Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis

Intra-abdominal spindle cell lesions are uncommon and often present a diagnostic challenge. An important group of such lesions are the gastrointestinal stromal tumours. Other intra-abdominal spindle cell lesions include fibromatosis, various sarcomas-in particular, leiomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumour-and, in women, endometrial stromal sarcoma. Less common lesions are inflammatory myofibroblastic tumours, the mesenteric spindle cell reactive lesions, retroperitoneal fibrosis, and solitary fibrous tumour. A variety of intra-abdominal tumours of nonmesenchymal origin may have a spindle cell/sarcomatoid morphology; these include sarcomatoid carcinoma, malignant melanoma and, in women, sarcomatoid granulosa cell tumour. Finally, metastatic sarcomas from pelvic or extra-abdominal organs need also be considered. A set of practical aids to the diagnosis of intra-abdominal spindle cell lesions is presented to assist pathologists dealing with such lesions, particularly with regards to the consideration of differential diagnoses.     

An approach to the diagnosis of spindle cell lesions of the breast

Although most breast spindle cell lesions (BSCLs) are rare, they constitute a wide spectrum of diseases, ranging from reactive processes to aggressive malignant tumours. Despite their varied histogenesis and behaviour, some lesions show an overlap of morphological features, making accurate diagnosis a challenging task, particularly in needle core biopsies. Clinical history and immunohistochemistry can help in making a correct diagnosis in morphologically challenging cases. To make an accurate diagnosis, it is important to maintain a wide differential diagnosis and be familiar with the diverse morphological appearances of these different entities. BSCLs can generally be classified into bland‐looking and malignant‐looking categories. In the former, the commonest diagnosis is scarring. However, it is important to distinguish low‐grade spindle cell metaplastic breast carcinoma from other benign entities, as the management is clearly different. In the malignant category, it is important to differentiate metaplastic carcinoma from other malignant primary and metastatic malignant spindle cell tumours of the breast, such as malignant phyllodes tumour, angiosarcoma, and melanoma. This review focuses on the classification and histological and molecular diagnosis of various BSCLs, with an emphasis on the diagnostic approach, including in core biopsies.     

Fine-needle aspiration of spindle cell and mesenchymal lesions of the salivary glands

Fine-needle aspiration (FNA) biopsy can accurately diagnose epithelial lesions of the salivary gland. Its role in the evaluation of salivary gland lesions containing a significant spindle cell component is less clear. We describe the cytologic features of 25 spindle cell lesions of the salivary gland and discuss the differential diagnosis and potential diagnostic pitfalls. Twenty-five aspiration smears (3.0%) containing a significant spindle cell or mesenchymal component were identified out of 844 salivary gland FNAs performed over a 5-year period. These aspiration smears were from 25 patients. The smears were classified into three categories: 1) reactive or inflammatory conditions, including one granulation tissue and four granulomatous sialoadenitis; 2) benign neoplasms, including one schwannoma, one fibromatosis, four lipomas, and nine pleomorphic adenomas; 3) malignant neoplasms, including one recurrent malignant fibrous histiocytoma (MFH), two metastatic melanomas, and two metastatic osteosarcomas. There was one false-negative biopsy. The metastatic desmoplastic malignant melanoma was initially interpreted as a reactive lymph node with fibrosis. A specific diagnosis was rendered in 21 (84%) cases. The schwannoma was diagnosed cytologically as benign spindle cell lesion, not otherwise specified (NOS), fibromatosis as an atypical cellular proliferation, and MFH as poorly differentiated malignant neoplasm. Salivary gland lesions with a significant spindle cell component are rarely encountered on FNA and constitute a heterogeneous group. A specific diagnosis can be rendered in the majority of cases by correlating clinical and cytologic findings.     

A study of eleven cutaneous malignant melanomas in adults with small-cell morphology: emphasis on diagnostic difficulties and unusual features

AIMS: To describe the clinicopathological and immunohistochemical features of cutaneous malignant melanomas with a pure or mixed small-cell pattern in 11 adult patients, and to discuss the diagnostic difficulties encountered. METHODS AND RESULTS: Haematoxylin and eosin-stained sections of each case of cutaneous small-cell malignant melanoma, together with locally recurrent skin lesions and, where available, metastatic deposits, were re-examined. Available immunohistochemical sections were evaluated. Clinical follow-up data were obtained in each case. One patient presented with metastatic disease, the others presented with cutaneous lesions. Suggested initial diagnoses included malignant melanoma, non-Hodgkin's lymphoma, Merkel cell carcinoma and sarcoma. All the tumours were in the vertical growth phase. Nine had a junctional component, often inconspicuous. The lesions showed either a pure small-cell pattern or a mixed pattern with more conventional areas. In one case, there was colonization of a basal cell carcinoma by invasive malignant melanoma. Variable retention of small-cell morphology in local recurrences and metastases was observed, although in some cases more typically pleomorphic cells were present. In the cases tested, there was strong immunostaining for S100 protein and NKI-C3, and variable immunostaining for HMB45 and Melan-A. Non-melanocytic markers were negative. CONCLUSIONS: The possibility of a small-cell malignant melanoma should be considered in the assessment of cutaneous and non-cutaneous small-cell neoplasms. The correct diagnosis requires careful evaluation for junctional activity, melanin production and the use of a panel of melanocytic markers.     

Melan-A/Mart-1 expression in various melanocytic lesions and in non-melanocytic soft tissue tumours

AIMS: The purpose of this study was to test different malignant non-melanocytic tumours with the commercially available antibody Melan-A to examine its diagnostic specificity and to compare the S100, Melan-A and HMB-45 reactivity in various melanocytic lesions. METHODS AND RESULTS: Seventy-three benign and malignant melanocytic lesions and 31 cases of non-melanocytic tumours, sarcomas, carcinomas and carcinoids, were selected. Immunohistochemical staining of paraffin sections, following a high temperature antigen unmasking technique, was performed. Melan-A stains junctional and dermal melanocytes in all benign melanocytic lesions with the exception of neuro-naevoid areas. The epithelioid and the spindle cells in malignant melanomas did not show considerable difference in their Melan-A reactivity. The predominantly spindle cell type mucosal melanomas contained more Melan-A-positive cells than HMB-45-positive cells and similar results were observed in metastatic malignant melanomas. In desmoplastic melanomas the positivity of Melan-A was not consistent. None of the sarcomas, carcinomas and carcinoids expressed Melan-A. Almost all soft tissue tumours, except for two malignant gastrointestinal stromal tumours, were unreactive for HMB-45. These two cases did not react with Melan-A antibody. CONCLUSIONS: Melan-A is a useful additional marker to differentiate non-melanocytic tumours from primary or metastatic melanoma. In melanocytic lesions the Melan-A staining pattern is similar to S100, but seems to be more specific. In desmoplastic melanomas, however, the variable Melan-A staining further necessitated detailed histological examination and the use of the S100 reaction.     

Superficial malignant peripheral nerve sheath tumor: a rare and challenging diagnosis

We reviewed the clinicopathologic features of 5 cases of malignant peripheral nerve sheath tumor (MPNST) manifesting in superficial locations associated with cutaneous neurofibromas (4 cases) or superficial peripheral nerve (1 case). Four cases had spindle cell morphologic features and were at least focally positive for S-100 protein, whereas the associated benign neural elements had more extensive S-100 immunoreactivity. The single epithelioid case was diffusely and strongly positive for S-100 protein. Melanoma markers, epithelial membrane antigen, glial fibrillary acidic protein, neurofilament, pancytokeratin (AE1/AE3), CD34, smooth muscle actin, and desmin were negative in all cases. There were no local recurrences, but 3 patients died of metastatic disease within 2 to 30 months (median, 21 months). MPNSTs can occur in a superficial location and may have an aggressive clinical course. Immunohistochemical markers are helpful in excluding other lesions in the differential diagnosis. However, identification of a benign precursor or origin from a nerve may be the most definitive way to properly classify these rare lesions.     

Primary de-differentiated,trans-differentiated and undifferentiated melanomas: overview of the clinicopathological,immunohistochemical and molecular spectrum

Primary cutaneous and mucosal melanoma shows a wide histological spectrum. The correct diagnosis depends upon the demonstration of melanocytic differentiation by recognition of an associated in-situ component or immunohistochemical evidence of a melanocytic phenotype using conventional melanocytic markers, such as S-100, SOX10, Melan-A and HMB-45. Exceptionally, melanomas lose their melanocytic phenotype, at least focally, and show differentiation towards other lineages. Review of the literature shows that de- and trans-differentiation in melanoma is rare but probably under-recognised and under-reported. These often large and frequently ulcerated tumours affect adults and show a wide anatomical distribution, including mucosal sites, although there is a predilection for sun-damaged skin of the head and neck. Histologically, the tumours are biphasic and contain a pre-existing conventional melanoma. The de-differentiated component closely resembles atypical fibroxanthoma, both morphologically and immunohistochemically. Trans-differentiated melanoma may show rhabdomyosarcomatous or spindle cell carcinomatous features. Undifferentiated melanomas are similar tumours in which the conventional melanoma component is absent. Their diagnosis depends entirely upon the clinical context and identification of a classical melanoma driver gene mutation, i.e. BRAF V600E. The diagnosis of these rare and unusual tumours is challenging, and requires thorough tumour sampling and recognition of the background of a pre-existing but often focal conventional melanoma together with molecular analysis.     

Malignant melanoma mimicking giant cell variant of glioblastoma multiforme: a case report and review of literature

We present a case of metastatic malignant melanoma in a patient initially diagnosed with glioblastoma multiforme, giant cell variant. A forty year old female presented to our institution for a re-resection of a recurrent right parietal lobe mass, presumed to be recurrent glioblastoma multiforme. PET scan during preoperative evaluation revealed a 3 cm left lower lobe lung mass. Metastatic glioblastoma to lung was considered in the differential diagnosis. Resection of the brain mass revealed a highly pleomorphic giant and spindle cell lesion with an immunophenotype strongly supportive of melanoma. Immunostains for melanocytic markers were subsequently performed on the lung biopsy specimen, and demonstrated diffuse staining of the atypical cells, supporting the diagnosis of malignant melanoma in the lung. This case demonstrates the importance of considering melanoma in the differential in any tumor with high grade features.     

Spindle cell tumours of the breast: practical approach to diagnosis

Spindle cell tumours of the breast are uncommon and often present diagnostic challenges. The most important is the sarcomatoid/metaplastic carcinoma, which has monophasic and biphasic variants. Each of these groups presents special diagnostic difficulties. In the monophasic variant the mesenchymal component predominates and the epithelial element forms a minor component often detected only after immunohistochemical study. The spindle cell areas may be bland and therefore under-diagnosed as nodular fasciitis or fibromatosis. Alternatively they may be highly malignant with a pattern that is misinterpreted as primary sarcoma of the breast. In the biphasic variant, the difficulty is in distinguishing between sarcomatoid carcinoma, myoepithelial carcinoma or malignant phyllodes tumour. Other spindle cell lesions of the breast include the various myofibroblastic tumours, the spindle cell variant of adenomyoepithelioma, the varied primary breast sarcomas, metastatic tumours with spindle cell morphology and, finally, the very rare follicular dendritic cell tumour. A simple practical approach to the diagnosis of spindle cell lesions is presented to help the general surgical pathologist to compile a differential diagnosis and to arrive at the correct conclusion     

Malignant melanoma with neuroendocrine differentiation: clinical, histological, immunohistochemical and ultrastructural features of three cases

AIM: To document the clinical, histological, immunohistochemical and ultrastructural features of three malignant melanomas showing neuroendocrine differentiation. METHODS AND RESULTS: Three patients, two with primary cutaneous melanoma and one with nasal mucosal melanoma, subsequently developing or simultaneously presenting with metastatic malignant melanoma, were studied by conventional histological technique, immunohistochemistry of formalin-fixed paraffin-wax embedded tissues, and electron microscopy of epoxy-resin-embedded tumour tissue. Tumours showed either small cell or conventional malignant melanoma cell morphology. One of the three primary melanocytic lesions (the nasal melanoma) exhibited neuroendocrine differentiation immunohistochemically. All three metastatic malignant melanomas showed, in varying combinations, immunohistochemical and ultrastructural evidence for neuroendocrine differentiation: they were positive for the melanocytic markers, S100 protein, HMB-45, Melan-A and tyrosinase, and the neuroendocrine markers chromogranin, synaptophysin and neurofilament protein. Ultrastructural study in two of the metastases revealed neuroendocrine granules but no lattice-bearing melanosomes. CONCLUSIONS: The cases described are the most comprehensively investigated malignant melanomas showing neuroendocrine differentiation to date, and the first to document neuroendocrine differentiation ultrastructurally in these tumours. Malignant melanoma with neuroendocrine differentiation therefore needs to be recognized among the other, better known variants of malignant melanoma.     

Differential diagnosis of non-epithelial tumors of the pancreas: malignant non-epithelial pancreatic tumor with focal pigmentation

Non-epithelial tumors only rarely affect the pancreas. In this report, we describe a malignant non-epithelial tumor with combined characteristics of malignant peripheral nerve sheath tumor (MPNST) and malignant melanoma. To more closely define the differential diagnosis of MPNST with focal pigmentation versus metastatic melanoma resembling MPNST, the tumor was investigated using histomorphology, immunohistochemistry, electron microscopy, and comparative genomic hybridization. As a result, from these analyses and from clinical findings, the diagnosis of a pancreatic MPNST with focal pigmentation was favored. However, the diagnosis of a malignant melanoma or a composite tumor could not be definitely ruled out, due to the considerable morphological and genotypical overlap between both entities, which can be explained by the close histogenetic relationship between both tumor entities.     

Fine-needle aspiration cytology of malignant peripheral nerve sheath tumors

The histopathologic features of malignant peripheral nerve sheath tumors (MPNSTs) have been well described. There have been limited studies on the cytologic features of MPNST. In this present study, we have retrospectively reviewed eight histopathology confirmed cases of MPNST over a 5-year period. Detailed cytomorphological analysis of these cases was carried out individually by two observers. On cytology, these cases were diagnosed as benign spindle-cell tumor (two), spindle-cell tumor possibly benign (one), spindle-cell tumor possibly malignant (one), malignant spindle-cell tumor (two), spindle-cell tumor, and neural origin (two). The cardinal cytomorphologic features were loosely cohesive clusters and fascicular arrangement of spindle cells with rounded ends. The kinking of nuclei was not a conspicuous finding. Fibrillary background was noted in two of the cases. Nuclear pleomorphism was ranged from mild to moderate degree. One case exhibited extensive intranuclear pseudoinclusions. Mitotic figures (including atypical forms) were present in almost all the cases. Possibly a constellation of cytologic features such as clusters of short and long fascicles of cells admixed with dissociated spindle cells of round-ended nuclei and prominent nucleoli on myxoid or fibrillary background and frequent mitosis may be helpful in diagnosis of MPNSTs. The cytomorphologic features along with clinical correlation are necessary to increase the diagnostic accuracy of MPNST on aspiration cytology.     

The spectrum of minimal deviation melanoma: a clinicopathologic study of 21 cases

A retrospective study of 21 patients with the histopathologic diagnosis of minimal deviation melanoma (MDM; n = 18) and borderline melanoma (BM; n = 3) was undertaken to determine the prognosis for these patients compared with that for patients with other types of malignant melanoma. The findings indicate that the prognosis for these uncommon nevomelanocytic tumors is somewhat better than that for other malignant melanomas. Follow-up periods in this series ranged from 18 to 96 months (mean, 57 months). Primary lesions ranged in thickness from 1.6 to 10.4 mm. The histopathologic subtypes included the Spitz variant (nine patients), the spindle cell variant (six patients), the combined spindle and epithelioid cell type (three patients), and the small epithelioid cell type (three patients). Only two of the patients died of widespread metastatic disease. Comparison of the histologic and clinical prognostic indicators of mortality in patients who have malignant melanoma with the clinical and pathologic features seen in this series of 21 patients would appear to indicate a diminished tendency toward metastatic or recurrent disease in patients with MDM and BM.     

Expression of the B-cell proliferation marker MUM1 by melanocytic lesions and comparison with S100, gp100 (HMB45), and MelanA.

The diagnosis of malignant melanoma remains one of the most difficult to render in surgical pathology, partially because of its extreme histologic variability. Limits in the sensitivity and/or specificity of the currently available melanocytic markers such as anti-S100, HMB45, and anti-MelanA further complicate this problem. Previous work has demonstrated that the B-cell proliferation/differentiation marker MUM1/IRF4 is detected in malignant melanoma and hematolymphoid malignancies, but not in any other neoplasm tested (including colonic, lung, breast, and ovarian carcinomas). In the current study, we have examined MUM1 protein expression in 61 melanocytic lesions and compared the diagnostic usefulness of this marker with that of anti-S100, HMB45, and anti-MelanA. The results indicate that MUM1 is positive in 33/36 (92%) cases of melanoma (21/22 [95%] conventional primary melanomas and 12/14 [86%] metastatic melanomas). In comparison, positivity was seen with anti-S100 in 36/36 cases (100%, 22 primary and 14 metastatic), HMB45 in 28 cases (78%, 17 primary and 11 metastatic), and anti-MelanA in 27 cases (75%, 19 primary and 8 metastatic). Although negative in schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors, MUM1 is detected in only one in eight cases of spindle cell and desmoplastic melanomas. With the exception of desmoplastic and spindle cell melanomas, MUM1 appears to be a sensitive and specific immunohistochemical stain for melanocytic lesions and may prove to be a useful addition to the current panel of melanoma markers.     

Spindle-cell non-pleomorphic atypical fibroxanthoma: analysis of a series and delineation of a distinctive variant

Atypical fibroxanthoma is a bizarre, cytologically malignant but usually clinically benign, lesion which typically arises in sun-damaged skin of the head and neck region in the elderly. Classically, its morphology is said to represent the dermal counterpart of pleomorphic malignant fibrous histiocytoma. We have identified 10 cases of a more monomorphic spindle-celled, fascicular variant which, paradoxically, was often mistaken for a clinically malignant lesion because it lacked the pleomorphism of conventional atypical fibroxanthoma. These tumours all arose in the head and neck region as polypoid lesions in the elderly. The tumours were confined to the dermis, often had an epidermal collarette, showed an eosinophilic fascicular morphology and were highly mitotic. All 10 were vimentin positive and five showed very focal actin positivity. Desmin, keratin and S-100 protein were negative in all cases. The clinical course was benign in all cases, justifying their accurate recognition. The principal differential diagnoses are spindle cell squamous carcinoma, spindle cell melanoma and leiomyosarcoma. Immunohistochemistry plays a key role in this distinction.     

Anchoring fibrils in a spindle cell squamous carcinoma

To the best of our knowledge anchoring fibrils in tumours have been reported to occur only in cutaneous cylindromas and squamous cell carcinomas of oral mucosa and larynx. In this paper we describe a difficult-to-diagnose malignant spindle cell tumour where the striking feature was the presence of large numbers of anchoring plaques and anchoring fibrils in the tumour matrix. On the basis of light microscopic and immunohistochemical studies several diagnoses were preferred, such as malignant fibrous histiocytoma, neurofibrosarcoma, malignant schwannoma, desmoplastic melanoma and spindle cell squamous carcinoma (more fully referred to as 'spindle cell variant of squamous cell carcinoma'). The presence of anchoring fibrils in this tumour strongly supports the diagnosis of spindle cell squamous carcinoma. Our knowledge about the occurrence of anchoring fibrils in tumours is scant, perhaps because they are likely to be missed unless they are present in large numbers, or perhaps because they are mistaken for native collagen fibrils. It seems to us that a systematic search for anchoring fibrils in tumours is warranted, for knowledge about their occurrence or absence in various types of tumours may add yet another diagnostic marker in the armamentarium of the diagnostic electron microscopist and it may also assist in resolving the histogenesis of some controversial neoplasms.     

Cytologic features of metastatic and recurrent melanoma in patients with primary cutaneous desmoplastic melanoma

Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by malignant spindle cells associated with prominent fibrocollagenous stroma. Primary melanomas may be entirely desmoplastic ("pure" DM) or exhibit a desmoplastic component admixed with a nondesmoplastic component ("combined" DM). The cytologic features of only 5 cases of DM have been reported previously. Fine-needle biopsy (FNB) specimens from 20 recurrent or metastatic lesions in patients with cutaneous DM and 20 recurrent or metastatic lesions from patients with primary cutaneous non-DM were examined and compared. FNB specimens of patients with DM were less cellular (P = .009) and less often exhibited intranuclear cytoplasmic invaginations (P = .008) and mitotic figures (P = .006) than specimens from patients with non-DM. "Combined" DMs were more commonly composed of epithelioid cells (P = .017) and less often contained bizarre/giant tumor cells (P = .010) than did "pure" DMs. Recurrent and metastatic DM has a range of cytologic appearances. Awareness of the cytologic features and careful clinicopathologic correlation will assist in accurate FNB diagnosis.     

A case of amelanotic spindle-cell melanoma presenting as metastases to breast and axillary lymph node: diagnosis by FNA cytology

Metastatic neoplasms to the breast are relatively rare. Spindle-cell lesions of the breast are also uncommon. Here we present a case of fine-needle aspiration (FNA) of an amelanotic, spindle-cell melanoma metastatic to the breast and axillary lymph node. The patient was a 47-yr-old female who presented with a right breast mass, left axillary adenopathy, and a pigmented skin lesion on the back. FNA of the right breast and left axilla showed malignant, nonpigmented spindle cells that were weakly positive for HMB-45 on immunocytochemistry. The skin biopsy showed a pigmented malignant melanoma with epithelioid features, and also weak positivity for HMB-45. Although malignant melanoma is one of the more common tumors to metastasize to the breast, this is the first known case that showed exclusive spindle-cell morphology. History and physical examination were crucial in making the correct FNA diagnosis. The cytologic differential diagnosis of spindle-cell tumors of breast and the discordant morphology between the primary and metastatic melanotic lesions observed in this case are discussed.     

Smooth muscle tumours presenting as pleural neoplasms

Five smooth muscle tumours presenting as pleural neoplasms are presented. The patients were three women and two men aged between 21 and 69 years (mean = 45 years). Clinically, one patient presented with chest pain, one with empyema and the other three were asymptomatic. Two of the tumours were located in the left side of the chest cavity and three in the right side. In four cases, the lesions presented as solitary pleural-based masses that varied in size from 10–18 cm in greatest dimension; in two of these cases, involvement of the diaphragm was present in addition to the pleural involvement. In one case, the tumour was seen to totally encase the right lung simulating the growth pattern of malignant mesothelioma. Histologically, three cases displayed an atypical spindle cell proliferation with marked cellular pleomorphism, mitoses and areas of hemorrhage and necrosis. The other two cases were characterized by a bland-appearing smooth muscle proliferation of uncertain malignant potential composed of elongated cells with a moderate amount of eosinophilic cytoplasm and cigar-shaped nuclei, lacking significant nuclear pleomorphism or mitotic activity. Immunohistochemical studies showed strong positivity for alpha-smooth muscle actin in all cases, and for desmin in four of five cases, and a focal positive reaction for keratin in one case. Ultrastructural examination in one of the high-grade tumours showed features of smooth muscle differentiation. Three of the patients were treated by complete surgical excision while, in the other two patients, the lesions were incompletely resected. Follow-up ranging from 2–12 months has not shown evidence of recurrence in those patients with complete surgical resection, or metastasis in any of the patients. These cases appear to represent a previously undescribed form of primary pleural neoplasm. Because of the differences in biological behaviour compared with other types of pleural neoplasms, smooth muscle tumours should be included in the differential diagnosis of primary spindle cell tumours of the pleura.     

Spitz naevus: diagnostic problems and their management implications

Spitz naevus is an uncommon, benign melanocytic neoplasm that shares many clinical and histological features with melanoma. While Spitz naevi typically occur in children and melanomas typically occur in adults, either tumour can occur in a patient of any age. In cases displaying all or most of the classical histological features, particularly when occurring in a young patient, it is possible to make a confident diagnosis of Spitz naevus. However, for those lesions with atypical features it may be difficult to predict the biological behaviour with certainty from the histopathological appearance. Hence, such tumours have been referred to by a variety of names including atypical Spitz naevus, atypical Spitz tumour and spitzoid tumours of uncertain malignant potential. However, even acknowledged experts in dermatopathology have a low concordance in distinguishing Spitz naevus with atypical features from melanoma. In this article, we highlight the histopathological features of Spitz naevi and those that may be useful in distinguishing Spitz naevi from melanomas. A suggested practical guide to clinical management of such lesions is provided.