Presented as a poster at the 44th Annual Scientific Meeting of the American Society of Cytopathology, Denver, Colorado, November 5-9 1996.
Most pathologists generally accept malignant fibrous histiocytoma (MFH) as the most common soft tissue sarcoma in adults. This study examines the authors' aspiration cytopathology experience with this tumor, describes its cytomorphology, and determines the reliability of such a diagnosis by fine-needle aspiration biopsy (FNAB).
The authors' files were reviewed for cases diagnosed as MFH by FNAB, and for surgical pathology cases of MFH previously aspirated but not diagnosed as such by cytology.
Fifty-two cases of MFH (by FNAB or histology) were recovered from the combined files; 42 aspirates had tissue confirmation. Patient age ranged from 15-88 years (mean, 63 years); the male:female ratio was 1.2. Thirty aspirates were from primary tumors, and 12 were from recurrences or metastases. From the 29 aspirates diagnosed as MFH, 24 (83%) were determined to be MFH on subsequent surgical excision. Four of the remaining cases were other sarcoma subtypes, and there was one organizing thrombus (false-positive). The remaining 13 aspirates were identified as unqualified sarcoma (11 cases) or a different sarcoma subtype (2 cases). Eleven of these were histologically diagnosed as MFH, and 2 as other sarcomas. No single cytologic feature or combination of features distinguished MFH. Patterns ranged from single cells to large storiform fragments. Spindled, plasmacytoid, and pleomorphic cell shapes were found; pleomorphic cells were often multinucleated. All cases of MFH had malignant nuclear morphology. Diagnostic pitfalls included low cellularity, obscuring blood and inflammation, and inadequate clinical and/or radiologic information.
Most pathologists generally accept malignant fibrous histiocytoma (MFH) as the most common soft tissue sarcoma in adults. Several large series have demonstrated fine-needle aspiration biopsy (FNAB) as an acceptable procedure in the evaluation of soft tissue masses.1-10 Sensitivity and specificity for the identification of soft tissue malignancies approach 95% and 98%, respectively, when performed and interpreted by experienced cytopathologists in the context of adequate clinical/radiographic information.5 In light of the recent controversy in the surgical pathology literature regarding the validity of MFH as a diagnostic entity,11 the authors examined their own aspiration cytopathology experience with this tumor.
The files from three institutions (Medical College of Virginia, Richmond, Virginia, State University of New York Health Science Center, Syracuse, New York, and the Instituto Portugues de Oncologia de Fransisco Gentil, Lisbon, Portugal) were reviewed for cases diagnosed as MFH by FNAB, and for surgical pathology cases of MFH previously aspirated but not diagnosed as such by cytology. Palpable tumors were aspirated by a cytopathologist using 23- or 25-gauge needles and standard FNAB technique; deep organ tumors were sampled under radiologic guidance, with immediate interpretation by a cytopathologist. Air-dried and/or alcohol fixed material was obtained and stained by the Diff-Quik® (Fisher Scientific, Biochemical Sciences, Inc., Swedesboro, NJ) or Papanicolaou method, respectively. In some cases, the needle was rinsed and aspirate material preserved in RPMI® (Biowhittaker, Walkersville, MD) for cytopsins or subsequent histologic processing as a cell block. Histologic slides of the surgical specimens were stained by routine hematoxylin and eosin. All FNAB smears were evaluated for multiple cytologic characteristics (Table 1): cellularity, pattern, presence of fragments and stroma, background blood, necrosis, and inflammation, number of cell types, nuclear features (shape, membrane, nuclear:cytoplasmic ratio, chromatin, and nucleoli), cytoplasmic features (amount, granularity, presence and quality of vacuoles), and mitoses.
Table 1. Evaluation of Cytologic Features
No. of cell types
Nuclear: cytoplasmic ratio
Presence and quality of vacuoles
Fifty-two cases of MFH, diagnosed by FNAB or histology, were recovered from the authors' combined files. The age of these 48 patients ranged from 15-88 years (mean, 63 years); the male:female ratio was 1.2. Thirty-three aspirates were from primary tumors, 11 from recurrences, and 5 from metastases; 3 were unknown. Location of the primary tumors included lower extremity (18), upper extremity (6), retroperitoneum (3), head and neck (2), chest wall (2), and suprapubic region (1). Location of recurrences included lower extremity (4), upper extremity (4), head and neck (2), and chest wall (1). Metastases involved lymph nodes (3) and lung (2).
Of the 52 cytology cases, 40 had surgical follow-up. Table 2 lists the cytologic diagnoses and corresponding surgical pathology diagnoses. There were three major cytologic diagnostic categories: MFH or favor MFH, pleomorphic sarcoma, and spindle cell neoplasm/sarcoma. Of the 35 FNAB diagnosed as MFH, 21 of 25 with subsequent histology (84%) were confirmed as MFH. However, when recurrences and metastases were excluded, the accuracy rate decreased to 72% (18 of 25). Three of the remaining cases were other sarcoma subtypes, and one was an organizing thrombus (false-positive). Seven of 9 pleomorphic sarcomas by cytology (78%) had histologic follow-up; six were MFH, and one remained sarcoma, not further specified. All 5 spindle cell neoplasms/sarcomas (100%) underwent tissue confirmation; 4 were MFH, and 1 was leiomyosarcoma (LMS). There was one FNAB each of lesions diagnosed as fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), and LMS that were subsequently diagnosed as MFH on tissue sections. Of the 12 FNAB without histologic follow-up, 10 were termed MFH, and 2 pleomorphic sarcoma. Five were primary tumors, and seven were recurrences or metastases of MFH. There were no false-negative (FN) results.
Table 2. Cytologic and Histologic Correlation
Cytologic diagnosis (n = 52)
Histologic diagnosis (n = 40)
MFH: malignant fibrous histiocytoma; NOS: not otherwise specified.
MFH (n = 35)
Malignant fibrous histiocytoma (21)
Sarcoma, NOS (1)
Pleomorphic sarcoma (n = 9)
Malignant fibrous histiocytoma (6)
Sarcoma, NOS (1)
Spindle cell sarcoma (n = 4)
Malignant fibrous histiocytoma (4)
Spindle cell neoplasm (n = 1)
Fibrosarcoma (n = 1)
Malignant fibrous histiocytoma (1)
Liposarcoma (n = 1)
Malignant fibrous histiocytoma (1)
Dermatofibrosarcoma protuberans (n = 1)
Malignant fibrous histiocytoma (1)
Histologic diagnosis and subtyping of MFH was performed according to previously published criteria.12, 13 The vast majority of cases were of the storiform subtype, with only three qualifying as the myxoid variant. Immunohistochemical stains on paraffin embedded tissue were available for review in only ten cases. The two LMS were actin positive, and the one pleomorphic rhabdomyosarcoma (RMS) was desmin and actin positive. The six MFH were all vimentin positive; A1ACT, HAM56, and factor XIII were variably expressed in four MFH, and the remaining two cases remained negative for all other markers except vimentin.
MFH (35 cases)
There were no cytologic features that distinguished MFH from other high grade/pleomorphic tumors (Table 3). Cellularity was variable, with 72% of cases having moderate to high cellularity (2-4+). Bloody background occurred in 21 aspirates; inflammation was minimal in most cases. Necrosis was observed in only three cases. Tissue fragments varied in size, from small to large. A predominant storiform pattern existed in ten MFH (Fig. 1 (116K)) and one LMS. A stromal component was absent in 35 aspirates; myxoid stroma was observed in 5, including 2 of the 3 cases of myxoid MFH (Fig. 2 (63K)). There were often two or three different cell types, which included fusiform spindle or round cells, large pleomorphic cells, and multinucleated giant cells (MGC) (Figs. 3 (62K) and 4 (113K)). Nuclei in the three cell types displayed malignant characteristics, with anisonucleosis, nucleomegaly increased nuclear:cytoplasmic ratio, notched nuclear membranes, and abnormal chromatin distribution (Fig. 5 (113K)). Nucleoli were variably present, and were either single or multiple. Cytoplasmic volume depended on cell type, from minimal in spindle cells to abundant in pleomorphic and MGCs, and was either finely granular or coarse. Vacuoles were usually absent; however, when present, they were small and scant. Mitotic figures were observed in ten cases, and usually were few in number but bizarre in morphology (Fig. 6 (156K)).
Of the two histopathologically diagnosed LMS, one case was a chest wall mass in a patient age 80 years; storiform fragments and spindle cells and MGCs were present. The other LMS represented a postirradiation sarcoma, occurring 10 years later in a patient with a history of MFH; FNAB smears revealed a single predominantly spindle cell population (Fig. 7 (124K)). The RMS could not be distinguished from MFH based on cytologic features alone (Fig. 8 (149K)). Cell block/cytospin material was not available for ancillary studies in these cases.
False-Positive (one case)
Evaluation of a single false-positive FNAB of a suprapubic mass in a 54-year-old male revealed overall low cellularity with obscuring blood and inflammation. Rare atypical spindled cells with enlarged nuclei were present. FNAB diagnosis was sarcoma, favoring MFH; subsequent excisional biopsy revealed an organizing thrombus. Immunostains on cytologic material were not performed.
Additional cytologic material as cell block or cytopsins was available in only 12 cases. Immunocytochemistry was performed in three cases (one cell block and two cytopsins); one MFH was correctly diagnosed, one remained spindle cell sarcoma, and one RMS was incorrectly classified as MFH (desmin/actin not performed).
The role of FNAB in the evaluation of soft tissue lesions remains controversial, although the diagnostic accuracy approaches that of other body sites in distinguishing between benign and malignant masses. In establishing a diagnosis of sarcoma, the sensitivity and specificity both approach 96%.5 Although the traditional diagnostic approach to soft tissue masses has been surgical biopsy, FNAB has become an acceptable procedure in the initial assessment of these lesions in some medical centers. The utility of this procedure is, of course, dependent on the procurement of an adequate sample. This may be a problem in densely fibrous or vascular lesions, and in certain benign and low grade mesenchymal tumors. Very little has been published comparing FNAB with core needle biopsy. Bennert et al.3 reported 100% correlation of the FNAB with subsequent histologic diagnosis of cases of sarcoma; in only seven cases did the core needle biopsy provide additional classification. More important, the core needle biopsy did not contribute to patient management.
To the authors' knowledge, this study represents the largest series in the cytopathology literature. Although the cytologic features of MFH have been previously described, most articles comprise relatively small numbers and/or case reports.2, 14-20 To the authors' knowledge, the largest series of MFH prior to the current study was reported by Walaas et al.21 Their description of the cytologic features of 40 cases included 2 main tumor cell types, atypical fibroblast-like cells and mononucleated and multinucleated large polymorphic histiocytic-like cells, with the latter exhibiting phagocytosis.
There are no distinctive cytologic features specific for MFH. Aspirates smears are typically cellular, with individual cells displaying obviously malignant features. Two to three cell types are usually present and are comprised of spindle or ovoid tumor cells intermixed with pleomorphic and/or MCGs. There were a few cases in which there was a single tumor cell population of spindle morphology; one of these cases was a LMS in which the nuclei had more of a blunted shape (Fig. 9 (76K)). Another represented an unclassifiable sarcoma with a pattern of small cells (Fig. 10 (95K)). Phagocytosis by large histiocytic-like giant cells was not a distinguishing feature, as suggested by Walaas et al.21 The pleomorphic RMS was virtually identical to MFH with the exception that the tumor cells tended to have cytoplasmic tails (Fig. 11 (82K)). Unfortunately, the use of ancillary immunohistochemistry was not particularly helpful in the subclassification of the cases in the current study.
The generally low mitotic activity observed in the cytologic cases of MFH is an unexpected but interesting finding; intuitively, one would expect relatively high mitotic rates, as identified in tissue sections. Prior quantification of mitoses has not been previously reported. A few articles mention the presence of mitoses with qualifications of typical and atypical.2, 19, 21 The low mitotic activity probably reflects the nature of the specimen (i.e., aspirate smears are comprised of a cell monolayer, whereas histologic sections are multilayered). In the 35 cases diagnosed by FNAB as MFH, 21 were subsequently confirmed. There were 3 misclassifications (14%), and one false-positive result. This latter case diagnosed as MFH represented an organizing thrombus in the suprapubic region. The atypia observed in the FNAB was misinterpreted due to very low cellularity and obscuring blood and inflammation. As in any other body site, diagnosing malignancy on suboptimal or inadequate aspirate material is a repeatedly treacherous pitfall. However, what constitutes an “adequate” aspirate of a soft tissue tumor has yet to be defined, and remains subjective. In the less specific categories of pleomorphic and spindle cell sarcoma, most of these tumors were histologically confirmed as MFH. In none of the current study cases was a sarcoma misdiagnosed as benign (0% false-negative rate).
The differential diagnosis of MFH includes any pleomorphic mesenchymal tumor, and pleomorphic nonmesenchymal tumor, such as anaplastic carcinoma and malignant melanoma.22, 23 If lymph node metastases are involved, then anaplastic/large cell lymphoma and lymphocyte-depleted Hodgkin's disease also should be considered, particularly because these two entities can have MGCs and scant lymphoglandular bodies. The distinction from MFH typically requires clinical and radiographic correlation with cytopathology, as well as ancillary testing. More specific subtyping of sarcomas by FNAB is more problematic. Difficulties exist in adequate sampling of morphologically heterogeneous tumors and in acquiring sufficient material for cell block processing and/or cytospins, particularly for immunocytochemistry that requires extensive (and expensive) antibody panels. Therefore, there is a strong argument for trying to eliminate specific subtyping of sarcomas by FNAB, and instead adopting more descriptive terminology reflective of tumor grade. The latter, as well as tumor size and depth, are prognostically valuable in patient management.4, 12, 24 Unfortunately, general consensus of sarcoma grading does not exist within the surgical pathology literature, making this a difficult proposition. Perhaps the best approach is to categorize these lesions by FNAB as follows: nonneoplastic, benign mesenchymal neoplasm, sarcoma (low or high grade), or spindle cell neoplasm, not further classifiable. Any further classification, if necessary, may be reserved for the surgical specimen.2
One could apply the same argument to the diagnosis of sarcomas in surgical pathology, depending on one's philosophy as a “lumper” or a “splitter.” There has been recent debate as to whether MFH should actually exist as a specific diagnostic entity.12, 25 Several publications have attempted to discern the tumor cell of origin based on tissue culture studies.26-34 There are two suggested hypotheses: the tumor cells are primitive mesenchymal cells that exhibit the behavior of a “facultative” histiocyte, or the tumor cells represent a common, final pathway of undifferentiated sarcomas. The diagnosis of MFH is typically one of exclusion, when evidence of more specific differentiation cannot be demonstrated. In Fletcher's recent article,11 74% of cases initially diagnosed as MFH were reclassified after additional histologic material was submitted for examination, and extensive immunochemistry and/or electron microscopy were performed. Of the remaining cases considered as MFH, there were no consistent morphologic characteristics that identified these tumors as MFH. Fletcher also pointed out that subclassification of pleomorphic sarcomas provided little additional information clinically, because prognosis and treatment response remained unaffected.11
The vast majority of the cytology cases in the current study did not have cell block material, or sufficient aspirate smears to perform an extensive immunohistochemical panel necessary to subcategorize the sarcomas. In the absence of such ancillary testing, the diagnosis of MFH was made based on cytologic appearance and clinical presentation. Dr. Fletcher's criticism of MFH arose after performing extensive immunohistochemical staining, additional archival tissue processing, and electron microscopic examination. This represents the ideal situation, albeit a very expensive one, and questionably realistic in light of today's conservative views regarding medical cost. If patient prognosis is unchanged despite such aggressive additional workup, perhaps the cytologic approach to soft tissue lesions should be descriptive.
To add to the confusion, there have been recent reports of MFH expressing cytokeratin, an antibody that in the past has been solely expressed by epithelial tumors.35 As discussed by Swanson36 and Frable,37 there are inherent problems with immunohistochemistry: interpretation is subjective, there is a lack of adequate reporting of techniques, and there is increasing sensitivity and concentration of recently developed antibody probes. What defines a “positive” signal? And more important, what does that signal mean?
Genetic alterations specific for certain types of soft tissue sarcomas have been investigated by a number of authors in the past several years, including RMS, synovial sarcoma, osteosarcoma, liposarcoma and its subtypes, malignant peripheral nerve sheath tumors, Ewing's sarcoma/primitive neuroectodermal tumor, clear cell sarcoma, epitheliod sarcoma, myxoid chrondrosarcoma, fibrosarcoma, LMS, alveolar soft part sarcoma, fibromatosis and desmoid tumors, DFSP, hemangiopericytoma, and MFH.37 There appear to be some specific genetic changes with some of these tumors. MFH has been characterized by some chromosome abnormalities, but at diverse sites that include 1q11, 3p12, 11p11, and 19p13.38, 39 Trisomy 7 has been found in two cases in unrelated patients.40 Szymanska et al. recently confirmed heterogeneous genetic findings in MFH.41
Given the diversity of MFH, as determined using special techniques, and the generally high grade and aggressive nature of this sarcoma, is subtyping by either histology or FNAB relevant? Until the desired grading scheme of soft tissue sarcomas is achieved, the debate will continue.