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An uncommon cause of cutaneous swelling of the thigh: Part 2
84
TEST AND TEACH
Pathology (2004), 36(1), February
An uncommon cause of cutaneous swelling of the thigh Part 2
EXPLANATION AND DIAGNOSIS: MALIGNANT GLOMUS TUMOUR The glomus apparatus regulates skin circulation and heat exchange, containing specialised arteriovenous anastomosis.1,2 Glomus tumours originate from this specialised apparatus and are perivascular neoplasms. Benign glomus tumours are uncommon, classically described in the subungual region as single or multiple lesions within the dermis and subcutaneous adipose layer.3–5 They have also been described in the mediastinum, respiratory tract, bone, gastrointestinal tract and female genital tract.1,3,5,6 Atypical and malignant glomus tumours are even rarer than their benign counterparts.7 In 1990, Gould et al.6 proposed three categories of locally aggressive glomus tumours. A glomus tumour with local infiltration is termed ‘locally infiltrative glomus tumour’ while a tumour with malignant cytological features merging with a typical benign glomus tumour is called ‘glomangiosarcoma arising in a benign glomus tumour’. The third category comprises a tumour containing undifferentiated malignant small round cells with some architectural and cytological resemblance to glomus tumour, for which the term ‘de novo glomangiosarcoma’ is applied. In 2001, Folpe et al.7 reclassified atypical glomus tumours based on the findings that deep location, size, atypical mitotic figures, high mitotic activity and high nuclear grade are predictors of tumour recurrence and metastasis. High nuclear grade alone, infiltrative growth pattern and vascular space involvement were not associated with metastases. Four categories of atypical glomus tumours were identified. Malignant glomus tumours possessed at least one of the following criteria: deep location and size of more than 2 cm; presence of atypical mitotic figures; or a combination of moderate-to-high nuclear grade and mitotic activity of more than 5 per 50 high power fields. Symplastic glomus tumours, while displaying marked nuclear atypia attributed to degenerative changes, lacked other malignant features. On the other hand, glomus tumours of uncertain malignant potential did not fulfil all the criteria for malignancy and possessed one of the following: superficial location with high mitotic activity; large size only; or deep location only. Glomangiomatosis lacked the criteria for malignant glomus tumour or that of uncertain malignant potential, displaying diffuse growth resembling angiomatosis with excess glomus cells. While careful follow-up is advocated for neoplasms of uncertain malignant potential category, metastatic behaviour is seen only in the malignant group. This classification is used in this discussion. Malignant glomus tumours usually occur in the deep soft tissue of patients whose age range from 30 to 70 years.4,7 Exceptionally, the tumours have afflicted patients younger than 20 years of age. Malignant glomus tumours show a predilection for the extremities; other sites of involvement cited include the spine, abdomen and lung.3,7
In Folpe’s series7, 38% of malignant glomus tumours metastasised and metastatic disease usually culminated in the death of the patient.3,8 Grossly, malignant glomus tumours present as welldefined nodules or masses that appear light brown to graywhite.1,5,6 Areas of haemorrhage can be identified. The size ranges from 0.5 to 7 cm.1,4,5,7 On light microscopy, malignant glomus tumours may disclose an appearance that varies from uniform round cells (Fig. 1, 3) to spindle cells resembling pleomorphic leiomyosarcomas or malignant fibrous histiocytoma.1,4,7,9 Typically, the tumour cells have distinct cytoplasmic borders and central nucleoli2,7 associated with moderate-to-high cytological grade and cellularity with increased mitotic counts including atypical mitoses. In our case, the tumour cells were oval to round associated with significant anisonucleosis; the mitotic index was up to 15 per 10 high power fields (Fig. 3). The presence of a benign glomus component is extremely useful in establishing the diagnosis, as exemplified in our case (Fig. 2). The neoplastic cells may also invest and invade blood vessels. Geographic necrosis may be identified. In difficult cases, electron microscopic studies and immunohistochemical stains are essential in making the correct diagnosis. On immunohistochemistry, malignant glomus tumours are positive for smooth muscle actin (Fig. 4), pan muscle actin, type IV collagen and vimentin. As in our case, desmin is usually negative. The stains for cytokeratins and S100 are also negative.1,3,4,6,7,9 Ultrastructurally, the cells of malignant glomus tumours show numerous cytoplasmic processes and pinocytotic vesicles.1,2 Within the cytoplasm are scattered microfilaments with dense bodies. Welldeveloped rough endoplasmic reticulum and mitochondria are present. Neurosecretory granules are not identified. Cell junctions and focal basement membrane-like structures can be seen at the cell membrane. Molecular studies have shown that expression of apoptotic inhibitor, bcl-2, is associated with an increased proliferative index by ten times.10 Within the nucleus, there is an abnormal increase in p53 expression. When a malignant glomus tumour co-exists with a benign glomus tumour component, the diagnosis is easily made. However if the tumour is composed exclusively of a malignant cell population, the differential diagnoses to be considered can be extensive. In cases where the malignant tumour manifests as a round cell tumour as in this case, Merkel cell carcinoma, eccrine spiradenoma, metastatic small cell carcinoma and metastatic carcinoid have to be considered; however these entities are cytokeratin positive in contrast to its negative expression in malignant glomus tumour.6,7 Ewing’s sarcoma/primitive neuroectodermal tumour of the skin and extra-osseous deep soft tissue does not stain for smooth muscle actin and type IV collagen and is CD99 positive in distinction from malignant glomus tumours.3,6 Neuroblastoma displays Homer–Wright rosettes not seen in malignant glomus tumour and expresses neurofilaments,
TEST AND TEACH
chromogranin and synaptophysin.6 Rhabdomyosarcoma with a small cell appearance may display large mutlinucleated giant cells with abundant eosinophilic cytoplasm2 and is positive for desmin, myoD1 and myogenin, which are not identified in malignant glomus tumours.7 Melanoma is S100 and HMB45 positive while the malignant glomus tumour is not. In the deep soft tissue, a diagnosis of haemangiopericytoma has to be considered. However, haemangiopericytoma shows spindle and epithelioid cells associated with staghorn blood vessels. Furthermore haemangiopericytoma is positive for factor XIII and negative for smooth muscle actin, thereby providing a histological separation from malignant glomus tumours.1,6 Leiomyosarcoma, in particular the epithelioid variant, is usually composed of cells with more abundant eosinophilic cytoplasm, being associated with thick-walled blood vessels rather than delicately branching small vessels as seen in malignant glomus tumour.7 Since both leiomyosarcoma and malignant glomus tumour are smooth muscle actin positive, the distinction between these two entities can be difficult. Key words: malignant glomus tumor, pathology, diagnosis. Address for correspondence: Dr Khoon Leong Chuah, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. E-mail: [email protected]
References
85
1. Hiruta N, Kameda N, Tokudome T, et al. Malignant glomus tumor: a case report and review of literature. Am J Surg Pathol 1997; 21: 1096–103. 2. Aiba M, Hirayama A, Kuramochi S. Glomangiosarcoma in a glomus tumor. An immunohistochemical and ultrastructural study. Cancer 1988; 61: 1467–71. 3. Gaertner EM, Steinberg DM, Huber M, et al. Pulmonary and mediastinal glomus tumors. Report of five cases including a pulmonary glomangiosarcoma: a clinicopathologic study with literature review. Am J Surg Pathol 2000; 24: 1105–14. 4. Brathwaite CD, Poppiti RJ. Malignant glomus tumor. A case report of widespread metastases in a patient with multiple glomus body hamartomas. Am J Surg Pathol 1996; 20: 233–8. 5. Haque S, Modlin IM, West AB. Multiple glomus tumors of the stomach with intravascular spread. Am J Surg Pathol 1992; 16: 291–9. 6. Gould EW, Manivel JC, Albores-Saavedra J, et al. Locally infiltrative glomus tumors and glomangiosarcomas. A clinical, ultrastructural and immunohistochemical study. Cancer 1990; 65: 310–8. 7. Folpe AL, Fanburg-Smith JC, Miettinen M, et al. Atypical and malignant glomus tumors. Analysis of 52 cases with proposal for the reclassification of glomus tumors. Am J Surg Pathol 2001; 25: 1–12. 8. Kayal JD, Hampton RW, Sheehan DJ, et al. Malignant glomus tumor: a case report and review of the literature. Dermatol Surg 2001; 27: 837–40. 9. Lopez-Rios F, Rodriguez-Peralto JL, Castano E, et al. Glomangiosarcoma of the lower limb: a case report with literature review. J Cutan Pathol 1997; 24: 571–4. 10. Hegyi L, Cormack GC, Grant JW. Histochemical investigation into the molecular mechanisms of malignant transformation in a benign glomus tumour. J Clin Pathol 1998; 51: 872–4.
TEST AND TEACH
Pathology (2004), 36(1), February
An uncommon cause of cutaneous swelling of the thigh Part 2
EXPLANATION AND DIAGNOSIS: MALIGNANT GLOMUS TUMOUR The glomus apparatus regulates skin circulation and heat exchange, containing specialised arteriovenous anastomosis.1,2 Glomus tumours originate from this specialised apparatus and are perivascular neoplasms. Benign glomus tumours are uncommon, classically described in the subungual region as single or multiple lesions within the dermis and subcutaneous adipose layer.3–5 They have also been described in the mediastinum, respiratory tract, bone, gastrointestinal tract and female genital tract.1,3,5,6 Atypical and malignant glomus tumours are even rarer than their benign counterparts.7 In 1990, Gould et al.6 proposed three categories of locally aggressive glomus tumours. A glomus tumour with local infiltration is termed ‘locally infiltrative glomus tumour’ while a tumour with malignant cytological features merging with a typical benign glomus tumour is called ‘glomangiosarcoma arising in a benign glomus tumour’. The third category comprises a tumour containing undifferentiated malignant small round cells with some architectural and cytological resemblance to glomus tumour, for which the term ‘de novo glomangiosarcoma’ is applied. In 2001, Folpe et al.7 reclassified atypical glomus tumours based on the findings that deep location, size, atypical mitotic figures, high mitotic activity and high nuclear grade are predictors of tumour recurrence and metastasis. High nuclear grade alone, infiltrative growth pattern and vascular space involvement were not associated with metastases. Four categories of atypical glomus tumours were identified. Malignant glomus tumours possessed at least one of the following criteria: deep location and size of more than 2 cm; presence of atypical mitotic figures; or a combination of moderate-to-high nuclear grade and mitotic activity of more than 5 per 50 high power fields. Symplastic glomus tumours, while displaying marked nuclear atypia attributed to degenerative changes, lacked other malignant features. On the other hand, glomus tumours of uncertain malignant potential did not fulfil all the criteria for malignancy and possessed one of the following: superficial location with high mitotic activity; large size only; or deep location only. Glomangiomatosis lacked the criteria for malignant glomus tumour or that of uncertain malignant potential, displaying diffuse growth resembling angiomatosis with excess glomus cells. While careful follow-up is advocated for neoplasms of uncertain malignant potential category, metastatic behaviour is seen only in the malignant group. This classification is used in this discussion. Malignant glomus tumours usually occur in the deep soft tissue of patients whose age range from 30 to 70 years.4,7 Exceptionally, the tumours have afflicted patients younger than 20 years of age. Malignant glomus tumours show a predilection for the extremities; other sites of involvement cited include the spine, abdomen and lung.3,7
In Folpe’s series7, 38% of malignant glomus tumours metastasised and metastatic disease usually culminated in the death of the patient.3,8 Grossly, malignant glomus tumours present as welldefined nodules or masses that appear light brown to graywhite.1,5,6 Areas of haemorrhage can be identified. The size ranges from 0.5 to 7 cm.1,4,5,7 On light microscopy, malignant glomus tumours may disclose an appearance that varies from uniform round cells (Fig. 1, 3) to spindle cells resembling pleomorphic leiomyosarcomas or malignant fibrous histiocytoma.1,4,7,9 Typically, the tumour cells have distinct cytoplasmic borders and central nucleoli2,7 associated with moderate-to-high cytological grade and cellularity with increased mitotic counts including atypical mitoses. In our case, the tumour cells were oval to round associated with significant anisonucleosis; the mitotic index was up to 15 per 10 high power fields (Fig. 3). The presence of a benign glomus component is extremely useful in establishing the diagnosis, as exemplified in our case (Fig. 2). The neoplastic cells may also invest and invade blood vessels. Geographic necrosis may be identified. In difficult cases, electron microscopic studies and immunohistochemical stains are essential in making the correct diagnosis. On immunohistochemistry, malignant glomus tumours are positive for smooth muscle actin (Fig. 4), pan muscle actin, type IV collagen and vimentin. As in our case, desmin is usually negative. The stains for cytokeratins and S100 are also negative.1,3,4,6,7,9 Ultrastructurally, the cells of malignant glomus tumours show numerous cytoplasmic processes and pinocytotic vesicles.1,2 Within the cytoplasm are scattered microfilaments with dense bodies. Welldeveloped rough endoplasmic reticulum and mitochondria are present. Neurosecretory granules are not identified. Cell junctions and focal basement membrane-like structures can be seen at the cell membrane. Molecular studies have shown that expression of apoptotic inhibitor, bcl-2, is associated with an increased proliferative index by ten times.10 Within the nucleus, there is an abnormal increase in p53 expression. When a malignant glomus tumour co-exists with a benign glomus tumour component, the diagnosis is easily made. However if the tumour is composed exclusively of a malignant cell population, the differential diagnoses to be considered can be extensive. In cases where the malignant tumour manifests as a round cell tumour as in this case, Merkel cell carcinoma, eccrine spiradenoma, metastatic small cell carcinoma and metastatic carcinoid have to be considered; however these entities are cytokeratin positive in contrast to its negative expression in malignant glomus tumour.6,7 Ewing’s sarcoma/primitive neuroectodermal tumour of the skin and extra-osseous deep soft tissue does not stain for smooth muscle actin and type IV collagen and is CD99 positive in distinction from malignant glomus tumours.3,6 Neuroblastoma displays Homer–Wright rosettes not seen in malignant glomus tumour and expresses neurofilaments,
TEST AND TEACH
chromogranin and synaptophysin.6 Rhabdomyosarcoma with a small cell appearance may display large mutlinucleated giant cells with abundant eosinophilic cytoplasm2 and is positive for desmin, myoD1 and myogenin, which are not identified in malignant glomus tumours.7 Melanoma is S100 and HMB45 positive while the malignant glomus tumour is not. In the deep soft tissue, a diagnosis of haemangiopericytoma has to be considered. However, haemangiopericytoma shows spindle and epithelioid cells associated with staghorn blood vessels. Furthermore haemangiopericytoma is positive for factor XIII and negative for smooth muscle actin, thereby providing a histological separation from malignant glomus tumours.1,6 Leiomyosarcoma, in particular the epithelioid variant, is usually composed of cells with more abundant eosinophilic cytoplasm, being associated with thick-walled blood vessels rather than delicately branching small vessels as seen in malignant glomus tumour.7 Since both leiomyosarcoma and malignant glomus tumour are smooth muscle actin positive, the distinction between these two entities can be difficult. Key words: malignant glomus tumor, pathology, diagnosis. Address for correspondence: Dr Khoon Leong Chuah, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. E-mail: [email protected]
References
85
1. Hiruta N, Kameda N, Tokudome T, et al. Malignant glomus tumor: a case report and review of literature. Am J Surg Pathol 1997; 21: 1096–103. 2. Aiba M, Hirayama A, Kuramochi S. Glomangiosarcoma in a glomus tumor. An immunohistochemical and ultrastructural study. Cancer 1988; 61: 1467–71. 3. Gaertner EM, Steinberg DM, Huber M, et al. Pulmonary and mediastinal glomus tumors. Report of five cases including a pulmonary glomangiosarcoma: a clinicopathologic study with literature review. Am J Surg Pathol 2000; 24: 1105–14. 4. Brathwaite CD, Poppiti RJ. Malignant glomus tumor. A case report of widespread metastases in a patient with multiple glomus body hamartomas. Am J Surg Pathol 1996; 20: 233–8. 5. Haque S, Modlin IM, West AB. Multiple glomus tumors of the stomach with intravascular spread. Am J Surg Pathol 1992; 16: 291–9. 6. Gould EW, Manivel JC, Albores-Saavedra J, et al. Locally infiltrative glomus tumors and glomangiosarcomas. A clinical, ultrastructural and immunohistochemical study. Cancer 1990; 65: 310–8. 7. Folpe AL, Fanburg-Smith JC, Miettinen M, et al. Atypical and malignant glomus tumors. Analysis of 52 cases with proposal for the reclassification of glomus tumors. Am J Surg Pathol 2001; 25: 1–12. 8. Kayal JD, Hampton RW, Sheehan DJ, et al. Malignant glomus tumor: a case report and review of the literature. Dermatol Surg 2001; 27: 837–40. 9. Lopez-Rios F, Rodriguez-Peralto JL, Castano E, et al. Glomangiosarcoma of the lower limb: a case report with literature review. J Cutan Pathol 1997; 24: 571–4. 10. Hegyi L, Cormack GC, Grant JW. Histochemical investigation into the molecular mechanisms of malignant transformation in a benign glomus tumour. J Clin Pathol 1998; 51: 872–4.