Histopathology 2016, 68, 461–468.
Correspondence The relationship between overt and in-situ lymphoma: a retrospective study of follicular and mantle cell lymphoma cases DOI: 10.1111/his.12753 © 2015 John Wiley & Sons Ltd
Sir: The deregulation of multiple molecular pathways is the biological basis for establishment of a neoplastic process. It often follows an evolution path based on the selection and accumulation of genomic alterations. This ‘histologic progression’ can be demonstrated easily in premalignant lesions of solid tumours.1 Among lymphoid malignancies, this concept finds a barrier in the physiological behaviour of lymphocytes and their homing patterns. However, several recent studies identified clonal lymphoid lesions such as monoclonal B cell lymphocytosis (MBL), monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma in situ (FLIS) and mantle cell lymphoma in situ (MCLIS) that share genotypical and phenotypical features specific of the corresponding overt lymphoid neoplasms – chronic lymphocytic leukaemia (CLL), multiple myeloma (MM), follicular lymphoma (FL) and mantle cell lymphoma (MCL), respectively.1,2 Currently, FLIS and MCLIS are thought to be the tissue equivalent of clonal circulating cells carrying the genetic alterations found in their overt counterpart lymphomas. These are mainly incidental findings, and are defined as lesions that remain compartmentalized (germinal centre/mantle zone) without altering the normal/reactive lymph node (LN) architecture.2,3 In 2011 Henopp et al.2 investigated FLIS prevalence in an unselected series of reactive LNs submitted for histopathological examination from patients without evidence of lymphoma, demonstrating a prevalence of 2.3%. Other studies have shown that the risk of FLIS progression to an overt lymphoma is limited. We performed a retrospective review to assess whether patients who develop FL/MCL inevitably have FLIS/MCLIS as a precursor lesion prior to the development of the OL. All patients diagnosed at the Royal Marsden Hospital with FL and MCL from 1996 to 2013 were screened for previous resections performed for reasons other than haematological
malignancies that included sampling of LNs or other areas with organized lymphoid tissue (e.g. tonsil/ appendix). A total of 1380 cases with FL and 126 cases with MCL were available for assessment. Twelve cases of FL (eight females, 66%) with a median age at diagnosis of overt follicular lymphoma of 67 years (range: 46–95 years) and two cases of MCL (a 79-year-old male and a 71-year-old female) fulfilled the inclusion criteria. All LNs from the previous resections underwent routine histological examination and staining for CD20, CD10, CD5, bcl2 (FL cases) and cyclin-D1 (MCL cases). If initial staining for bcl-2 (Dako, Cambridge, UK) was negative, additional staining with the alternative anti-bcl-2 antibody (clone E17; GeneTex, Irvine, CA, USA) was performed. Among the FL cases, 10 had pre-existing FLIS. The average interval between FL diagnosis and the previous resection with FLIS was 97.5 months (6–264 months). In-situ lymphoma was identified in both MCL cases, with an interval between MCL diagnosis and the previous biopsy of 120 and 240 months, respectively. Most patients are alive with stable disease (11 of 14) (Table 1). The hallmark molecular events in FL and MCL, t(14;18) and t(11;14), respectively, arise from similar mechanisms of incorrect repair of variable, diversity and joining (VDJ) recombination in the immunoglobulin heavy chain gene locus and double-strand DNA breaks of different origins at the oncogene loci. These genetic alterations give a longer life span to naive B lymphocytes, allowing longer exposure to different immunological events and additional genetic hits.3 Several studies have shown the presence of these translocations in circulating B lymphocytes of healthy individuals, which probably represents the earliest event in the multistep oncogenic process evolving into overt lymphoma. It is hypothesized that these cells expand to produce clonal populations that retain their innate capacity of homing into reactive follicles.2 In-situ lymphomas are described currently as minimal infiltrates of clonal B cells in morphologically reactive lymphoid tissues showing phenotypical and genetic features of specific B cell lymphoma subtypes with a distinct topographical distribution (Table 2).4 Several studies have tried to relate these ‘early lesions’ clonally to the respective overt malignancy. In 2001, Bonzheim et al.5 described clonally related FLIS and FL. Mamessier et al.6 showed that small copy number variations tended to increase significantly between pre-FL and overt FL lesions. These ‘pre-FL’
462
Correspondence
Table 1. Overt and in-situ lymphoma relationship: cases overview Follicular lymphoma (FL) Original Bps (B1)
Overt FL (B2)
Interval (months)
Dx-sample
Year
FLIS (bcl-2)
F/70
IDC-LN
1996
+
1–2
2002
72
02
F/62
IDC-LN
2007
+
1–2
2013
192
03
F/57
MM-LN
2005
+
1
2011
72
Alive. PS 0. On Rx maintenance
04
F/78
IDC-LN
1997
3B
2001
48
Deceased (2012). IDC relapsed
05
F/75
IDC-LN
1985
+
3B
1997
144
06
F/78
IDC-LN
1999
+
1
2007
96
Alive. On Rx maintenance
07
M/66
Stomach CA-LN
2005
+
1
2012
84
Alive. PS 0. No current Tx
08
M/46
MM-LN
1989
+
1
2011
264
Alive. PS 0. No current Tx
09
M/63
SCC Met-LN
2001
1–2
2002
12
10
F/95
Colon CA-Apd
1995
+
1
1996
6
11
M/56
PA-SG
2006
+
3A
2013
84
Alive. PS 0. No current Tx
12
F/61
Warthin Tu-SG
2005
+
1–2
2013
96
Alive. PS 0. On Rx maintenance
Patient
Gender/ age
01
Grade
Year
Follow up DLBCL transformation (2007). Relapse (2009). Alive. PS 0. On R-CODOX M IVAC Alive. PS 0. No tx
Alive. IDC relapsed
Alive. Relapse 2014. On R-CVP Deceased (2003). Pneumonia
Mantle cell lymphoma (MCL) Original Bps (B1)
Stage
Year
Interval (months)
Follow up
+
IA
2008
240
Alive. Stable disease
+
IVA
2013
120
Deceased (2014)
Dx-sample
Year
MCLIS (cyc-D1)
M/79
MM-LN
1988
F/71
IDC-LN
2003
Patient
Gender/ age
01 02
Overt MCL (B2)
F, Female; M, Male; FLIS, Follicular lymphoma in situ; MCLIS, Mantle cell lymphoma in situ; LNC ß lymph node; MM, Malignant melanoma; Met, Metastasis; IDC, Invasive ductal carcinoma; CA, Carcinoma; SCCmet, Squamous cell carcinoma metastasis to lymph node; Bps, Biopsy; Dx, Diagnosis; LN, Lymph node; Apd, Appendix; PA, Pleomorphic adenoma; SG, Salivary gland; DLBCL, Difuse large B-cell lymphoma; PS, Performance status; R-CODOX-M/IVAC, Rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/etoposide, ifosfamide, cytarabine; Tx, Treatment; Rx, Radiotherapy; R-CVP, Rituximab, cyclophosphamide, vincristine, prednisone; cyc-D1, Cyclin-D1.
lesions already showed a greater genetic instability, which confirmed their status of early lesions in the natural history of FL. This study strengthens the proposal of a multistep oncogenic model in the natural history of these lymphomas placing in-situ lesions at the early end of malignancy progression. While the numbers in this study are small, our findings suggest that the vast majority of patients
who develop FL will have had pre-existing FLIS. With MCL the situation may be the same, but no definite conclusion can be inferred from the two cases reported. ACKNOWLEDGEMENT
We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. Histopathology, 68, 461–468.
Correspondence
463
Table 2. In-situ lymphoma: FLIS and MCLIS diagnostic criteria FLIS Morphology
Preserved
MCLIS Preserved/little or no spread to interfollicular area
IHC *Exclude partial involvement by overt FL or MCL
Bcl-2 (strong + in GC) CD10 (strong + in GC) Lower ki67/MIB-1
CD20+ CD5+ Cyclin-D1+
Clinical data
No evidence of coexistent overt lymphoma
No evidence of coexistent overt lymphoma
Management
Close follow-up is suggested
Close follow-up is suggested
IHC, Immunohistochemistry; FLIS, Follicular lymphoma in situ; MCLIS, Mantle cell lymphoma in situ; GC, Germinal centre; LN, Lymph node. CONFLICT OF INTEREST
The authors declare no conflicting interests. Larissa Sena Teixeira Mendes Andrew Wotherspoon Histopathology Department, The Royal Marsden Hospital, London, UK 1. Ganapathi KA, Pittaluga S, Odejide OO et al. Early lymphoid lesion: conceptual, diagnostic and clinical challenges. Haematologica 2014; 99; 1421–1432. 2. Henopp T, Quintanilla-Martinez L, Fend F, Adam P. Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes. Histopathology 2011; 59; 139–142. 3. Adam P, Schiefer A, Prill S et al. Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues. Mod. Pathol. 2012; 25; 1629–1636. 4. Jegalian AG, Eberle AC, Pack SD et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118; 2976– 2984. 5. Bonzheim I, Salaverna I, Haake A et al. A unique case of follicular lymphoma provides insights to the clonal evolution from follicular lymphoma in situ to manifest follicular lymphoma. Blood 2011; 118; 3442–3444. 6. Mamessier E, Song JY, Eberle FC et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica 2014; 99; 481–488.
Acantholytic squamous cell carcinoma of the lung showing significant signet ring cell component DOI: 10.1111/his.12762 © 2015 John Wiley & Sons Ltd Histopathology, 68, 461–468.
Sir: Acantholytic squamous cell carcinoma (SCC) is a rare variant of SCC and develops most commonly in sun-exposed areas of skin. Acantholytic SCC is also known as adenoid SCC, pseudovascular SCC, pseudovascular adenoid SCC and pseudoangiosarcomatous SCC, because the artefactual clefts that result from acantholysis resemble glandular lumens or vascular spaces in surgically resected specimens. Only a few cases of acantholytic SCC of the lung have been reported.1–3 Signet ring SCC is an extremely uncommon variant, and very few cases exclusively in the skin have been reported.4 Here we report the first case of acantholytic SCC with a focal signet ring cell component in the lung. A 64-year-old man who was a 35 pack-year ex-smoker, presented with a solitary pulmonary nodule on chest radiography during a regular medical examination. Chest computed tomography (CT) revealed a 2.8-cm mass in the left upper lobe. Wholebody positron emission tomography showed no hypermetabolic lesion except the left upper lobe mass. CT-guided fine-needle aspiration was performed and the cytological diagnosis was ‘suspicious of nonsmall-cell carcinoma’. The cytological features of this case were reported elsewhere (Cytopathology, in press). The patient underwent a left upper lobe lobectomy with mediastinal lymph node dissection. Macroscopically, a grey–tan solid mass measuring 2.9 9 2.4 cm was found at the periphery of the posterior segment (Figure 1A). Microscopically, the predominant tumour cells were discohesive and showed solid growth filling alveolar spaces lacking a specific pattern (Figure 1B). These tumour cells were round with bright eosinophilic cytoplasm and well-defined cytoplasmic borders. The tumour nuclei were round and pleomorphic and had vesicular chromatin with prominent nucleoli. Fewer than 1% of the tumour
Correspondence The relationship between overt and in-situ lymphoma: a retrospective study of follicular and mantle cell lymphoma cases DOI: 10.1111/his.12753 © 2015 John Wiley & Sons Ltd
Sir: The deregulation of multiple molecular pathways is the biological basis for establishment of a neoplastic process. It often follows an evolution path based on the selection and accumulation of genomic alterations. This ‘histologic progression’ can be demonstrated easily in premalignant lesions of solid tumours.1 Among lymphoid malignancies, this concept finds a barrier in the physiological behaviour of lymphocytes and their homing patterns. However, several recent studies identified clonal lymphoid lesions such as monoclonal B cell lymphocytosis (MBL), monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma in situ (FLIS) and mantle cell lymphoma in situ (MCLIS) that share genotypical and phenotypical features specific of the corresponding overt lymphoid neoplasms – chronic lymphocytic leukaemia (CLL), multiple myeloma (MM), follicular lymphoma (FL) and mantle cell lymphoma (MCL), respectively.1,2 Currently, FLIS and MCLIS are thought to be the tissue equivalent of clonal circulating cells carrying the genetic alterations found in their overt counterpart lymphomas. These are mainly incidental findings, and are defined as lesions that remain compartmentalized (germinal centre/mantle zone) without altering the normal/reactive lymph node (LN) architecture.2,3 In 2011 Henopp et al.2 investigated FLIS prevalence in an unselected series of reactive LNs submitted for histopathological examination from patients without evidence of lymphoma, demonstrating a prevalence of 2.3%. Other studies have shown that the risk of FLIS progression to an overt lymphoma is limited. We performed a retrospective review to assess whether patients who develop FL/MCL inevitably have FLIS/MCLIS as a precursor lesion prior to the development of the OL. All patients diagnosed at the Royal Marsden Hospital with FL and MCL from 1996 to 2013 were screened for previous resections performed for reasons other than haematological
malignancies that included sampling of LNs or other areas with organized lymphoid tissue (e.g. tonsil/ appendix). A total of 1380 cases with FL and 126 cases with MCL were available for assessment. Twelve cases of FL (eight females, 66%) with a median age at diagnosis of overt follicular lymphoma of 67 years (range: 46–95 years) and two cases of MCL (a 79-year-old male and a 71-year-old female) fulfilled the inclusion criteria. All LNs from the previous resections underwent routine histological examination and staining for CD20, CD10, CD5, bcl2 (FL cases) and cyclin-D1 (MCL cases). If initial staining for bcl-2 (Dako, Cambridge, UK) was negative, additional staining with the alternative anti-bcl-2 antibody (clone E17; GeneTex, Irvine, CA, USA) was performed. Among the FL cases, 10 had pre-existing FLIS. The average interval between FL diagnosis and the previous resection with FLIS was 97.5 months (6–264 months). In-situ lymphoma was identified in both MCL cases, with an interval between MCL diagnosis and the previous biopsy of 120 and 240 months, respectively. Most patients are alive with stable disease (11 of 14) (Table 1). The hallmark molecular events in FL and MCL, t(14;18) and t(11;14), respectively, arise from similar mechanisms of incorrect repair of variable, diversity and joining (VDJ) recombination in the immunoglobulin heavy chain gene locus and double-strand DNA breaks of different origins at the oncogene loci. These genetic alterations give a longer life span to naive B lymphocytes, allowing longer exposure to different immunological events and additional genetic hits.3 Several studies have shown the presence of these translocations in circulating B lymphocytes of healthy individuals, which probably represents the earliest event in the multistep oncogenic process evolving into overt lymphoma. It is hypothesized that these cells expand to produce clonal populations that retain their innate capacity of homing into reactive follicles.2 In-situ lymphomas are described currently as minimal infiltrates of clonal B cells in morphologically reactive lymphoid tissues showing phenotypical and genetic features of specific B cell lymphoma subtypes with a distinct topographical distribution (Table 2).4 Several studies have tried to relate these ‘early lesions’ clonally to the respective overt malignancy. In 2001, Bonzheim et al.5 described clonally related FLIS and FL. Mamessier et al.6 showed that small copy number variations tended to increase significantly between pre-FL and overt FL lesions. These ‘pre-FL’
462
Correspondence
Table 1. Overt and in-situ lymphoma relationship: cases overview Follicular lymphoma (FL) Original Bps (B1)
Overt FL (B2)
Interval (months)
Dx-sample
Year
FLIS (bcl-2)
F/70
IDC-LN
1996
+
1–2
2002
72
02
F/62
IDC-LN
2007
+
1–2
2013
192
03
F/57
MM-LN
2005
+
1
2011
72
Alive. PS 0. On Rx maintenance
04
F/78
IDC-LN
1997
3B
2001
48
Deceased (2012). IDC relapsed
05
F/75
IDC-LN
1985
+
3B
1997
144
06
F/78
IDC-LN
1999
+
1
2007
96
Alive. On Rx maintenance
07
M/66
Stomach CA-LN
2005
+
1
2012
84
Alive. PS 0. No current Tx
08
M/46
MM-LN
1989
+
1
2011
264
Alive. PS 0. No current Tx
09
M/63
SCC Met-LN
2001
1–2
2002
12
10
F/95
Colon CA-Apd
1995
+
1
1996
6
11
M/56
PA-SG
2006
+
3A
2013
84
Alive. PS 0. No current Tx
12
F/61
Warthin Tu-SG
2005
+
1–2
2013
96
Alive. PS 0. On Rx maintenance
Patient
Gender/ age
01
Grade
Year
Follow up DLBCL transformation (2007). Relapse (2009). Alive. PS 0. On R-CODOX M IVAC Alive. PS 0. No tx
Alive. IDC relapsed
Alive. Relapse 2014. On R-CVP Deceased (2003). Pneumonia
Mantle cell lymphoma (MCL) Original Bps (B1)
Stage
Year
Interval (months)
Follow up
+
IA
2008
240
Alive. Stable disease
+
IVA
2013
120
Deceased (2014)
Dx-sample
Year
MCLIS (cyc-D1)
M/79
MM-LN
1988
F/71
IDC-LN
2003
Patient
Gender/ age
01 02
Overt MCL (B2)
F, Female; M, Male; FLIS, Follicular lymphoma in situ; MCLIS, Mantle cell lymphoma in situ; LNC ß lymph node; MM, Malignant melanoma; Met, Metastasis; IDC, Invasive ductal carcinoma; CA, Carcinoma; SCCmet, Squamous cell carcinoma metastasis to lymph node; Bps, Biopsy; Dx, Diagnosis; LN, Lymph node; Apd, Appendix; PA, Pleomorphic adenoma; SG, Salivary gland; DLBCL, Difuse large B-cell lymphoma; PS, Performance status; R-CODOX-M/IVAC, Rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/etoposide, ifosfamide, cytarabine; Tx, Treatment; Rx, Radiotherapy; R-CVP, Rituximab, cyclophosphamide, vincristine, prednisone; cyc-D1, Cyclin-D1.
lesions already showed a greater genetic instability, which confirmed their status of early lesions in the natural history of FL. This study strengthens the proposal of a multistep oncogenic model in the natural history of these lymphomas placing in-situ lesions at the early end of malignancy progression. While the numbers in this study are small, our findings suggest that the vast majority of patients
who develop FL will have had pre-existing FLIS. With MCL the situation may be the same, but no definite conclusion can be inferred from the two cases reported. ACKNOWLEDGEMENT
We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. Histopathology, 68, 461–468.
Correspondence
463
Table 2. In-situ lymphoma: FLIS and MCLIS diagnostic criteria FLIS Morphology
Preserved
MCLIS Preserved/little or no spread to interfollicular area
IHC *Exclude partial involvement by overt FL or MCL
Bcl-2 (strong + in GC) CD10 (strong + in GC) Lower ki67/MIB-1
CD20+ CD5+ Cyclin-D1+
Clinical data
No evidence of coexistent overt lymphoma
No evidence of coexistent overt lymphoma
Management
Close follow-up is suggested
Close follow-up is suggested
IHC, Immunohistochemistry; FLIS, Follicular lymphoma in situ; MCLIS, Mantle cell lymphoma in situ; GC, Germinal centre; LN, Lymph node. CONFLICT OF INTEREST
The authors declare no conflicting interests. Larissa Sena Teixeira Mendes Andrew Wotherspoon Histopathology Department, The Royal Marsden Hospital, London, UK 1. Ganapathi KA, Pittaluga S, Odejide OO et al. Early lymphoid lesion: conceptual, diagnostic and clinical challenges. Haematologica 2014; 99; 1421–1432. 2. Henopp T, Quintanilla-Martinez L, Fend F, Adam P. Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes. Histopathology 2011; 59; 139–142. 3. Adam P, Schiefer A, Prill S et al. Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues. Mod. Pathol. 2012; 25; 1629–1636. 4. Jegalian AG, Eberle AC, Pack SD et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118; 2976– 2984. 5. Bonzheim I, Salaverna I, Haake A et al. A unique case of follicular lymphoma provides insights to the clonal evolution from follicular lymphoma in situ to manifest follicular lymphoma. Blood 2011; 118; 3442–3444. 6. Mamessier E, Song JY, Eberle FC et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica 2014; 99; 481–488.
Acantholytic squamous cell carcinoma of the lung showing significant signet ring cell component DOI: 10.1111/his.12762 © 2015 John Wiley & Sons Ltd Histopathology, 68, 461–468.
Sir: Acantholytic squamous cell carcinoma (SCC) is a rare variant of SCC and develops most commonly in sun-exposed areas of skin. Acantholytic SCC is also known as adenoid SCC, pseudovascular SCC, pseudovascular adenoid SCC and pseudoangiosarcomatous SCC, because the artefactual clefts that result from acantholysis resemble glandular lumens or vascular spaces in surgically resected specimens. Only a few cases of acantholytic SCC of the lung have been reported.1–3 Signet ring SCC is an extremely uncommon variant, and very few cases exclusively in the skin have been reported.4 Here we report the first case of acantholytic SCC with a focal signet ring cell component in the lung. A 64-year-old man who was a 35 pack-year ex-smoker, presented with a solitary pulmonary nodule on chest radiography during a regular medical examination. Chest computed tomography (CT) revealed a 2.8-cm mass in the left upper lobe. Wholebody positron emission tomography showed no hypermetabolic lesion except the left upper lobe mass. CT-guided fine-needle aspiration was performed and the cytological diagnosis was ‘suspicious of nonsmall-cell carcinoma’. The cytological features of this case were reported elsewhere (Cytopathology, in press). The patient underwent a left upper lobe lobectomy with mediastinal lymph node dissection. Macroscopically, a grey–tan solid mass measuring 2.9 9 2.4 cm was found at the periphery of the posterior segment (Figure 1A). Microscopically, the predominant tumour cells were discohesive and showed solid growth filling alveolar spaces lacking a specific pattern (Figure 1B). These tumour cells were round with bright eosinophilic cytoplasm and well-defined cytoplasmic borders. The tumour nuclei were round and pleomorphic and had vesicular chromatin with prominent nucleoli. Fewer than 1% of the tumour
