were diffusely CD30+, with a membrane staining devoid of paranuclear dot. The lesions were tested for p80/ALK1 expression. Surprisingly, we found a diffuse cytoplasmic positivity. Interestingly, using break‐apart fluorescent in situ hybridization (FISH), we evidenced an ALK rearrangement in nearly 50% of the neoplastic cells. The expression of CD30 and ALK1 with ALK gene rearrangement raised the possibility of three diagnoses: a primary cutaneous anaplastic large cell lymphoma (ALCL), a cutaneous inflammatory myofibroblastic tumor (IMT), an AFH of the skin associated with ALK gene rearrangement and CD30 positivity. The three hypotheses were discussed and finally, although p80/ALK1 expression and cytogenetic abnormalities in fibrous histiocytoma (FH) are not yet reported to the best of our knowledge, we favored the diagnosis of AFH.     

Unusual benign fibrous and fibrohistiocytic tumors of the skin.

This article reviews recently reported unusual benign fibrous and fibrohistiocytic tumors of the skin. Some of these lesions are variants of common and well-known entities. Because some of these variants have cytologic atypia, they could be confused with malignant neoplasms.     

Spindle-cell and pleomorphic neoplasms of the skin. A clinicopathologic and immunohistochemical study of 30 cases, with emphasis on "atypical fibroxanthomas"

Atypical fibroxanthoma belongs to the family of spindle-cell and pleomorphic neoplasms of the skin. The lineage of differentiation of this tumor and the means whereby it can be diagnostically separated from other similar morphologic entities have been controversial. In order to address these issues, the authors studied 30 spindle-cell and/or pleomorphic cutaneous tumors, including atypical fibroxanthomas (AFXs), superficial malignant fibrous histiocytomas (MFHs), dermatofibrosarcoma protuberans (DFSPs), sarcomatoid squamous-cell carcinomas (SCCs), spindle-cell malignant melanomas (MMs), and leiomyosarcomas, (LMSs). These cases were analyzed using a panel of eight antibodies and the immunoperoxidase technique. AFXs were reactive for vimentin, alpha-1-antichymotrypsin (AACT), alpha-1-antitrypsin (AAT), and cathepsin-B (CB) but failed to display cytokeratin (CK), epithelial membrane antigen (EMA), S-100 protein, and desmin. MFHs and DFSPs exhibited immunophenotypic profiles that were nearly identical to that just described. In contrast, SCCs were typified by positivity for CK and EMA; MMs exhibited uniform reactivity for S-100 protein; and LMSs contained desmin in four of five cases. A surprising result was the expression of S-100 by LMSs. Also, all tumors displayed at least one of the three proteolytic enzymes assessed in this study (AAT, AACT, and CB), demonstrating the relative diagnostic nonspecificity of these determinants. It is concluded that AFXs are "fibrohistiocytic" neoplasms, with substantial morphologic and immunohistochemical similarity to MFHs. The immunohistochemical classification of spindle-cell and pleomorphic tumors of the skin necessitates the use of antibody panels to assess the presence of markers that are characteristic of each diagnostic group.     

Case for diagnosis

Atypical fibroxanthoma is a rare cutaneous tumor found mainly in elderly people on sun-exposed areas of the body. Histologically, atypical fibroxanthoma is considered a malignant fibrous histiocytoma with bizarre neoplastic cells, marked pleomorphism, hyperchromatic nuclei and abundant mitoses. It must be differentiated from other skin tumors, usually by immunohistochemistry, since its diagnosis is made by exclusion.     

EMA positivity in epithelioid fibrous histiocytoma: a potential diagnostic pitfall

Background: Epithelioid fibrous histiocytoma (EFH) represents a morphologic variant of cutaneous fibrous histiocytoma (FH) but can lack many characteristic features. The presence of epithelioid cytomorphology may mimic other dermal neoplasms. Our anecdotal experience of epithelial membrane antigen (EMA) expression in some examples of EFH has caused diagnostic difficulty. Our aim was to examine the immunohistochemical profile and incidence of EMA expression in EFH. Methods: Forty‐four cases of EFH were retrieved from consultation files. Clinicopathologic and immunohistochemical features were evaluated. Results: Membranous EMA positivity was found in tumor cells in 27/42 cases (64%). Focal positivity for factor XIIIa was found in 10/14 (71%) and D2‐40 in 14/27 (52%). Scattered smooth muscle actin (SMA)‐positive tumor cells were seen in 11/43 (25%). Focal positivity for claudin‐1 was found in 3/42 (7%). CD163 staining highlighted stromal macrophages; however, in five cases it was difficult to exclude focal staining of tumor cells. Tumor cells were consistently negative for pan‐keratin, AE1/AE3, S100, CD31, CD34, CD68, desmin, p63, GFAP and CD45/LCA. Conclusion: Frequent EMA expression in EFH represents an unexpected finding and constitutes a potential diagnostic pitfall. Although of uncertain significance, this finding, when combined with established morphologic differences, raises the possibility that EFH is unrelated to classic FH. Doyle LA, Fletcher CDM. EMA positivity in epithelioid fibrous histiocytoma: a potential diagnostic pitfall.     

Current Topics of Immunohistochemistry as Applied to Skin Tumors

Suppressor oncogene p53 is expressed more frequently in the nodular portion than the superficial spreading portion of the same melanoma. PCNA expression follows the same pattern but it is strongly expressed already in the superficial spreading portion. CD34 is found to label dermatofibrosarcoma protuberans. There is the mixture of negative strands but the immunostains are predominantly positive in the three cases studied. Neurogenic tumors are reactive but the intensity of staining is only moderate. Fibrous histiocytoma, dermatofibroma and other fibrohistiocytic tumors are non-reactive. CD34 is expressed in the outer root sheath of hair follicle below the sebaceous gland level. A case of piloepidermal cyst is CD34 positive. CD34 is expressed in vascular endothelial cells; not only hemangiomas but also lymphangiosarcoma is CD34 positive. A case of indeterminate cell histiocytosis following scabies and superficial variant of clear cell sarcoma are discussed as examples of new entities.     

Diagnostic value of CD163 in cutaneous spindle cell lesions

Background:  The histologic diagnosis of atypical fibroxanthoma (AFX) can sometimes be challenging. No specific marker exists to confirm the diagnosis other than excluding other entities. CD163 has been shown to have great specificity for tumors of monocyte/histiocyte lineage. In this study, we evaluated the diagnostic utility of CD163 in diagnosing AFX and in identifying skin lesions with histiocytic/dendritic derivation.
Methods:  A total of 157 cases, including 14 AFXs, 5 spindle cell squamous cell carcinomas (SCCs), and 7 spindle cell/desmoplastic melanomas, along with other cutaneous spindle cell and histiocytic/fibrohistiocytic lesions, were stained with CD163.
Results:  CD163 was expressed in 11 of 14 (79%) AFXs, with moderate to strong intensity. No staining was observed in cases of spindle cell SCC (0/5) and dermatofibrosarcoma protuberans (0/10). Rare spindle cell/desmoplastic melanomas (2/7) and cutaneous leiomyosarcomas (1/5) demonstrated positive staining. CD163 reactivity was seen in 24 of 29 of benign fibrous histiocytomas (BFHs), including 8 of 8 celular fibrous histiocytomas and 6 of 9 epithelioid cell histiocytomas. The majority of cutaneous histiocytic lesions, including juvenile xanthogranuloma, Langerhans cell histiocytosis and Rosai–Dorfman disease, were positive for CD163.
Conclusion:  CD163 is a useful adjunct in distinguishing AFX from other malignant cutaneous spindle cell tumors and offers improved specificity in identifying cutaneous histiocytic/dendritic lesions.     

Lipidized fibrous histiocytoma: clinicopathologic analysis of 22 cases

We report the clinicopathologic analysis of 23 tumors from 22 patients with lipidized fibrous histiocytoma (FH), which has been an underrecognized variant of cutaneous FH. The 16 men and 6 women patients (male/female ratio, 2.7:1) ranged in age from 21 to 82 years (median, 50 years). The location of the tumor was concentrated strikingly in the lower limb, especially around the ankle, hence the alternative informal designation of "ankle-type" FH. The tumors showed relatively large size compared with those of conventional FH, ranging up to 8 cm in greatest dimension (median, 2.5 cm), and tended to be polypoid and yellowish in color. Hyperlipidemia was only a rare and perhaps incidental association in two cases. Histologically, lipidized FH was characterized by accumulation of numerous foam cells, smaller numbers of siderophages, and stromal hyalinization typically appearing "wiry," keloidlike, or osteoidlike, although focal features of ordinary FH almost always coexisted and were identified as a focal storiform or curlicue pattern of spindle tumor cells, epidermal hyperplasia, and peripheral "entrapped" dermal collagen. Although follow-up data are limited, the prognosis appears to be good with no recurrence, even after incomplete excision. These clinicopathologic features highlight lipidized FH as a distinctive variant, which can be distinguished from ordinary or other variants of FH, as well as from other foam cell-rich cutaneous lesions, especially xanthoma.