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Acute granular lymphoid leukemia
HUMAN PATHOLOGY
Volume 18, No. 8 [August 1987J
TABLE 1, Probabilities of Survival in Minimal Deviation Melanoma T
Tt
7'2
Pt
P~
P3
Soong
Case
(mm)
(yr)
(yr)
(%)
(%)
(%)
Table
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1.6 1.62 1.7 1.75 1.82 2.15 2.42 2.47 2.74 2.9 2.9 2.9 3.55 3.6 3.66 4.23 4.31 4.5 6.2 8.24 10.4
3.67 5.42 4.33 6.00 5.17 8.00 4.33 5.00 4.42 3.42 4.08 4.00 7.5 5.42 4.33 3 1.00 5.42 5.08 6.17 4.33
4 5 4 6 5 8 4 5 4 3 4 4 8 5 4 3 I 5 5 6 4
95 94 82 92 91 83 67 74 53 92 91 91 42 59 37 73 I00 12 1 1 1
94 91 78 88 87 76 55 65 39 88 89 89 28 47 23 63 100 5 0 0 0
98 98 91 96 96 92 84 87 75 96 96 96 69 79 63 88 100 40 12 11 15
6 6 6 6 7 6 8 7 9 7 6 6 6 7 9 8 9 9 9 8 7
The authors reply:--Our article was i n t e n d e d basically to point out morphologic features in the minimal deviation m e l a n o m a that tend to distinguish it from tile o t h e r forms o f m e l a n o m a . T h e d i f f e r e n c e s a r e b a s e d on cytologic findings, a n d the article indicated that the survival might be better. O u r series is too small to be subjected to the exotic statistical analysis that Dr. Vollmer p e r f o r m e d . Basically, we believe he has overanalyzed this series. We would also like to clarify that n o n e o f the r e p o r t e d patients had nodal dissections. We p o i n t o u t that even with Dr. Vollmer's analysis, f o u r o f the patients had survivals better than expected. Obviously, to conclude that the survival o f minimal deviation m e l a n o m a is b e t t e r t h a n that o f o t h e r m e l a n o m a s , one would need a larger series a n d longer follow-ups. Since we d o r e p o r t deaths in o u r series, it is clear that at least some minimal deviation melanomas have full metastatic capability. T h e main point o f o u r article was to acquaint pathologists with the diagnostic features so that these lesions can be separated a n d studied individually. MILDRED E. PHILLIPS, M D
D e p a r t m e n t o f Pathology State University o f New York Stony Brook, New York
* T is tumor thickness (mm). T1 is the observed time (yrs) of follow-up, and T2 is the time used for calculating the survival probability. PI is the estimate of the probability of surviving to time T 2 for an average patient with this thickness and other prognostic variables; P2 is the probability estimate for those without node dissection; and Pa is the probability estimate for those having node dissections.
ARTHURJ. SOBER, MD D e p a r t m e n t o f Dermatology Massachusetts General Hospital Boston, Massachusetts MARTIN C. MIHM, JR, MD
D e p a r t m e n t o f Pathology Massachusetts General Hospital Boston, Massachusetts a n d that two additional patients (cases 13 a n d 15) would have h a d a b e t t e r than even chance to survive to their follow-up time if they had had l y m p h n o d e dissection. T h e s e results suggest that "minimal deviation" m o r p h o l o g y may not discriminate between usual a n d unusual survival, because the authors indicated that the only morphologic difference between these 16 patients and the r e m a i n d e r was the Breslow thickness. T h a t four o f their patients survived l o n g e r than would be expected (their estimated probabilities were far less than 5 p e r cent) is o f great interest, a n d I w o n d e r if the authors might have some explanation o t h e r than the "minimal deviation" morphology. Did any o f these f o u r have early lymph node dissections? P e r h a p s the greatest frustration in studying prognostic factors in malignant m e l a n o m a is obtaining the necessary follow-up information, and anything u n d e r 10 years may be insufficient to define prognostically separate groups in stage I melanoma. I f the authors follow their patients ano t h e r five to nine years, they may be able to show j u s t how these "minimal deviation" tumors differ from the norm, but at this point the behavior o f most o f their cases seems no d i f f e r e n t from that o f the o r d i n a r y melanomas.
ROBIN T. VOLLMER, MD Veterans Administration Medical Center Durham, N o r t h Carolina 1. Phillips ME, Margolis RJ, Merot Y, et al: The spectrum of minimal deviation melanoma: a dinicopathologic study of 21 cases. HuM PATHOL 17:796, 1986 2. Soong S-J: A computerized mathematical model and scoring system in melanoma patients. In Balch CM, Mihon GW (eds): Cutaneous Melanoma. Philadelphia, JB Lippincou Co., 1985, p 353
870
Acute Granular Lymphoid Leukemia
To the editor:--In the J a n u a r y issue, Simpkins et al. 1 describe a case o f acute g r a n u l a r lymphoid leukemia with unusual cytochemistry a n d immunologic phenotype. It is a well-studied case. However, the authors fail to discuss the most likely explanation for their findings: acute mixed lineage leukemia. 2 Cases with so-called unusual phenotypes or discordance between i m m u n o p h e n o t y p i c profiles and morphologic a n d / o r cytochemical findings should be conside r e d candidates for acute mixed lineage leukemia. Similar cases have been c o n f i r m e d to be also genotypically heterogeneous. 2 F u r t h e r m o r e , in the specific case cited by the authors, they used the monoclonal antibodies MO1 ( C D l l ) a n d MO2 (CD 14) which do not cover the range o f myeloid/ monocytic differentiation. Rather, these antibodies react with antigens that r e p r e s e n t late stages o f monocyte-granulocytd*differentiation a n d are relatively weakly expressed on m y e l o i d l e u k e m i a s . ~.4 M o n o c l o n a l a n t i b o d i e s My7 (CDI3) a n d My9 (CD33) cover a b r o a d e r range o f myeloid a n d monocytic differentiation stages, show greater fluorescence intensity at early stages o f myeloid maturation, and are highly reactive in acute myeloid leukemia. 4,s Unfortunately, they do not seem to have been included in the panel o f antibodies r e p o r t e d in this study, and the authors therefore leave u n c o n f i r m e d , by immunologic phenotyping, the a b o v e - m e n t i o n e d possibility. RIOARDO E. DUQUE, M.D.
D e p a r t m e n t o f Pathology University o f Florida College o f Medicine Gainesville, Florida
CORRESPONDENCE 1. Simpkins H, Shoaf F, Katz J. Acute granular lymphoid leukemia with unusual cytochemistry and immunologic phenotype, tlu.~t PATHOL 18:93, 1987 2. Mirro J, Zipf TF, Pui CH, et al: Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance. Blood 66:1115, 1985
firmed, in a study of 41 cases o f chronic lymphocytic leukemia, that this usually holds true; in every case tested, Jn rearrangement was detectable after digestion with every enzyme. 3
3. Griffin JD, Mayer RJ, Weinstein HJ, et al: Surface marker analysis of acute myeloblastic leukemia: identification of differentiation-associated phenotypes. Blood 62:557, 1983 4. Todd RF Ill, Nadler LM, SchlossmanSF. Antigens on human monocytes identified by monoclonalantibodies.J lmmuno1126:1435,1981 5. Matutes E, Rodriguez B, Polli N, et al: Characterization of myeloidleukemias with monoclonal antibodies 3C5 and MY9. Hematol Oncol 3:179, 1985
The authors reply:--Dr. Duque raises the possibility of a mixed lineage myeloblastic lymphoblastic leukemia and suggests that immunophenotyping with two monoclonal antibodies, My7 and My9, should have been performed. Unfortunately, when the study was performed (over three years ago), these monoclonal antibodies were not routinely used in the clinical laboratory. Secondly, the possibility that this was a mixed lineage leukemia was.discussed in great detail in the original paper that I submitted to Human Pathology, but this had to be deleted to accommodate the space restrictions o f the Case Studies section of the journal. Similarly, many o f the manuscripts' original references had to be removed. In addition, in this particular case, there was no evidence o f myelocytic differentiation, i.e., histochemically, which was the criteria used by other authors to define the myelocytic lineage of a mixed leukemia. I hope that as more cases of this type are recognized, the subject can be reviewed in greater detail. HENRY SIMPKINS, MD, PHD T h e Staten Island Hospital State University of New York Downstate Staten Island, New York
JH Rearrangements in Hodgkin's Disease
To the Editor:--Weiss et al? describe immunoglobulin gene rearrangement in biopsy specimens from seven cases of Hodgkin's disease. T h e y showed heavy chain gene rearrangement using a J n probe, after digestion with BamHI in two cases and EcoRI in two cases. In none o f these four caseswas the rearrangement detected after both BamHI and EcoRI digestion, and in no case was the rearrangement detected after HindlII digestion. These results are surprising because a clonal J n rearrangement should be detectable after digestion with each o f these three enzymes (BamHI, EcoRI, and HindlII), as shown by the accompanying gene map (fig. 1).2 I have con-
E
H
NIGEL O'CONNOR, MD, MRCP Department of Hematology T h e Royal Free Hospital London, England
1. Weiss LK, Strickler JO, Hu E, et al: Immunoglobulin gene rearrangements in Hodgkin's disease. Hu.~t PATHOL 17:1009, 1986 2. Foroni L, Catovsky D, Rabbitts Ttt, et al: DNA rearrangements ofimmunoglobulin genes correlate with phenotypic markers in B-cell malignancies. Mol Biol Med 2:63, 1984 3. O'Connor NTJ: Genotypic analysis of human lymphoma [thesis]. London: London University, 1986
Tl*e authors reply:--We, too, were surprised by our inability to find immunoglobulin heavy chain gene rearrangements with a second enzyme in tissues from the four cases of Hodgkin's disease that showed rearrangements of the heavy chain gene. Although this is an unusual finding, particularly in four consecutive cases, it is not unprecedented in o u r experience. It is possible that analyses of certain rearranged genes lead to coincident rearranged and germline bands. This problem is compounded by the fact that bands corresponding to large fragments, in the size range of some germline bands (over about 20 kilobases in length), do not resolve well d u r i n g the c o n v e n t i o n a l S o u t h e r n blot p r o c e d u r e . F u r t h e r m o r e , bands corresponding to very large fragments (perhaps over 30 kilobases in size) are sometimes difficult to transfer from gels to membranes, so rearrangements that are present may not be detected in such circumstances. This difficulty may be especially relevant to analyses o f solid tissues, as opposed to leukemic specimens, because these tissues are often highly heterogeneous and contain only a small clonal component that produces at best only weak bands. Such was apparently the case in o u r study, in which the immunoglobulin heavy chain gene rearrangements identified were weak in intensity, indicating that the clonal populations identified were at the limits o f detection. LAWRENCE/~I. WEISS, MD ROGER WARNKE, MD JEFFREY SKLAR, MD Department o f Pathology Stanford University School o f Medicine Stanford, California
H
B
FIGURE 1. Map "of the joining region [JH) of the immunoglobulin heavy chain gene, showing the restriction enzyme cutting sites for BamHI [B], EcoRI [E], and Hindlll [/-/]. J. probe
871
E
B
I-----4 I kb
Volume 18, No. 8 [August 1987J
TABLE 1, Probabilities of Survival in Minimal Deviation Melanoma T
Tt
7'2
Pt
P~
P3
Soong
Case
(mm)
(yr)
(yr)
(%)
(%)
(%)
Table
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1.6 1.62 1.7 1.75 1.82 2.15 2.42 2.47 2.74 2.9 2.9 2.9 3.55 3.6 3.66 4.23 4.31 4.5 6.2 8.24 10.4
3.67 5.42 4.33 6.00 5.17 8.00 4.33 5.00 4.42 3.42 4.08 4.00 7.5 5.42 4.33 3 1.00 5.42 5.08 6.17 4.33
4 5 4 6 5 8 4 5 4 3 4 4 8 5 4 3 I 5 5 6 4
95 94 82 92 91 83 67 74 53 92 91 91 42 59 37 73 I00 12 1 1 1
94 91 78 88 87 76 55 65 39 88 89 89 28 47 23 63 100 5 0 0 0
98 98 91 96 96 92 84 87 75 96 96 96 69 79 63 88 100 40 12 11 15
6 6 6 6 7 6 8 7 9 7 6 6 6 7 9 8 9 9 9 8 7
The authors reply:--Our article was i n t e n d e d basically to point out morphologic features in the minimal deviation m e l a n o m a that tend to distinguish it from tile o t h e r forms o f m e l a n o m a . T h e d i f f e r e n c e s a r e b a s e d on cytologic findings, a n d the article indicated that the survival might be better. O u r series is too small to be subjected to the exotic statistical analysis that Dr. Vollmer p e r f o r m e d . Basically, we believe he has overanalyzed this series. We would also like to clarify that n o n e o f the r e p o r t e d patients had nodal dissections. We p o i n t o u t that even with Dr. Vollmer's analysis, f o u r o f the patients had survivals better than expected. Obviously, to conclude that the survival o f minimal deviation m e l a n o m a is b e t t e r t h a n that o f o t h e r m e l a n o m a s , one would need a larger series a n d longer follow-ups. Since we d o r e p o r t deaths in o u r series, it is clear that at least some minimal deviation melanomas have full metastatic capability. T h e main point o f o u r article was to acquaint pathologists with the diagnostic features so that these lesions can be separated a n d studied individually. MILDRED E. PHILLIPS, M D
D e p a r t m e n t o f Pathology State University o f New York Stony Brook, New York
* T is tumor thickness (mm). T1 is the observed time (yrs) of follow-up, and T2 is the time used for calculating the survival probability. PI is the estimate of the probability of surviving to time T 2 for an average patient with this thickness and other prognostic variables; P2 is the probability estimate for those without node dissection; and Pa is the probability estimate for those having node dissections.
ARTHURJ. SOBER, MD D e p a r t m e n t o f Dermatology Massachusetts General Hospital Boston, Massachusetts MARTIN C. MIHM, JR, MD
D e p a r t m e n t o f Pathology Massachusetts General Hospital Boston, Massachusetts a n d that two additional patients (cases 13 a n d 15) would have h a d a b e t t e r than even chance to survive to their follow-up time if they had had l y m p h n o d e dissection. T h e s e results suggest that "minimal deviation" m o r p h o l o g y may not discriminate between usual a n d unusual survival, because the authors indicated that the only morphologic difference between these 16 patients and the r e m a i n d e r was the Breslow thickness. T h a t four o f their patients survived l o n g e r than would be expected (their estimated probabilities were far less than 5 p e r cent) is o f great interest, a n d I w o n d e r if the authors might have some explanation o t h e r than the "minimal deviation" morphology. Did any o f these f o u r have early lymph node dissections? P e r h a p s the greatest frustration in studying prognostic factors in malignant m e l a n o m a is obtaining the necessary follow-up information, and anything u n d e r 10 years may be insufficient to define prognostically separate groups in stage I melanoma. I f the authors follow their patients ano t h e r five to nine years, they may be able to show j u s t how these "minimal deviation" tumors differ from the norm, but at this point the behavior o f most o f their cases seems no d i f f e r e n t from that o f the o r d i n a r y melanomas.
ROBIN T. VOLLMER, MD Veterans Administration Medical Center Durham, N o r t h Carolina 1. Phillips ME, Margolis RJ, Merot Y, et al: The spectrum of minimal deviation melanoma: a dinicopathologic study of 21 cases. HuM PATHOL 17:796, 1986 2. Soong S-J: A computerized mathematical model and scoring system in melanoma patients. In Balch CM, Mihon GW (eds): Cutaneous Melanoma. Philadelphia, JB Lippincou Co., 1985, p 353
870
Acute Granular Lymphoid Leukemia
To the editor:--In the J a n u a r y issue, Simpkins et al. 1 describe a case o f acute g r a n u l a r lymphoid leukemia with unusual cytochemistry a n d immunologic phenotype. It is a well-studied case. However, the authors fail to discuss the most likely explanation for their findings: acute mixed lineage leukemia. 2 Cases with so-called unusual phenotypes or discordance between i m m u n o p h e n o t y p i c profiles and morphologic a n d / o r cytochemical findings should be conside r e d candidates for acute mixed lineage leukemia. Similar cases have been c o n f i r m e d to be also genotypically heterogeneous. 2 F u r t h e r m o r e , in the specific case cited by the authors, they used the monoclonal antibodies MO1 ( C D l l ) a n d MO2 (CD 14) which do not cover the range o f myeloid/ monocytic differentiation. Rather, these antibodies react with antigens that r e p r e s e n t late stages o f monocyte-granulocytd*differentiation a n d are relatively weakly expressed on m y e l o i d l e u k e m i a s . ~.4 M o n o c l o n a l a n t i b o d i e s My7 (CDI3) a n d My9 (CD33) cover a b r o a d e r range o f myeloid a n d monocytic differentiation stages, show greater fluorescence intensity at early stages o f myeloid maturation, and are highly reactive in acute myeloid leukemia. 4,s Unfortunately, they do not seem to have been included in the panel o f antibodies r e p o r t e d in this study, and the authors therefore leave u n c o n f i r m e d , by immunologic phenotyping, the a b o v e - m e n t i o n e d possibility. RIOARDO E. DUQUE, M.D.
D e p a r t m e n t o f Pathology University o f Florida College o f Medicine Gainesville, Florida
CORRESPONDENCE 1. Simpkins H, Shoaf F, Katz J. Acute granular lymphoid leukemia with unusual cytochemistry and immunologic phenotype, tlu.~t PATHOL 18:93, 1987 2. Mirro J, Zipf TF, Pui CH, et al: Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance. Blood 66:1115, 1985
firmed, in a study of 41 cases o f chronic lymphocytic leukemia, that this usually holds true; in every case tested, Jn rearrangement was detectable after digestion with every enzyme. 3
3. Griffin JD, Mayer RJ, Weinstein HJ, et al: Surface marker analysis of acute myeloblastic leukemia: identification of differentiation-associated phenotypes. Blood 62:557, 1983 4. Todd RF Ill, Nadler LM, SchlossmanSF. Antigens on human monocytes identified by monoclonalantibodies.J lmmuno1126:1435,1981 5. Matutes E, Rodriguez B, Polli N, et al: Characterization of myeloidleukemias with monoclonal antibodies 3C5 and MY9. Hematol Oncol 3:179, 1985
The authors reply:--Dr. Duque raises the possibility of a mixed lineage myeloblastic lymphoblastic leukemia and suggests that immunophenotyping with two monoclonal antibodies, My7 and My9, should have been performed. Unfortunately, when the study was performed (over three years ago), these monoclonal antibodies were not routinely used in the clinical laboratory. Secondly, the possibility that this was a mixed lineage leukemia was.discussed in great detail in the original paper that I submitted to Human Pathology, but this had to be deleted to accommodate the space restrictions o f the Case Studies section of the journal. Similarly, many o f the manuscripts' original references had to be removed. In addition, in this particular case, there was no evidence o f myelocytic differentiation, i.e., histochemically, which was the criteria used by other authors to define the myelocytic lineage of a mixed leukemia. I hope that as more cases of this type are recognized, the subject can be reviewed in greater detail. HENRY SIMPKINS, MD, PHD T h e Staten Island Hospital State University of New York Downstate Staten Island, New York
JH Rearrangements in Hodgkin's Disease
To the Editor:--Weiss et al? describe immunoglobulin gene rearrangement in biopsy specimens from seven cases of Hodgkin's disease. T h e y showed heavy chain gene rearrangement using a J n probe, after digestion with BamHI in two cases and EcoRI in two cases. In none o f these four caseswas the rearrangement detected after both BamHI and EcoRI digestion, and in no case was the rearrangement detected after HindlII digestion. These results are surprising because a clonal J n rearrangement should be detectable after digestion with each o f these three enzymes (BamHI, EcoRI, and HindlII), as shown by the accompanying gene map (fig. 1).2 I have con-
E
H
NIGEL O'CONNOR, MD, MRCP Department of Hematology T h e Royal Free Hospital London, England
1. Weiss LK, Strickler JO, Hu E, et al: Immunoglobulin gene rearrangements in Hodgkin's disease. Hu.~t PATHOL 17:1009, 1986 2. Foroni L, Catovsky D, Rabbitts Ttt, et al: DNA rearrangements ofimmunoglobulin genes correlate with phenotypic markers in B-cell malignancies. Mol Biol Med 2:63, 1984 3. O'Connor NTJ: Genotypic analysis of human lymphoma [thesis]. London: London University, 1986
Tl*e authors reply:--We, too, were surprised by our inability to find immunoglobulin heavy chain gene rearrangements with a second enzyme in tissues from the four cases of Hodgkin's disease that showed rearrangements of the heavy chain gene. Although this is an unusual finding, particularly in four consecutive cases, it is not unprecedented in o u r experience. It is possible that analyses of certain rearranged genes lead to coincident rearranged and germline bands. This problem is compounded by the fact that bands corresponding to large fragments, in the size range of some germline bands (over about 20 kilobases in length), do not resolve well d u r i n g the c o n v e n t i o n a l S o u t h e r n blot p r o c e d u r e . F u r t h e r m o r e , bands corresponding to very large fragments (perhaps over 30 kilobases in size) are sometimes difficult to transfer from gels to membranes, so rearrangements that are present may not be detected in such circumstances. This difficulty may be especially relevant to analyses o f solid tissues, as opposed to leukemic specimens, because these tissues are often highly heterogeneous and contain only a small clonal component that produces at best only weak bands. Such was apparently the case in o u r study, in which the immunoglobulin heavy chain gene rearrangements identified were weak in intensity, indicating that the clonal populations identified were at the limits o f detection. LAWRENCE/~I. WEISS, MD ROGER WARNKE, MD JEFFREY SKLAR, MD Department o f Pathology Stanford University School o f Medicine Stanford, California
H
B
FIGURE 1. Map "of the joining region [JH) of the immunoglobulin heavy chain gene, showing the restriction enzyme cutting sites for BamHI [B], EcoRI [E], and Hindlll [/-/]. J. probe
871
E
B
I-----4 I kb