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A solitary lung lesion with heterogeneous histological features
INSTRUCTIVE CASE
A solitary lung lesion with heterogeneous histological features
located within the left lower lobe and was not avid on PETeCT. Repeat CT scan 3 months later showed a 1 mm increase in size of the lesion. The site of the nodule precluded core biopsy and at request of the patient the lesion was excised without a repeat interval scan to exclude malignancy. A 45 20 10 mm wedge of lung tissue was sent for pathological examination. On sectioning there was a 12 7 5 mm greyish white circumscribed tumour situated 4 mm from the stapled resection margin and 1 mm from the pleural surface, however no pleural puckering was noted. The tumour appeared well delineated from the surrounding lung parenchyma. Microscopically the tumour displayed a mixed pattern of features including papillary, sclerotic and solid areas (Figure 2aed). The tumour was composed of two predominant cell types with cuboidal surface cells lining the papillary components and round stromal cells within the papillary stalks and solid areas. Scattered lipid laden macrophages were also noted throughout the tumour. No lymphovascular invasion was identified and there was no evidence of necrosis. Immunocytochemistry showed the surface cells to be positive for TTF1, CK7 and EMA. The stromal cells were also positive TTF1 and EMA but negative for CK7. Both tumours were negative for AE1/3, CK20, CD34, chromogranin, synaptophysin, CD56 and HMB45. Staining for the proliferation marker Ki-67 showed membranous staining of the tumour cells (Figure 3). Thus the morphological and immunocytochemical features were in keeping with a sclerosing pneumocytoma.
Sarah L Bell Craig P Dick
Abstract Sclerosing pneumocytoma is a rare low grade lung tumour which often presents as an incidental finding on chest imaging. These tumours are typically solitary, well circumscribed, peripheral lung lesions which have a well defined pathology characterized by a dual cell population. These tumours typically display a range of architectural appearances which raises a number of potential differential diagnoses. Tumours with a predominantly papillary architecture or clear cell morphology may be erroneously diagnosed as metastatic adenocarcinoma. A peculiar feature of these tumours is membrane immunopositivity with the proliferation marker Ki-67/MIB-1 which can assist in the diagnosis. We describe a case of this unusual tumour and consider the range of pathological differentials, which are a potential pitfall in the diagnosis.
Keywords sclerosing haemangioma; sclerosing pneumocytoma
Important points for clinical practice Introduction
Clinical features aid in the differential diagnosis of these tumours as they are typically well circumscribed, solitary, peripheral masses which are asymptomatic and discovered incidentally on chest imaging.
Sclerosing pneumocytoma is a rare low grade lung tumour in which the clinicopathological features are well described. Histologically it is characterized by a dual cell population of cuboidal ‘surface’ cells and round ‘stromal’ cells arranged in a variety of distinct architectural patterns. These tumours are usually found incidentally following chest imaging. The majority of cases are therefore asymptomatic at presentation and are typically well circumscribed, solitary in nature and peripherally located within the lung. We describe a case of this unusual tumour presenting in a 54-year-old woman and discuss the characteristic histopathological and immunocytochemical features. We also discuss potential pitfalls in the diagnosis of these tumours.
Case description A 54-year-old asymptomatic lady, with a past history of rectal carcinoma in 2006 followed by local recurrence in 2009, was found to have a left lung nodule on CT scan (Figure 1). The lung nodule appeared well circumscribed and was peripherally
Sarah L Bell BSc(Med Sci) MBChB(Hons) DipFMS is a Specialty Trainee in Histopathology at Western Infirmary, Glasgow, Scotland, UK. Conflicts of interest: none declared. Figure 1 Shows a solitary, well circumscribed lesion (white arrow) in the periphery of the left lower lobe on lateral chest magnetic resonance imaging.
Craig P Dick BSc MBChB PhD FRCPath is a Consultant Pathologist at Western Infirmary, Glasgow, Scotland, UK. Conflicts of interest: none declared.
DIAGNOSTIC HISTOPATHOLOGY 18:2
94
Ó 2011 Elsevier Ltd. All rights reserved.
INSTRUCTIVE CASE
These tumours display a range of histological patterns, thus raising a number of possible differential diagnoses including benign and malignant lung tumours and metastatic carcinoma. A peculiar feature of these tumours is membranous positivity with the proliferation marker Ki67/MIB-1. This feature is potentially helpful in the differential diagnosis of this lesion from lung carcinomas.
Discussion Clinical features Sclerosing pneumocytoma (SP) typically occurs in adults with mean age of presentation in the 50th decade and have a predilection for women.1 The majority of patients are asymptomatic but some patients experience symptoms in keeping with a mass lesion in the lung including cough, haemoptysis and chest pain. Radiologically they are solitary, well defined circular opacities often found incidentally following screening chest X-ray or CT, such as in this case. Administration of intravenous contrast agents often shows inhomogenous enhancement of the tumour.2 Areas of cystic degeneration may be seen following CT scan and rarely there is calcification associated with the tumour. Rarely multiple pneumocytomas may present within the same lung and in association with other histological tumour subtypes such as carcinoid tumours.3 The overwhelming majority of these tumours follow a benign clinical course with less than 4% showing lymph node involvement at diagnosis. However, nodal involvement in these patients does not appear to effect long term outcome.4 Histopathological features Microscopically, the tumours are well circumscribed, non encapsulated lesions with a distinct morphological appearance. These tumours were first described in 1956 by Liebow and Hubbell5 as ‘sclerosing haemangiomas’ reflecting the sclerosis and reactive vascular changes commonly seen within the tumour. Currently, the consensus view is that the neoplastic cells are of epithelioid histogenesis comprising two cell types, namely round ‘stromal’ cells with abundant pale cytoplasm and bland nuclei and cuboidal ‘surface’ cells. Both cell types are derived from immature respiratory epithelium with phenotypic features of type II alveolar pneumocytes.6,7 The tumours can display up to four distinct architectural patterns including papillary, solid, angiomatous and sclerotic areas and may be associated with chronic inflammation, calcification and cystic degeneration. Both cell types stain positively with thyroid transcription factor 1 (TTF-1) in keeping with derivation from respiratory epithelium and aiding in the differential diagnosis.8 The cuboidal surface cells typically stain positively with EMA, CK7 and pancytokeratin markers such as AE1/AE3, however our case did not show positivity with this marker. The stromal cells also stain positively with EMA however variable cytokeratin expression is a feature in keeping with an intermediate level of differentiation.
Figure 2 Shows a well circumscribed tumour which is clearly delineated from the surrounding lung parenchyma. (a; H&E 2.5). This tumour displays a variety of histological patterns including solid and sclerotic areas (b, c; H&E 10) and papillary areas with associated macrophages (d; H&E 20).
Differential diagnoses Based on morphology, the main histopathological differential diagnoses to consider include1: metastatic renal cell carcinoma papillary carcinoma (primary and secondary)
Figure 3 Immunocytochemistry for the proliferation marker MIB-1 shows characteristic staining in a membranous pattern. (MIB-1 20).
DIAGNOSTIC HISTOPATHOLOGY 18:2
95
Ó 2011 Elsevier Ltd. All rights reserved.
INSTRUCTIVE CASE
bronchoalveolar carcinoma carcinoid tumours clear cell (sugar) tumour of lung papillary adenoma The predominantly papillary architecture of some sclerosing pneumocytomas may mimic bronchoalveolar carcinoma or papillary adenocarcinoma. In this scenario immunocytochemistry is largely unhelpful other than excluding metastatic tumours. However, SPs are usually well circumscribed and cytologically bland with evidence of a dual cell population and heterogeneity of architectural patterns. Cases of SP with a predominantly papillary architecture can be misdiagnosed as metastatic thyroid papillary carcinoma (in which TTF-1 will be positive) or metastatic renal cell carcinoma. Nuclear features of papillary thyroid carcinoma and positivity with thyroglobulin distinguishes SP from this diagnosis. Negative staining for TTF-1 with cytological atypia is more in keeping with a metastatic renal cell carcinoma than SP. Both the cuboidal cells and stromal cells in SP are negative for neuroendocrine markers such as chromogranin and synaptophysin thus aiding in the differential diagnosis from carcinoid tumours. The stromal cells can occasionally display a clear cell morphology therefore mimicking clear cell tumour of lung and clear cell renal cell carcinoma. Benign clear cell (sugar) tumours of the lung characteristically show an abundance of clear cells which stain strongly positive with the melanocytic marker HMB45.
and variegation of histological appearances. This heterogeneity can lead to a number of potential alternative differential diagnoses. Positivity for TTF-1 along with membranous staining for MIB-1 can aid in this differential diagnosis. As such they should be added to the repertoire of lesions presenting as solitary, circumscribed peripheral masses in the lung. A
REFERENCES 1 Keylock CPT, Galvin J, Franks TJ. Sclerosing haemangioma of the lung. Arch Pathol Lab Med 2009; 133: 820e5. 2 Cheung YC, Ng SH, Chang JW, Tan CF, Huang SF, Yu CT. Histopathological and CT features of pulmonary sclerosing haemangiomas. Clin Radiol 2003; 58: 630e5. 3 Chon SH, Jeon YB, Jung TY, et al. Multiple sclerosing hemangiomas of the lung e a case report. Korean J Thorac Cardiovasc Surg 1999; 32: 408e12. 4 Miyagawa-Hayashino A, Tazelaar HD, Langel DJ, Colby TV. Pulmonary sclerosing haemangioma with lymph node metastases: report of 4 cases. Arch Pathol Lab Med 2003; 127: 321e5. 5 Liebow AA, Hubbell DS. Sclerosing haemangioma (histocytoma, xanthoma) of the lung. Cancer 1956; 9: 53e75. 6 Devouassoux-Shisheboran M, Hayashi T, Linnoila I, Koss M, Travis W. A clinicopathologic study of 100 cases of pulmonary sclerosing haemangioma with immunohistochemical studies. Am J Surg Pathol 2000; 24: 906e16. 7 Rodriguez-Soto J, Colby TV, Rouse RV. A critical examination of the immunophenotype of pulmonary sclerosing hemangioma. Am J Surg Pathol 2000; 24: 442e50. 8 Chan AC, Chan AK. Pulmonary sclerosing haemangioma consistently expresses thyroid transcription factor (TTF-1): a new clue to its histogenesis. Am J Surg Pathol 2000; 24: 1531e6. 9 Leonardo E, Volante M, Barbareschi M, et al. Cell membrane reactivity of MIB-1 antibody to Ki67 in human tumours. Fact or artefact? Appl Immunohistochem Mol Morphol 2007; 15: 220e3. 10 Hattori H. Sclerosing haemangioma of the lung is positive for MIB-1in cell membrane and cytoplasmic staining pattern. Histopathology 2002; 40: 291e3.
Membranous staining of MIB-1/Ki-67 A peculiar observation in our case is membranous staining with the proliferation marker MIB-1. This phenomenon has previously been described in sclerosing pneumocytomas and is recognized in trabecular tumours of the thyroid and some salivary gland pleomorphic adenomas.9,10 This feature is helpful in distinguishing sclerosing pneumocytoma from well differentiated primary lung adenocarcinomas which would not display a membranous pattern of MIB-1 staining and additionally show a high nuclear proliferation index. In summary sclerosing pneumocytomas are unusual low grade lung tumours which are characterized by a dual cell population
DIAGNOSTIC HISTOPATHOLOGY 18:2
96
Ó 2011 Elsevier Ltd. All rights reserved.
A solitary lung lesion with heterogeneous histological features
located within the left lower lobe and was not avid on PETeCT. Repeat CT scan 3 months later showed a 1 mm increase in size of the lesion. The site of the nodule precluded core biopsy and at request of the patient the lesion was excised without a repeat interval scan to exclude malignancy. A 45 20 10 mm wedge of lung tissue was sent for pathological examination. On sectioning there was a 12 7 5 mm greyish white circumscribed tumour situated 4 mm from the stapled resection margin and 1 mm from the pleural surface, however no pleural puckering was noted. The tumour appeared well delineated from the surrounding lung parenchyma. Microscopically the tumour displayed a mixed pattern of features including papillary, sclerotic and solid areas (Figure 2aed). The tumour was composed of two predominant cell types with cuboidal surface cells lining the papillary components and round stromal cells within the papillary stalks and solid areas. Scattered lipid laden macrophages were also noted throughout the tumour. No lymphovascular invasion was identified and there was no evidence of necrosis. Immunocytochemistry showed the surface cells to be positive for TTF1, CK7 and EMA. The stromal cells were also positive TTF1 and EMA but negative for CK7. Both tumours were negative for AE1/3, CK20, CD34, chromogranin, synaptophysin, CD56 and HMB45. Staining for the proliferation marker Ki-67 showed membranous staining of the tumour cells (Figure 3). Thus the morphological and immunocytochemical features were in keeping with a sclerosing pneumocytoma.
Sarah L Bell Craig P Dick
Abstract Sclerosing pneumocytoma is a rare low grade lung tumour which often presents as an incidental finding on chest imaging. These tumours are typically solitary, well circumscribed, peripheral lung lesions which have a well defined pathology characterized by a dual cell population. These tumours typically display a range of architectural appearances which raises a number of potential differential diagnoses. Tumours with a predominantly papillary architecture or clear cell morphology may be erroneously diagnosed as metastatic adenocarcinoma. A peculiar feature of these tumours is membrane immunopositivity with the proliferation marker Ki-67/MIB-1 which can assist in the diagnosis. We describe a case of this unusual tumour and consider the range of pathological differentials, which are a potential pitfall in the diagnosis.
Keywords sclerosing haemangioma; sclerosing pneumocytoma
Important points for clinical practice Introduction
Clinical features aid in the differential diagnosis of these tumours as they are typically well circumscribed, solitary, peripheral masses which are asymptomatic and discovered incidentally on chest imaging.
Sclerosing pneumocytoma is a rare low grade lung tumour in which the clinicopathological features are well described. Histologically it is characterized by a dual cell population of cuboidal ‘surface’ cells and round ‘stromal’ cells arranged in a variety of distinct architectural patterns. These tumours are usually found incidentally following chest imaging. The majority of cases are therefore asymptomatic at presentation and are typically well circumscribed, solitary in nature and peripherally located within the lung. We describe a case of this unusual tumour presenting in a 54-year-old woman and discuss the characteristic histopathological and immunocytochemical features. We also discuss potential pitfalls in the diagnosis of these tumours.
Case description A 54-year-old asymptomatic lady, with a past history of rectal carcinoma in 2006 followed by local recurrence in 2009, was found to have a left lung nodule on CT scan (Figure 1). The lung nodule appeared well circumscribed and was peripherally
Sarah L Bell BSc(Med Sci) MBChB(Hons) DipFMS is a Specialty Trainee in Histopathology at Western Infirmary, Glasgow, Scotland, UK. Conflicts of interest: none declared. Figure 1 Shows a solitary, well circumscribed lesion (white arrow) in the periphery of the left lower lobe on lateral chest magnetic resonance imaging.
Craig P Dick BSc MBChB PhD FRCPath is a Consultant Pathologist at Western Infirmary, Glasgow, Scotland, UK. Conflicts of interest: none declared.
DIAGNOSTIC HISTOPATHOLOGY 18:2
94
Ó 2011 Elsevier Ltd. All rights reserved.
INSTRUCTIVE CASE
These tumours display a range of histological patterns, thus raising a number of possible differential diagnoses including benign and malignant lung tumours and metastatic carcinoma. A peculiar feature of these tumours is membranous positivity with the proliferation marker Ki67/MIB-1. This feature is potentially helpful in the differential diagnosis of this lesion from lung carcinomas.
Discussion Clinical features Sclerosing pneumocytoma (SP) typically occurs in adults with mean age of presentation in the 50th decade and have a predilection for women.1 The majority of patients are asymptomatic but some patients experience symptoms in keeping with a mass lesion in the lung including cough, haemoptysis and chest pain. Radiologically they are solitary, well defined circular opacities often found incidentally following screening chest X-ray or CT, such as in this case. Administration of intravenous contrast agents often shows inhomogenous enhancement of the tumour.2 Areas of cystic degeneration may be seen following CT scan and rarely there is calcification associated with the tumour. Rarely multiple pneumocytomas may present within the same lung and in association with other histological tumour subtypes such as carcinoid tumours.3 The overwhelming majority of these tumours follow a benign clinical course with less than 4% showing lymph node involvement at diagnosis. However, nodal involvement in these patients does not appear to effect long term outcome.4 Histopathological features Microscopically, the tumours are well circumscribed, non encapsulated lesions with a distinct morphological appearance. These tumours were first described in 1956 by Liebow and Hubbell5 as ‘sclerosing haemangiomas’ reflecting the sclerosis and reactive vascular changes commonly seen within the tumour. Currently, the consensus view is that the neoplastic cells are of epithelioid histogenesis comprising two cell types, namely round ‘stromal’ cells with abundant pale cytoplasm and bland nuclei and cuboidal ‘surface’ cells. Both cell types are derived from immature respiratory epithelium with phenotypic features of type II alveolar pneumocytes.6,7 The tumours can display up to four distinct architectural patterns including papillary, solid, angiomatous and sclerotic areas and may be associated with chronic inflammation, calcification and cystic degeneration. Both cell types stain positively with thyroid transcription factor 1 (TTF-1) in keeping with derivation from respiratory epithelium and aiding in the differential diagnosis.8 The cuboidal surface cells typically stain positively with EMA, CK7 and pancytokeratin markers such as AE1/AE3, however our case did not show positivity with this marker. The stromal cells also stain positively with EMA however variable cytokeratin expression is a feature in keeping with an intermediate level of differentiation.
Figure 2 Shows a well circumscribed tumour which is clearly delineated from the surrounding lung parenchyma. (a; H&E 2.5). This tumour displays a variety of histological patterns including solid and sclerotic areas (b, c; H&E 10) and papillary areas with associated macrophages (d; H&E 20).
Differential diagnoses Based on morphology, the main histopathological differential diagnoses to consider include1: metastatic renal cell carcinoma papillary carcinoma (primary and secondary)
Figure 3 Immunocytochemistry for the proliferation marker MIB-1 shows characteristic staining in a membranous pattern. (MIB-1 20).
DIAGNOSTIC HISTOPATHOLOGY 18:2
95
Ó 2011 Elsevier Ltd. All rights reserved.
INSTRUCTIVE CASE
bronchoalveolar carcinoma carcinoid tumours clear cell (sugar) tumour of lung papillary adenoma The predominantly papillary architecture of some sclerosing pneumocytomas may mimic bronchoalveolar carcinoma or papillary adenocarcinoma. In this scenario immunocytochemistry is largely unhelpful other than excluding metastatic tumours. However, SPs are usually well circumscribed and cytologically bland with evidence of a dual cell population and heterogeneity of architectural patterns. Cases of SP with a predominantly papillary architecture can be misdiagnosed as metastatic thyroid papillary carcinoma (in which TTF-1 will be positive) or metastatic renal cell carcinoma. Nuclear features of papillary thyroid carcinoma and positivity with thyroglobulin distinguishes SP from this diagnosis. Negative staining for TTF-1 with cytological atypia is more in keeping with a metastatic renal cell carcinoma than SP. Both the cuboidal cells and stromal cells in SP are negative for neuroendocrine markers such as chromogranin and synaptophysin thus aiding in the differential diagnosis from carcinoid tumours. The stromal cells can occasionally display a clear cell morphology therefore mimicking clear cell tumour of lung and clear cell renal cell carcinoma. Benign clear cell (sugar) tumours of the lung characteristically show an abundance of clear cells which stain strongly positive with the melanocytic marker HMB45.
and variegation of histological appearances. This heterogeneity can lead to a number of potential alternative differential diagnoses. Positivity for TTF-1 along with membranous staining for MIB-1 can aid in this differential diagnosis. As such they should be added to the repertoire of lesions presenting as solitary, circumscribed peripheral masses in the lung. A
REFERENCES 1 Keylock CPT, Galvin J, Franks TJ. Sclerosing haemangioma of the lung. Arch Pathol Lab Med 2009; 133: 820e5. 2 Cheung YC, Ng SH, Chang JW, Tan CF, Huang SF, Yu CT. Histopathological and CT features of pulmonary sclerosing haemangiomas. Clin Radiol 2003; 58: 630e5. 3 Chon SH, Jeon YB, Jung TY, et al. Multiple sclerosing hemangiomas of the lung e a case report. Korean J Thorac Cardiovasc Surg 1999; 32: 408e12. 4 Miyagawa-Hayashino A, Tazelaar HD, Langel DJ, Colby TV. Pulmonary sclerosing haemangioma with lymph node metastases: report of 4 cases. Arch Pathol Lab Med 2003; 127: 321e5. 5 Liebow AA, Hubbell DS. Sclerosing haemangioma (histocytoma, xanthoma) of the lung. Cancer 1956; 9: 53e75. 6 Devouassoux-Shisheboran M, Hayashi T, Linnoila I, Koss M, Travis W. A clinicopathologic study of 100 cases of pulmonary sclerosing haemangioma with immunohistochemical studies. Am J Surg Pathol 2000; 24: 906e16. 7 Rodriguez-Soto J, Colby TV, Rouse RV. A critical examination of the immunophenotype of pulmonary sclerosing hemangioma. Am J Surg Pathol 2000; 24: 442e50. 8 Chan AC, Chan AK. Pulmonary sclerosing haemangioma consistently expresses thyroid transcription factor (TTF-1): a new clue to its histogenesis. Am J Surg Pathol 2000; 24: 1531e6. 9 Leonardo E, Volante M, Barbareschi M, et al. Cell membrane reactivity of MIB-1 antibody to Ki67 in human tumours. Fact or artefact? Appl Immunohistochem Mol Morphol 2007; 15: 220e3. 10 Hattori H. Sclerosing haemangioma of the lung is positive for MIB-1in cell membrane and cytoplasmic staining pattern. Histopathology 2002; 40: 291e3.
Membranous staining of MIB-1/Ki-67 A peculiar observation in our case is membranous staining with the proliferation marker MIB-1. This phenomenon has previously been described in sclerosing pneumocytomas and is recognized in trabecular tumours of the thyroid and some salivary gland pleomorphic adenomas.9,10 This feature is helpful in distinguishing sclerosing pneumocytoma from well differentiated primary lung adenocarcinomas which would not display a membranous pattern of MIB-1 staining and additionally show a high nuclear proliferation index. In summary sclerosing pneumocytomas are unusual low grade lung tumours which are characterized by a dual cell population
DIAGNOSTIC HISTOPATHOLOGY 18:2
96
Ó 2011 Elsevier Ltd. All rights reserved.