© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
J Cutan Pathol 2014: 41: 536–538 doi: 10.1111/cup.12336 John Wiley & Sons. Printed in Singapore
Journal of Cutaneous Pathology
A case of metastatic non-neural granular cell tumor in a 13-year-old girl Conventional granular cell tumor represents a mesenchymal neoplasm observed in a variety of locations and is now believed to be of Schwann cell origin. Granular cell change has also been observed in a variety of different tumors, but recently described in the skin has been a distinct entity termed non-neural granular cell tumor, which lacks expression of S100 protein and is of uncertain histogenesis. This tumor typically displays a greater degree of nuclear atypia and mitotic activity than conventional granular cell tumor but appears to behave in a relatively benign fashion, as only two previous instances of lymph node metastasis have been documented. Herein, we report a case of non-neural granular cell tumor arising on the back of a 13-year-old girl, and later axillary lymph node metastasis with extracapsular extension was observed.
Peter Newton1 , Michael Schenker2 , Viney Wadehra1 and Akhtar Husain1
Keywords: dermatopathology, S100, skin tumors
Dr Peter Newton Cellular Pathology, Queen Elizabeth Hospital, Gateshead, NE9 6SX, UK Tel: 01914452272 e-mail: [email protected]
Newton P, Schenker M, Wadehra V, Husain A. A case of metastatic non-neural granular cell tumor in a 13-year-old girl. J Cutan Pathol 2014; 41: 536–538. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Conventional granular cell tumor is an uncommon neoplasm that is encountered in a variety of locations, including the skin. Now widely believed to be of Schwann cell origin, it displays strong positive staining for S100 protein. The majority of granular cell tumors appear cytologically bland and behave in a benign fashion, and only rare cases of recurrent and metastatic disease have been documented. Criteria for stratifying the risk of malignancy in granular cell tumors have been proposed,1 although the presence of metastasis remains the only true defining feature of malignancy. A distinctive S100 protein-negative variant of cutaneous granular cell tumor has been observed. First described in a series of four cases in 1991,2 this entity was termed primitive polypoid granular cell tumor. More recently, two larger series of 11 and 13 cases were published in 20053,4 and used the term non-neural granular cell tumor. These tumors display
536
1
Department of Cellular Pathology, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK, and 2 Department of Plastic Surgery, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
Accepted for publication July 7, 2013
a greater degree of cytological atypia and mitotic activity than that seen in a classical granular cell tumor, yet the majority behave in a benign fashion, as only two cases of lymph node metastasis have been reported.4,5 Herein, we describe a case of metastatic non-neural granular cell tumor occurring in a 13year-old girl, which to our knowledge represents only the third reported case with nodal involvement and the only case to exhibit extracapsular extension arising from the involved node. Report of a patient A 13-year-old immunocompetent girl with no past medical history of note presented in early 2007 with a slowly growing subcutaneous nodule overlying the left scapula. An initial excision biopsy was incomplete and was followed by wider excision with skin grafting. Both excision specimens had similar appearances and contained a circumscribed tumor within the deep
Metastatic granular cell tumor
Fig. 1. The tumor was composed of sheets of monotonous cells with abundant eosinophilic cytoplasm.
Fig. 2. At higher power, the cells have abundant finely granular cytoplasm and small bland nuclei with occasional nucleoli.
dermis with significant extension into the subcutis, measuring 26 mm in maximum dimension. It was composed of sheets of cells with abundant finely granular eosinophilic cytoplasm (Fig. 1). The nuclei were round with pale chromatin and single central nucleoli. No significant nuclear atypia was seen (Fig. 2), and only a single mitotic figure was identified in 10 high power fields. Immunohistochemistry was performed, which showed positive staining of the tumor cells for vimentin, CD10 and the lysosomal marker α1-antitrypsin. There was also focal positive staining for CD68. The tumor cells were negative for S100 protein in the presence of positive internal and external controls and were negative for PGP9.5, CD34, CD56, CD99, Factor XIIIa, Desmin, AE1/AE3 and Melan A. Excision was complete with a margin of 3 mm in the second specimen, and following this the patient was reviewed regularly in clinic.
Throughout 2008 and 2009 the grafted area contained a lesion consistent with a small keloid scar. However, by April 2010 this had become painful and had increased considerably in size. Suspecting a recurrent granular cell tumor, a further excision was performed in June 2010. At that time, examination of the patient’s left axilla revealed a large firm nodule, a fine needle aspiration (FNA) of which was also performed in the operating room. Pathologic examination of the excision specimen revealed keloidal scarring only. An FNA of the axillary nodule showed numerous large cells with low nuclear to cytoplasmic ratios and abundant finely granular cytoplasm but with bland nuclear features and small central nucleoli. Occasional spindled cells were seen, as were areas of prominent vascular proliferation. Scanty lymphoid cells were seen but not in sufficient numbers to confirm aspiration from a lymph node. No morphological features of malignancy (nuclear atypia, mitotic activity and necrosis) were seen in the FNA specimen, but similar bland appearances have been documented during cytological examination of malignant granular cell tumors previously.6 In view of this and the patient’s past history, the FNA was reported as showing metastatic granular cell tumor. Interestingly, immunocytochemistry performed on the FNA specimen did show positive staining for S100 protein, but this was carried out on a liquidbased cytology preparation which may have affected antigenicity. In view of this finding, the patient underwent axillary dissection, which revealed metastatic granular cell tumor in 5 of 18 lymph nodes (Fig. 3). The histomorphology and immunophenotype of the axillary tumor were identical to that of the primary tumor in 2007, with negative staining for S100 protein in the presence of positive internal and external controls. There was an extensive extracapsular spread within the axillary tissue, with the largest deposit measuring 32 mm in diameter. A postoperative computed tomography (CT) scan of thorax and abdomen excluded disseminated metastasis. Arrangements for regular clinical review have been made. Discussion Non-neural granular cell tumor is a recently described entity arising in the skin. It most commonly presents as a polypoid mass, although more deep seated examples have also been described. Unlike conventional granular cell tumor, the tumor cells do not express S100 protein but have been shown to express the lysosomal marker NKI-C3 in nearly all cases, in addition to variably expressing CD68.
537
Newton et al.
Fig. 3. Examination of the axillary specimen showed metastatic granular cell tumor involving five lymph nodes.
In keeping with this, our example showed strong staining for the lysosomal marker α1-antitrypsin and focal staining for CD68. We also observed strong positive staining for CD10, which is in agreement with two more recent reports.5,7 The histogenesis of non-neural granular cell tumor is uncertain. In addition to negative staining for S100 protein, various epithelial and melanocytic markers are also not expressed. This is important, since granular cell change has been described in a variety of different tumors secondary to intracytoplasmic
accumulation of lysosomes, including melanoma, basal cell carcinoma and dermatofibroma. Hence, appropriate immunophenotyping is required in addition to histopathologic assessment to exclude these potentially more worrying entities before a diagnosis of non-neural granular cell tumor is made. Previous reports have described non-neural granular cell tumor as showing a greater spectrum of atypia and mitotic activity than conventional granular cell tumor, but nevertheless relatively benign behavior has been observed, with only two documented cases of lymph node metastasis. Our example appeared particularly bland and showed only minimal mitotic activity and yet behaved in an aggressive manner with large lymph node metastases with extracapsular extension. Previous examples of nodal metastasis have been smaller (20 and 1.7 mm) and node confined, with the smaller of these two examples being apparent only following a sentinel lymph node biopsy.4,5 Given the discrepancies we have demonstrated between morphology and biological behavior, it is unclear whether the criteria previously proposed to define risk of malignancy in classical granular cell tumor are also applicable to this entity. Hence, appropriate follow up should be instituted in all patients to allow appropriate management of the rare malignant examples and to allow further characterization of the behavior of this uncommon neoplasm.
References 1. Fanburg-Smith JC, Meiss-Kindblom JM, Fante R, et al. Malignant granular cell tumor of soft tissue. Diagnostic criteria and clinicopathological correlation. Am J Surg Pathol 1998; 22: 779. 2. LeBoit PE, Barr RJ, Burall S, et al. Primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin. Am J Surg Pathol 1991; 15: 48. 3. Chaudhry IH, Calonje E. Dermal nonneural granular cell tumor (so-called primitive
538
polypoid granular cell tumor): a distinctive entity further delineated in a clinicopathological study of 11 cases. Histopathology 2005; 47: 179. 4. Lazar AJ, Fletcher CD. Primitive nonneural granular cell tumors of skin: clinicopathologic analysis of 13 cases. Am J Surg Pathol 2005; 29: 927. 5. Habeeb AA, Weinreb I, Ghazarian D. Primitive non-neural granular cell tumor with lymph node metastasis. J Clin Pathol 2009; 62: 847.
6. Canacci AM, Nunez C, Getty P, et al. Diagnosis of malignant granular cell tumor metastatic to bone by fine needle aspiration cytology: a case report. Acta Cytol 2010; 54: 190. 7. Habeeb AA, Salama S. Primitive nonneural granular cell tumor (so-called typical polypoid granular cell tumor). Report of 2 cases with immunohistochemical and ultrastructural correlation. Am J Dermatopathol 2008; 30: 156.
J Cutan Pathol 2014: 41: 536–538 doi: 10.1111/cup.12336 John Wiley & Sons. Printed in Singapore
Journal of Cutaneous Pathology
A case of metastatic non-neural granular cell tumor in a 13-year-old girl Conventional granular cell tumor represents a mesenchymal neoplasm observed in a variety of locations and is now believed to be of Schwann cell origin. Granular cell change has also been observed in a variety of different tumors, but recently described in the skin has been a distinct entity termed non-neural granular cell tumor, which lacks expression of S100 protein and is of uncertain histogenesis. This tumor typically displays a greater degree of nuclear atypia and mitotic activity than conventional granular cell tumor but appears to behave in a relatively benign fashion, as only two previous instances of lymph node metastasis have been documented. Herein, we report a case of non-neural granular cell tumor arising on the back of a 13-year-old girl, and later axillary lymph node metastasis with extracapsular extension was observed.
Peter Newton1 , Michael Schenker2 , Viney Wadehra1 and Akhtar Husain1
Keywords: dermatopathology, S100, skin tumors
Dr Peter Newton Cellular Pathology, Queen Elizabeth Hospital, Gateshead, NE9 6SX, UK Tel: 01914452272 e-mail: [email protected]
Newton P, Schenker M, Wadehra V, Husain A. A case of metastatic non-neural granular cell tumor in a 13-year-old girl. J Cutan Pathol 2014; 41: 536–538. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Conventional granular cell tumor is an uncommon neoplasm that is encountered in a variety of locations, including the skin. Now widely believed to be of Schwann cell origin, it displays strong positive staining for S100 protein. The majority of granular cell tumors appear cytologically bland and behave in a benign fashion, and only rare cases of recurrent and metastatic disease have been documented. Criteria for stratifying the risk of malignancy in granular cell tumors have been proposed,1 although the presence of metastasis remains the only true defining feature of malignancy. A distinctive S100 protein-negative variant of cutaneous granular cell tumor has been observed. First described in a series of four cases in 1991,2 this entity was termed primitive polypoid granular cell tumor. More recently, two larger series of 11 and 13 cases were published in 20053,4 and used the term non-neural granular cell tumor. These tumors display
536
1
Department of Cellular Pathology, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK, and 2 Department of Plastic Surgery, The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
Accepted for publication July 7, 2013
a greater degree of cytological atypia and mitotic activity than that seen in a classical granular cell tumor, yet the majority behave in a benign fashion, as only two cases of lymph node metastasis have been reported.4,5 Herein, we describe a case of metastatic non-neural granular cell tumor occurring in a 13year-old girl, which to our knowledge represents only the third reported case with nodal involvement and the only case to exhibit extracapsular extension arising from the involved node. Report of a patient A 13-year-old immunocompetent girl with no past medical history of note presented in early 2007 with a slowly growing subcutaneous nodule overlying the left scapula. An initial excision biopsy was incomplete and was followed by wider excision with skin grafting. Both excision specimens had similar appearances and contained a circumscribed tumor within the deep
Metastatic granular cell tumor
Fig. 1. The tumor was composed of sheets of monotonous cells with abundant eosinophilic cytoplasm.
Fig. 2. At higher power, the cells have abundant finely granular cytoplasm and small bland nuclei with occasional nucleoli.
dermis with significant extension into the subcutis, measuring 26 mm in maximum dimension. It was composed of sheets of cells with abundant finely granular eosinophilic cytoplasm (Fig. 1). The nuclei were round with pale chromatin and single central nucleoli. No significant nuclear atypia was seen (Fig. 2), and only a single mitotic figure was identified in 10 high power fields. Immunohistochemistry was performed, which showed positive staining of the tumor cells for vimentin, CD10 and the lysosomal marker α1-antitrypsin. There was also focal positive staining for CD68. The tumor cells were negative for S100 protein in the presence of positive internal and external controls and were negative for PGP9.5, CD34, CD56, CD99, Factor XIIIa, Desmin, AE1/AE3 and Melan A. Excision was complete with a margin of 3 mm in the second specimen, and following this the patient was reviewed regularly in clinic.
Throughout 2008 and 2009 the grafted area contained a lesion consistent with a small keloid scar. However, by April 2010 this had become painful and had increased considerably in size. Suspecting a recurrent granular cell tumor, a further excision was performed in June 2010. At that time, examination of the patient’s left axilla revealed a large firm nodule, a fine needle aspiration (FNA) of which was also performed in the operating room. Pathologic examination of the excision specimen revealed keloidal scarring only. An FNA of the axillary nodule showed numerous large cells with low nuclear to cytoplasmic ratios and abundant finely granular cytoplasm but with bland nuclear features and small central nucleoli. Occasional spindled cells were seen, as were areas of prominent vascular proliferation. Scanty lymphoid cells were seen but not in sufficient numbers to confirm aspiration from a lymph node. No morphological features of malignancy (nuclear atypia, mitotic activity and necrosis) were seen in the FNA specimen, but similar bland appearances have been documented during cytological examination of malignant granular cell tumors previously.6 In view of this and the patient’s past history, the FNA was reported as showing metastatic granular cell tumor. Interestingly, immunocytochemistry performed on the FNA specimen did show positive staining for S100 protein, but this was carried out on a liquidbased cytology preparation which may have affected antigenicity. In view of this finding, the patient underwent axillary dissection, which revealed metastatic granular cell tumor in 5 of 18 lymph nodes (Fig. 3). The histomorphology and immunophenotype of the axillary tumor were identical to that of the primary tumor in 2007, with negative staining for S100 protein in the presence of positive internal and external controls. There was an extensive extracapsular spread within the axillary tissue, with the largest deposit measuring 32 mm in diameter. A postoperative computed tomography (CT) scan of thorax and abdomen excluded disseminated metastasis. Arrangements for regular clinical review have been made. Discussion Non-neural granular cell tumor is a recently described entity arising in the skin. It most commonly presents as a polypoid mass, although more deep seated examples have also been described. Unlike conventional granular cell tumor, the tumor cells do not express S100 protein but have been shown to express the lysosomal marker NKI-C3 in nearly all cases, in addition to variably expressing CD68.
537
Newton et al.
Fig. 3. Examination of the axillary specimen showed metastatic granular cell tumor involving five lymph nodes.
In keeping with this, our example showed strong staining for the lysosomal marker α1-antitrypsin and focal staining for CD68. We also observed strong positive staining for CD10, which is in agreement with two more recent reports.5,7 The histogenesis of non-neural granular cell tumor is uncertain. In addition to negative staining for S100 protein, various epithelial and melanocytic markers are also not expressed. This is important, since granular cell change has been described in a variety of different tumors secondary to intracytoplasmic
accumulation of lysosomes, including melanoma, basal cell carcinoma and dermatofibroma. Hence, appropriate immunophenotyping is required in addition to histopathologic assessment to exclude these potentially more worrying entities before a diagnosis of non-neural granular cell tumor is made. Previous reports have described non-neural granular cell tumor as showing a greater spectrum of atypia and mitotic activity than conventional granular cell tumor, but nevertheless relatively benign behavior has been observed, with only two documented cases of lymph node metastasis. Our example appeared particularly bland and showed only minimal mitotic activity and yet behaved in an aggressive manner with large lymph node metastases with extracapsular extension. Previous examples of nodal metastasis have been smaller (20 and 1.7 mm) and node confined, with the smaller of these two examples being apparent only following a sentinel lymph node biopsy.4,5 Given the discrepancies we have demonstrated between morphology and biological behavior, it is unclear whether the criteria previously proposed to define risk of malignancy in classical granular cell tumor are also applicable to this entity. Hence, appropriate follow up should be instituted in all patients to allow appropriate management of the rare malignant examples and to allow further characterization of the behavior of this uncommon neoplasm.
References 1. Fanburg-Smith JC, Meiss-Kindblom JM, Fante R, et al. Malignant granular cell tumor of soft tissue. Diagnostic criteria and clinicopathological correlation. Am J Surg Pathol 1998; 22: 779. 2. LeBoit PE, Barr RJ, Burall S, et al. Primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin. Am J Surg Pathol 1991; 15: 48. 3. Chaudhry IH, Calonje E. Dermal nonneural granular cell tumor (so-called primitive
538
polypoid granular cell tumor): a distinctive entity further delineated in a clinicopathological study of 11 cases. Histopathology 2005; 47: 179. 4. Lazar AJ, Fletcher CD. Primitive nonneural granular cell tumors of skin: clinicopathologic analysis of 13 cases. Am J Surg Pathol 2005; 29: 927. 5. Habeeb AA, Weinreb I, Ghazarian D. Primitive non-neural granular cell tumor with lymph node metastasis. J Clin Pathol 2009; 62: 847.
6. Canacci AM, Nunez C, Getty P, et al. Diagnosis of malignant granular cell tumor metastatic to bone by fine needle aspiration cytology: a case report. Acta Cytol 2010; 54: 190. 7. Habeeb AA, Salama S. Primitive nonneural granular cell tumor (so-called typical polypoid granular cell tumor). Report of 2 cases with immunohistochemical and ultrastructural correlation. Am J Dermatopathol 2008; 30: 156.
