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Lymphoblastic lymphoma presenting in cutaneous sites
Volume 25 Number 6, Part 1 December 1991
22. Kestel JL, Blair DS. Keratoacanthoma treated with methotrexate. Arch Dermato11973;108:723-4. 23. Lloyd KM, Madsen DK, Lin PY. Grzybowski's eruptive keratoacanthoma. J AM ACAD DERMATOL 1989;21:1023-4. 24. Fanti PA, Tosti A, Peluso AM, et al. Multiple keratoacanthoma in discoid lupus erythematosus. J AM ACAD DERMATOL 1989;21:809-10. 25. Klein E, Milgram H, Traenkle HL. Tumors of the skin. II: Keratoacanthoma; local effect of 5-fluorouracil. Skin 1962;153-6. 26. Kurtis B, Rosen T. Treatment of cutaneous neoplasms by intralesional injections of 5-fluorouracil (5-FU). J Dermatol Surg Onco11980;6:122-7. 27. Parker CM, Hanke CWo Large keratoacanthomas in difficult locations treated with intralesional 5-fluorouracil. J AM ACAD DERMATOL 1986;14:770-7.
Intralesional MTX for keratoacanthomas 28. Belisario J C. Topical cytotoxic therapy for cutaneous cancer and precancer. Arch Dermatol 1965;92:292-303. 29. White JE. Methotrexate inhibition of deoxyuridine incorporation in the skin of three day old rats. J Invest Dermato1 1971;56:294-310. 30. Prutkin L. An ultrastructural study of the keratoacanthoma treated with methotrexate and 5-fluorouracil. Dermatologica 1968;137:373-80. 31. Ghadially FN. The role of the hair follicle in the origin and evolution of some cutaneous neoplasms of man and experimental animals. Cancer 1961;14:801-6. 32. Magee KL, Rapini RP, Duvic M, etal. Human papillomavirus associated with keratoacanthoma. Arch Dermatol 1989;125:1587-9.
Lymphoblastic lymphoma presenting in cutaneous sites A clinicopathologic analysis of six cases Christian A. Sander, MD,a, • 1. Jeffrey Medeiros, MD,a Lynne V. Abruzzo, MD, PhD,a Ivan D. Horak, MD,b and Elaine S. Jaffe, MDa Bethesda, Maryland Six patients with malignant lymphoma oflymphoblastic type involving cutaneous sites at time of diagnosis are presented. Skin sites of the head and neck were involved in all patients and included the scalp (three patients), forehead (two patients), and malar region of the face (one patient). Two patients also had additional sites of skin disease (neck, breast, and anterior trunk). In two patients the skin was the predominant site of disease, whereas in the remaining patients staging workup revealed generalized lymphoma. The histologic findings in each patient were typical of lymphoblastic lymphoma; the neoplastic cells were small with blastic nuclear chromatin. In three patients the neoplastic cells were convoluted, and in three they were nonconvoluted. Immunophenotypically, four lymphomas were of pre-B cell type, and two lymphomas were of T cell type. There was no correlation between histologic features and the immunophenotype. Since the majority of lymphoblastic lymphomas are of T cell type, the predominance of pre-B cell tumors involving the skin may suggest that pre-B cell neoplasms have a predilection for cutaneous involvement. In further support of this hypothesis, both lymphomas that appear to have arisen in the skin had a pre-B cell immunophenotype. (J AM ACAD DERMATOL 1991;25:1023-31.) From theHematopathologySection, Laboratory ofPathology," and the Clinical Pharmacology Branch, b National Cancer Institute, National Institutes of Health. Accepted for publication June 17, 1991. Reprint requests: L. Jeffrey Medeiros, MD, Building 10, Room 2Nl 08, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892.
*Supported by a grant from the Mildred-Scheel-Stiftung, Bonn, Germany. 16/1/31766
Malignant lymphoma of the lymphoblastic type (LBL) occurs predominantly in young children and adolescents. I-3 The characteristic histologic feature is the presence of small lymphoid cells with immature or "blastic" nuclear chromatin. 1-3 The great majority of LBLs have an immature T cell immunophenotype.4-6 Cutaneous involvement in patients with LBL is uncommon. For example, in the N ational Cancer Institute-sponsored study of lym1023
Journal of the American Academy of Dermatology
1024 Sanderetal phoma classifications, less than 20% of patients with LBL had skin disease at time of presentation. 7 In this study the clinical, pathologic, and imrnunophenotypic findings of six cases of LBL with cutaneous involvement at the time of diagnosis are reported. Our results suggest that LBL, like other non-Hodgkin's lymphomas, preferentially involves the head and neck when the skin is involved. In addition, in contrast to the majority of LBLs that have a T cell imrnunophenotype, four of six cutaneous LBLs in this study had a pre-B cell immunophenotype. Thus pre-B cell LBLs appear to have a tropism for the skin. CASE REPORTS
Case 1 A 24-year-old woman developed a purpuric skin lesion inferior to her left eye in April 1986. Purpura or ecchymoses, or both, subsequently developed in the malar regibns of her face and on the anterior chest and breasts. Results of a complete blood count and bone marrow biopsy were negative. Radiologic studies of the head, thorax and abdomen were unremarkable. The cutaneous pur~ura persisted, and a left conjunctival mass appeared. Biopsy specimens from the right malar region and the left conjunctiva were diagnostic of LBL. The patient was referred to the Clinical Center of the National Institutes of Health (NIH) for further evaluation and therapy. Physical examination revealed. numerous sites of cutaneous purpura and an enlarged submental lymph node. A biopsy specimen of a purpuric lesion of the skin of the right breast was diagnostic of LBL. The submental lymph node was excised and was also involved. A needle biopsy specimen of the liver and a bone marrow biopsy specimen were both involved by lymphoma. The patient was treated with cyclophosphamide, cytosine arabinoside, VM-26, 2' -deoxycoformycin, vincristine, and prednisone. Findings of repeat staging studies after four cycles of induction therapy were negative for lymphoma. After three cycles of consolidation therapy (doxorubicin (Adriamycin), vincristine, prednisone, and 2'deoxycoformycin) the patient refused additional treatment. Leukemic transformation developed and she died 21 months after initial diagnosis.
Case 2 A 25-year-old man had a 4-week history of multiple scalp nodules, lethargy, weakness, dyspnea, right-sided . pleuritic pain, and a 17-pound weight loss. Physical examination revealed multiple scalp nodules up to 1.5 em and lymphadenopathy of the cervical, supraclavicular, and axillary regions. Chest radiograph and computed tomographic (CT) SCan revealed a mediastinal mass and a
right pleural effusion. The patient underwent surgical resection of the mediastinal mass. The histologic findings were diagnostic of LBL. The patient was referred to the Clinical Center of NIH for staging and therapy. A biopsy specimen of a scalp nodule showed involvement by LBL. Other staging studies, including complete blood cell count, bone marrow biopsy, and CT scans of the abdomen and pelvis, revealed negative findings. The patient was treated with whole brain irradiation, intrathecal methotrexate, cyclophosphamide, doxorubicin, vincristine, L-asparaginase, 6-mercaptopurine, and prednisone. Complete remission was achieved, and the patient is currently well, 3 months after induction therapy. He is continuing to receive maintenance therapy.
Case 3 A red nodule developed on the forehead of a 26-yearold man. A punch biopsy specimen was interpreted as suspected lymphoma. Two months later acute abdominal pain developed. Physical examination revealed a 6 X 9 cm red nodule of the forehead, hepatosplenomegaly, and right iliac lymphadenopathy. A bone marrow biopsy specimen showed involvement by LBL. No circulating blasts were identified in the peripheral blood. The patient was referred to the Clinical Center ofNIH. His prior biopsy specimens were reviewed; the initial skin biopsy specimen was thought to be involved by LBL. He was treated with cyclophosphamide, doxorubicin, L-asparaginase, methotrexate, teniposide, cytosine arabinoside, prednisone, and intrathecal methotrexate. A complete clinical response was achieved, and the patient underwent autologous bone marrow transplantation after 4 months of intensive chemotherapy. However, 11 months later hepatosplenomegaly and leukemic involvement occurred, with positive results from bone marrow biopsy. Complete clinical remission was again achieved with additional chemotherapy, and the patient then underwent allogeneic bone marrow transplantation. Six months after the second transplant, the patient died of systemic fungal sepsis. Autopsy revealed no evidence oflymphoma.
Case 4 Persistent left flank pain developed in a 39-year-old woman. She also described recent weight loss and multiple skin nodules, presentfor weeks. There was no evidence of lymphadenopathy. Laboratory studies revealed an elevated serum amylase level; findings from all other studies, including a complete blood cell count, were normal. Pancreatitis was suspected. An abdominal ultrasonogram and CT scan were unremarkable. An endoscopy of the upper gastrointestinal tract and biopsy of two small mucosal nodules were done. The histologic findings were interpreted as a malignant neoplasm consistent with malignant lymphoma.
Volume 25 Number 6, Part 1 December 199!
Cutaneous lymphoblastic lymphoma 1025
Table I. Monoclonal antibodies used Antibody
Frozen section studies T6 (CDl) TIl (CD2) Leu-4 (CD3) Leu-3a (CD4) Leu-l (CDS) 3AI (CD7) Leu-2a (CD8) K, A JL, 0, 'Y, a B4 (CDl9) Bl (CD20) Leu-14 (CD22) CALLA* (CDlO) My7 (CD13) Paraffin section studies Leu-22 (CD43)
Antibody source
Reported specificity
Coulter Clone, Hialeah, Fla. Coulter Becton Dickinson, Mountain View, Calif. Becton Dickinson Becton Dickinson Courtesy of B. F. Haynes, MD Becton Dickinson Tago, Burlingame, Calif. Tago Coulter Coulter Becton Dickinson Becton Dickinson Coulter Becton Dickinson
UCHL-l (CD 45RO)
DAKO, Santa Barbara, Calif.
LN-l (CDw75) LN-2 (CD74)
ICN Immuno Biologicals, Costa Mesa, Calif. ICN Immuno Biologicals
L26 (CD20) Lysozyme
DAKO DAKO
Thymocytesjimmature T cells; Langerhans cells of skin T cells (sheep erythrocyte receptor) Tcens T-helperjinducer cells; macrophages T cells and low-grade B cell lymphomas Most T cells T-cytotoxicjsuppressor cells B cells B cells B-lineage cells B-lineage cells B-lineage cells Most acute lymphoblastic leukemia; some lymphomas Granulocytes T-lineage cells; immature granulocytes; macrophages Most T cells; macrophages (weak) Surface immunoglobulin positive B cells B-lineage cells, monocytesj macrophages B.lineage cells Macrophagesjmonocytes
*Common acute lymphoblastic leukemia antigen.
The physical examination was repeated, and numerous nodules of the scalp and neck were found. An axillary lymph node was palpable. M~ltiple nodules in the breasts were also present. Biopsy specimens of skin of the neck, axillary lymph node, and a breast nodule were diagnostic of LBL. Retrospective review of the gastric biopsy specimens was consistent with LBL. The patient was treated with cyclophosphamide, doxorubicin, etoposide, vincristine, procarbazine, bleomycin, prednisone, topical nitrogen mustard 6, intrathecal methotrexate, cytosine arabinoside, and hydrocortisone. The patient's disease is currently in complete remission, 3 months after diagnosis.
Case 5 A 6-year-old girl had an ill-defined nodule of her forehead. Physical examination did not reveal other skin Ie· sions or lymphadenopathy. The clinical diagnosis was granuloma faciale or granuloma annulare. A punch biopsy specimen of the forehead nodule was seen, in consultation, in the Hematopathology Laboratory of NIH and was interpreted as LBL. The patient has since been lost to follow-up.
Case 6 A small, raised scalp nodule developed in the right parietooccipital region of a 6-year-old girl. This nodule had been present for 8 months. Physical examination revealed bilaterally enlarged cervical lymph nodes. A complete blood cell count and other staging studies revealed negative findings. Punch biopsy of the scalp nodule was done. In consultation, the biopsy specimen was reviewed in the Hematopathology Laboratory of NIH and was interpreted as LBL. Subsequently, a cervical lymph node was excised that was also involved by LBL. The patient was treated with cyclophosphamide, hydroxyldaunorubicin, vincristine, prednisone, and methotrexate. Complete clinical remission was achieved. The patient is well, without evidence of lymphoma, 12 years after diagnosis.
PATIENTS AND METHODS All cases from 1978 to 1990 were collected from the Surgical Pathology files of the Clinical Center of NIH or from the consultation files of one ofthe authors (E. S. J.). Hematoxylin and eosin-stained sections from formalin· or B5-fixed paraffin-embedded sections were prepared at
Journal of the American Academy of Derma tology
1026 Sander et al. Table II. Summary of clinical information Patient No.
Age (yr)/
1
24/F
2
Cutaneous sites of disease at presentation
Sex
Additional sites of disease*
Therapy
Staget
Oinical follow-up
Conjunctiva; submental lymph node Mediastinum
IV
Chemotherapy
Died of disease, 18 mo
25/M
Malar regions of face; breast; anterior trunk Scalp
IV
Chemotherapy
3
26/M
Forehead
Bone marrow
IV
4
39/F
Scalp; neck
IV
5
6/F
Forehead
Stomach; axillary lymph node; breasts
Chemotherapy; bone marrow transplantation Chemotherapy
Complete remission, 3 mo Two separate relapses; died of sepsis w /0 lymphoma, 28 mo Complete remission, 3 mo
NA
IE
NA
6
6/F
Scalp
Cervical lymph node
lIE
Chemotherapy
Lost to clinical follow-up Complete remission, 12 yr
NA, Not available. *Pathologie confirmed sites. t Ann Arbor system. 12
the submitting institutions. In addition, in two cases additional histologic sections were prepared from submitted paraffin blocks. In each patient the initial skin biopsy specimen with LBL was studied. In five patients additional sites of disease were also studied: submental lymph node, conjunctiva, bone marrow, and liver specimens in case 1; mediastinal mass and bone marrow in case 2; bone marrow in case 3; stomach, breast, and axillary lymph node specimens in case 4; and cervical lymph node in case
6.
Frozen section immunophenotypic studies were performed in four cases with use of a method described previously.8 In three patients the cutaneous sites of disease were immunophenotyped, whereas in case 4 an axillary lymph node was studied. The panel of monoclonal antibodies used is listed in Table 1. In one lesion immunoglobulin expression and both the E rosette and EAC rosette assay techniques were performed on cytospin preparations according to methods reported earlier? In two lesions immunophenotypic studies were performed on fixed, paraffin-embedded sections with a limited antibody panel (see Table I) with the immunoperoxidase technique. lO In five cases terminal deoxynuc1eotidyl transferase (TdT) was assessed with an immunoperoxidase method described previously.!! RESULTS
Clinical findings The clinical findings are summarized in Table II. The mean age of the patients was 21 years (range 6 to 39 years). Four were female; two were male. The
sites of cutaneous disease at presentation were the scalp (three patients), forehead (two patients), right malar region (one patient), anterior aspect of the trunk (one patient), neck (one patient), and breast (one patient). Two patients had two or more sites of cutaneous disease at time of presentation. Four patients had additional sites of disease found during staging studies. These included lymph nodes (one cervical, one submental, one axillary), mediastinum, conjunctiva, breasts, liver, bone marrow, and stomach. The clinical stage (Ann Arbor system 12) at time of diagnosis was stage IE for one patient, stage lIE for one patient, and stage IV for four patients. Five patients (one lost to follow-up) were known to have been treated with multiagent chemotherapy. At time of last follow-up, disease in three patients was in complete remission; one patient had two separate relapses of disease, each treated with bone marrow transplantation, and subsequently died of sepsis without evidence of lymphoma; and one patient died of disease (after complete remission and subsequent relapse).
Histologic findings In every skin biopsy specimen there was a monotonous infiltrate of small lymphoid cells that diffusely replaced regions of the dermis (Fig. 1). In three patients the neoplasm was distributed in a patchy fashion. In the remaining three patients the neo-
Volume 25 Number 6, Part 1 December 1991
Cutaneous lymphoblastic lymphoma 1027
Fig. 1. Case 5. Pre-B cell LBL. At low power the neoplasm replaces reticular dermis and extends into subcutaneous tissue. (Hematoxylin-eosin stain; X25.)
Fig. 2. Case 5. Pre-B cell LBL. Neoplastic cells are nonconvoluted with "blastic" nuclear chromatin and small or inconspicuous nucleoli. (Hematoxylin-eosin stain; X630.)
plasm diffusely replaced the dermis, with infiltration into the subcutaneous tissue. A grenz zone was present in five patients. The neoplastic cells in every skin specimen had minimal cytoplasm and finely distributed nuclear chromatin; the nucleoli were small or absent in five patients (Fig. 2), whereas in one specimen (case 4)
the nucleoli were clearly distinct although not large (Fig. 3). In three cases the neoplastic cells were convoluted; in three they were nonconvoluted (see Figs. 2 and 3). Mitotic figures were found in every case and ranged from one to three per high-power field (X400). Five patients had noncutaneous sites involved by lymphoma. In each case the neoplastic
Journal of the American Academy of Dermatology
1028 Sander et al.
Fig. 3. Case 4. Pre-B cell LBL. Neoplastic cells have central, clearly visible small nucleoli. (Hematoxylin-eosin stain; X400.)
Table III. Immunologic determinants of LBL: Frozen section studies Immunophenotype
Case No.
1 (skin) 2 (skin) 3 (lymph node) 4 (skin)
+ +
+
+
+
+
+ +
+
+
+
+
+ +
ND ND
+
+ + +
+
+ + +
Late cortical T + myeloid Midcortical T Pre-B Pre-B
Table IV. Immunologic determinants of LBL: Paraffin-section studies Case No.
5 (skin) 6* (skin)
UCHL-l
+
+
+
Lysozyme
Immunophenotype
Pre-B Pre-B
*TdT+, EAC+, E rosette- assay with the use of cytospins of fresh tissue.
cells were identical to those seen in the skin specimens. A "starry-sky" pattern was noted in two of three lymph nodes replaced by lymphoma. Foci of necrosis were found within the mediastinal mass.
Immunophenotypic results The immunophenotypic results are summarized in Tables III and IV. Two neoplasms had a T cell immunophenotype. Case 1 had a mixed late cortical T cell and myeloid irnmunophenotype (CD2+, CD3-, CDS-, CD7+, CDl-, CD4+, CD8-, CD13+). Case
2 had a midcortical T cell immunophenotype (CD2+, CD3+, CDS+, CD7+, CDl+, CD4+, CD8+). Four had a pre-B cell irnmunophenotype. Cases 3 and 4 were studied with microscopic examination of frozen sections. In both cases neither cytoplasmic nor surface immunoglobulin was present and the neoplastic cells expressed the pan-B cell antigen CD 19 (Fig. 4, A). Case 3 was also CD22+. The neoplastic cells in both cases were negative for cell antigens (Fig. 4, B). Cases 5 and 6 were analyzed with fixed, paraffin-embedded sections. In both the
Volume 25 Number 6, Part 1 December 1991
Cutaneous lymphoblastic lymphoma 1029
Fig. 4. Case 4. Pre-B cell LBL. The neoplastic cells express the pan-B cell antigen CD 19 (A) and were negative for all pan-T cell antigens. CDS is illustrated (B). (Immunoperoxidase stain with frozen sections; X400.)
neoplastic cells reacted with the B cell antibody LN-2 (Fig. 5) and did not stain with the LN-l, UCHL-l, Leu-22, LCA, and antilysozyme anti~ bodies consistent with a pre-B cell immunophen~ type. Case 5was also positive with the L26 antibody, while case 6, with use of functional markers, was positive for the EAC but not the E rosette assays. Of five neoplasms assayed for TdT, all were positive.
Four tumors were studied with the CDIO antigen (common acute lymphoblastic leukemia antigen); two T cell and two pre-B cell neoplasms were positive for this antigen. DISCUSSION
In this study we describe the clinical and pathologic findings in six patients with LBL that involved
1030
Sander et al.
Fig. 5. Case 6. Pre-B cell LBL. In this case (as well as in case 5) neoplastic celIs react with B cell antibody LN2 and do not stain with T cell antibodies Leu-22 and UCHL-l, consistent with a pre-B cell immunophenotype. (Immunoperoxidase with fixed, paraffin-embedded sections; X200.)
the skin at the time of presentation. This is an unusual occurrence. Approximately 3.5% to 7% of all malignant lymphomas of the skin are of the lymphoblastic type. 13 Furthermore, in the International Working Formulation study less than 20% of all cases of LBL involved cutaneous sites at time of presentation. 7 In addition, two patients (cases 5 and 6) inthis study probably had LBL arising in the skin. There are few reports in the literature of primary cutaneous LBL, and the majority of cases were reported before the development of monoclonal antibodies and immunophenotypic studies. Four of six cases in this study had a pre-B cell immunophenotype. The high prevalence of pre-B cell tumors is unusual because the vast majority of LBLs have an immature T cell immunophenotype.4-6 In addition, the two tumors that may have arisen in the skin in all three cases had a pre-B cell immunophenotype. Thus pre-B cell LBLs may have a predilection for cutaneous sites or for arising in the skin, or both. This hypothesis has been suggested by others. 14, 15 Link et al. 14 reported two children with
Journal of the American Academy of Dermatology
pre-B cell LBLs of skin. Vaillant et a1,l6 and Bernard et aL 15 have also described cases of cutaneous LBL of the "non-B, non-T cell irnmunophenotype" (the cases of Bernard et al. 15 were reported before the availability of monoclonal antibodies). These cases are also likely to be pre-B cell LBLs because LBL and acute lymphoblastic leukemia have many features in common, and "non-T, non-B" acute lymphoblastic leukemias usually have immunoglobulin gene rearrangements. 17 This study also suggests that LBL, when it involves cutaneous sites, has a predilection for the head and neck. All six patients had lesions of the scalp, forehead, or face, although two patients also had other cutaneous sites of disease. Other types of B cell lymphoma, as well as cutaneous hyperplasias, also have a predilection for the head and neck. 18-20 The prognosis of patients with cutaneous LBL does not appear to be different from that of other patients with LBL without cutaneous involvement. Patients with cutaneous LBL are commonly found to have generalized lymphoma during the staging workup. The neoplasm is high grade, and thus patients often respond to intensive chemotherapy, irrespective of immunophenotype. Nevertheless, determining the immunophenotype of the cutaneous lesion(s) may be useful because patients with pre-B cell LBL rarely have a mediastinal mass and may often have involvement of unusual sites such as bone. 4 All cases in this study were immunophenotyped with a large panel of antibodies. Two T cell and two pre-B cell LBLs were studied for CDIO antigen expression; both were positive for this antigen. These results confirm those of others4• 5, 21-23 who have found that the CDIO antigen is expressed by both T cell and pre-B cell LBLs. Biopsy material from two patients in this study was imrnunophenotyped in fixed, paraffin-embedded sections. In both cases the neoplastic cells reacted with the LN-2 antibody, and one LBL was also positive for L26 antibody. In both cases cells were negative for LN-l and T cell and histiocyte-associated markers. Although thesemethods yield incomplete immunophenotyping data compared with frozen section or flow cytometric analysis of fresh or frozen tissue, recent studies have demonstrated the value of immunophenotypic studies in fixed, paraffin-embedded histologic sections in the diagnosis of pre-B cell and T cell acute lymphoblastic leukemia. 24,25 Thus these methods also appear to be helpful in the assessment of LBLs.
Volume 25 Number 6, Part 1 December 1991 REFERENCES 1. Nathwani BN, Kim H, Rappaport H. Malignant lym-
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22. Kestel JL, Blair DS. Keratoacanthoma treated with methotrexate. Arch Dermato11973;108:723-4. 23. Lloyd KM, Madsen DK, Lin PY. Grzybowski's eruptive keratoacanthoma. J AM ACAD DERMATOL 1989;21:1023-4. 24. Fanti PA, Tosti A, Peluso AM, et al. Multiple keratoacanthoma in discoid lupus erythematosus. J AM ACAD DERMATOL 1989;21:809-10. 25. Klein E, Milgram H, Traenkle HL. Tumors of the skin. II: Keratoacanthoma; local effect of 5-fluorouracil. Skin 1962;153-6. 26. Kurtis B, Rosen T. Treatment of cutaneous neoplasms by intralesional injections of 5-fluorouracil (5-FU). J Dermatol Surg Onco11980;6:122-7. 27. Parker CM, Hanke CWo Large keratoacanthomas in difficult locations treated with intralesional 5-fluorouracil. J AM ACAD DERMATOL 1986;14:770-7.
Intralesional MTX for keratoacanthomas 28. Belisario J C. Topical cytotoxic therapy for cutaneous cancer and precancer. Arch Dermatol 1965;92:292-303. 29. White JE. Methotrexate inhibition of deoxyuridine incorporation in the skin of three day old rats. J Invest Dermato1 1971;56:294-310. 30. Prutkin L. An ultrastructural study of the keratoacanthoma treated with methotrexate and 5-fluorouracil. Dermatologica 1968;137:373-80. 31. Ghadially FN. The role of the hair follicle in the origin and evolution of some cutaneous neoplasms of man and experimental animals. Cancer 1961;14:801-6. 32. Magee KL, Rapini RP, Duvic M, etal. Human papillomavirus associated with keratoacanthoma. Arch Dermatol 1989;125:1587-9.
Lymphoblastic lymphoma presenting in cutaneous sites A clinicopathologic analysis of six cases Christian A. Sander, MD,a, • 1. Jeffrey Medeiros, MD,a Lynne V. Abruzzo, MD, PhD,a Ivan D. Horak, MD,b and Elaine S. Jaffe, MDa Bethesda, Maryland Six patients with malignant lymphoma oflymphoblastic type involving cutaneous sites at time of diagnosis are presented. Skin sites of the head and neck were involved in all patients and included the scalp (three patients), forehead (two patients), and malar region of the face (one patient). Two patients also had additional sites of skin disease (neck, breast, and anterior trunk). In two patients the skin was the predominant site of disease, whereas in the remaining patients staging workup revealed generalized lymphoma. The histologic findings in each patient were typical of lymphoblastic lymphoma; the neoplastic cells were small with blastic nuclear chromatin. In three patients the neoplastic cells were convoluted, and in three they were nonconvoluted. Immunophenotypically, four lymphomas were of pre-B cell type, and two lymphomas were of T cell type. There was no correlation between histologic features and the immunophenotype. Since the majority of lymphoblastic lymphomas are of T cell type, the predominance of pre-B cell tumors involving the skin may suggest that pre-B cell neoplasms have a predilection for cutaneous involvement. In further support of this hypothesis, both lymphomas that appear to have arisen in the skin had a pre-B cell immunophenotype. (J AM ACAD DERMATOL 1991;25:1023-31.) From theHematopathologySection, Laboratory ofPathology," and the Clinical Pharmacology Branch, b National Cancer Institute, National Institutes of Health. Accepted for publication June 17, 1991. Reprint requests: L. Jeffrey Medeiros, MD, Building 10, Room 2Nl 08, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892.
*Supported by a grant from the Mildred-Scheel-Stiftung, Bonn, Germany. 16/1/31766
Malignant lymphoma of the lymphoblastic type (LBL) occurs predominantly in young children and adolescents. I-3 The characteristic histologic feature is the presence of small lymphoid cells with immature or "blastic" nuclear chromatin. 1-3 The great majority of LBLs have an immature T cell immunophenotype.4-6 Cutaneous involvement in patients with LBL is uncommon. For example, in the N ational Cancer Institute-sponsored study of lym1023
Journal of the American Academy of Dermatology
1024 Sanderetal phoma classifications, less than 20% of patients with LBL had skin disease at time of presentation. 7 In this study the clinical, pathologic, and imrnunophenotypic findings of six cases of LBL with cutaneous involvement at the time of diagnosis are reported. Our results suggest that LBL, like other non-Hodgkin's lymphomas, preferentially involves the head and neck when the skin is involved. In addition, in contrast to the majority of LBLs that have a T cell imrnunophenotype, four of six cutaneous LBLs in this study had a pre-B cell immunophenotype. Thus pre-B cell LBLs appear to have a tropism for the skin. CASE REPORTS
Case 1 A 24-year-old woman developed a purpuric skin lesion inferior to her left eye in April 1986. Purpura or ecchymoses, or both, subsequently developed in the malar regibns of her face and on the anterior chest and breasts. Results of a complete blood count and bone marrow biopsy were negative. Radiologic studies of the head, thorax and abdomen were unremarkable. The cutaneous pur~ura persisted, and a left conjunctival mass appeared. Biopsy specimens from the right malar region and the left conjunctiva were diagnostic of LBL. The patient was referred to the Clinical Center of the National Institutes of Health (NIH) for further evaluation and therapy. Physical examination revealed. numerous sites of cutaneous purpura and an enlarged submental lymph node. A biopsy specimen of a purpuric lesion of the skin of the right breast was diagnostic of LBL. The submental lymph node was excised and was also involved. A needle biopsy specimen of the liver and a bone marrow biopsy specimen were both involved by lymphoma. The patient was treated with cyclophosphamide, cytosine arabinoside, VM-26, 2' -deoxycoformycin, vincristine, and prednisone. Findings of repeat staging studies after four cycles of induction therapy were negative for lymphoma. After three cycles of consolidation therapy (doxorubicin (Adriamycin), vincristine, prednisone, and 2'deoxycoformycin) the patient refused additional treatment. Leukemic transformation developed and she died 21 months after initial diagnosis.
Case 2 A 25-year-old man had a 4-week history of multiple scalp nodules, lethargy, weakness, dyspnea, right-sided . pleuritic pain, and a 17-pound weight loss. Physical examination revealed multiple scalp nodules up to 1.5 em and lymphadenopathy of the cervical, supraclavicular, and axillary regions. Chest radiograph and computed tomographic (CT) SCan revealed a mediastinal mass and a
right pleural effusion. The patient underwent surgical resection of the mediastinal mass. The histologic findings were diagnostic of LBL. The patient was referred to the Clinical Center of NIH for staging and therapy. A biopsy specimen of a scalp nodule showed involvement by LBL. Other staging studies, including complete blood cell count, bone marrow biopsy, and CT scans of the abdomen and pelvis, revealed negative findings. The patient was treated with whole brain irradiation, intrathecal methotrexate, cyclophosphamide, doxorubicin, vincristine, L-asparaginase, 6-mercaptopurine, and prednisone. Complete remission was achieved, and the patient is currently well, 3 months after induction therapy. He is continuing to receive maintenance therapy.
Case 3 A red nodule developed on the forehead of a 26-yearold man. A punch biopsy specimen was interpreted as suspected lymphoma. Two months later acute abdominal pain developed. Physical examination revealed a 6 X 9 cm red nodule of the forehead, hepatosplenomegaly, and right iliac lymphadenopathy. A bone marrow biopsy specimen showed involvement by LBL. No circulating blasts were identified in the peripheral blood. The patient was referred to the Clinical Center ofNIH. His prior biopsy specimens were reviewed; the initial skin biopsy specimen was thought to be involved by LBL. He was treated with cyclophosphamide, doxorubicin, L-asparaginase, methotrexate, teniposide, cytosine arabinoside, prednisone, and intrathecal methotrexate. A complete clinical response was achieved, and the patient underwent autologous bone marrow transplantation after 4 months of intensive chemotherapy. However, 11 months later hepatosplenomegaly and leukemic involvement occurred, with positive results from bone marrow biopsy. Complete clinical remission was again achieved with additional chemotherapy, and the patient then underwent allogeneic bone marrow transplantation. Six months after the second transplant, the patient died of systemic fungal sepsis. Autopsy revealed no evidence oflymphoma.
Case 4 Persistent left flank pain developed in a 39-year-old woman. She also described recent weight loss and multiple skin nodules, presentfor weeks. There was no evidence of lymphadenopathy. Laboratory studies revealed an elevated serum amylase level; findings from all other studies, including a complete blood cell count, were normal. Pancreatitis was suspected. An abdominal ultrasonogram and CT scan were unremarkable. An endoscopy of the upper gastrointestinal tract and biopsy of two small mucosal nodules were done. The histologic findings were interpreted as a malignant neoplasm consistent with malignant lymphoma.
Volume 25 Number 6, Part 1 December 199!
Cutaneous lymphoblastic lymphoma 1025
Table I. Monoclonal antibodies used Antibody
Frozen section studies T6 (CDl) TIl (CD2) Leu-4 (CD3) Leu-3a (CD4) Leu-l (CDS) 3AI (CD7) Leu-2a (CD8) K, A JL, 0, 'Y, a B4 (CDl9) Bl (CD20) Leu-14 (CD22) CALLA* (CDlO) My7 (CD13) Paraffin section studies Leu-22 (CD43)
Antibody source
Reported specificity
Coulter Clone, Hialeah, Fla. Coulter Becton Dickinson, Mountain View, Calif. Becton Dickinson Becton Dickinson Courtesy of B. F. Haynes, MD Becton Dickinson Tago, Burlingame, Calif. Tago Coulter Coulter Becton Dickinson Becton Dickinson Coulter Becton Dickinson
UCHL-l (CD 45RO)
DAKO, Santa Barbara, Calif.
LN-l (CDw75) LN-2 (CD74)
ICN Immuno Biologicals, Costa Mesa, Calif. ICN Immuno Biologicals
L26 (CD20) Lysozyme
DAKO DAKO
Thymocytesjimmature T cells; Langerhans cells of skin T cells (sheep erythrocyte receptor) Tcens T-helperjinducer cells; macrophages T cells and low-grade B cell lymphomas Most T cells T-cytotoxicjsuppressor cells B cells B cells B-lineage cells B-lineage cells B-lineage cells Most acute lymphoblastic leukemia; some lymphomas Granulocytes T-lineage cells; immature granulocytes; macrophages Most T cells; macrophages (weak) Surface immunoglobulin positive B cells B-lineage cells, monocytesj macrophages B.lineage cells Macrophagesjmonocytes
*Common acute lymphoblastic leukemia antigen.
The physical examination was repeated, and numerous nodules of the scalp and neck were found. An axillary lymph node was palpable. M~ltiple nodules in the breasts were also present. Biopsy specimens of skin of the neck, axillary lymph node, and a breast nodule were diagnostic of LBL. Retrospective review of the gastric biopsy specimens was consistent with LBL. The patient was treated with cyclophosphamide, doxorubicin, etoposide, vincristine, procarbazine, bleomycin, prednisone, topical nitrogen mustard 6, intrathecal methotrexate, cytosine arabinoside, and hydrocortisone. The patient's disease is currently in complete remission, 3 months after diagnosis.
Case 5 A 6-year-old girl had an ill-defined nodule of her forehead. Physical examination did not reveal other skin Ie· sions or lymphadenopathy. The clinical diagnosis was granuloma faciale or granuloma annulare. A punch biopsy specimen of the forehead nodule was seen, in consultation, in the Hematopathology Laboratory of NIH and was interpreted as LBL. The patient has since been lost to follow-up.
Case 6 A small, raised scalp nodule developed in the right parietooccipital region of a 6-year-old girl. This nodule had been present for 8 months. Physical examination revealed bilaterally enlarged cervical lymph nodes. A complete blood cell count and other staging studies revealed negative findings. Punch biopsy of the scalp nodule was done. In consultation, the biopsy specimen was reviewed in the Hematopathology Laboratory of NIH and was interpreted as LBL. Subsequently, a cervical lymph node was excised that was also involved by LBL. The patient was treated with cyclophosphamide, hydroxyldaunorubicin, vincristine, prednisone, and methotrexate. Complete clinical remission was achieved. The patient is well, without evidence of lymphoma, 12 years after diagnosis.
PATIENTS AND METHODS All cases from 1978 to 1990 were collected from the Surgical Pathology files of the Clinical Center of NIH or from the consultation files of one ofthe authors (E. S. J.). Hematoxylin and eosin-stained sections from formalin· or B5-fixed paraffin-embedded sections were prepared at
Journal of the American Academy of Derma tology
1026 Sander et al. Table II. Summary of clinical information Patient No.
Age (yr)/
1
24/F
2
Cutaneous sites of disease at presentation
Sex
Additional sites of disease*
Therapy
Staget
Oinical follow-up
Conjunctiva; submental lymph node Mediastinum
IV
Chemotherapy
Died of disease, 18 mo
25/M
Malar regions of face; breast; anterior trunk Scalp
IV
Chemotherapy
3
26/M
Forehead
Bone marrow
IV
4
39/F
Scalp; neck
IV
5
6/F
Forehead
Stomach; axillary lymph node; breasts
Chemotherapy; bone marrow transplantation Chemotherapy
Complete remission, 3 mo Two separate relapses; died of sepsis w /0 lymphoma, 28 mo Complete remission, 3 mo
NA
IE
NA
6
6/F
Scalp
Cervical lymph node
lIE
Chemotherapy
Lost to clinical follow-up Complete remission, 12 yr
NA, Not available. *Pathologie confirmed sites. t Ann Arbor system. 12
the submitting institutions. In addition, in two cases additional histologic sections were prepared from submitted paraffin blocks. In each patient the initial skin biopsy specimen with LBL was studied. In five patients additional sites of disease were also studied: submental lymph node, conjunctiva, bone marrow, and liver specimens in case 1; mediastinal mass and bone marrow in case 2; bone marrow in case 3; stomach, breast, and axillary lymph node specimens in case 4; and cervical lymph node in case
6.
Frozen section immunophenotypic studies were performed in four cases with use of a method described previously.8 In three patients the cutaneous sites of disease were immunophenotyped, whereas in case 4 an axillary lymph node was studied. The panel of monoclonal antibodies used is listed in Table 1. In one lesion immunoglobulin expression and both the E rosette and EAC rosette assay techniques were performed on cytospin preparations according to methods reported earlier? In two lesions immunophenotypic studies were performed on fixed, paraffin-embedded sections with a limited antibody panel (see Table I) with the immunoperoxidase technique. lO In five cases terminal deoxynuc1eotidyl transferase (TdT) was assessed with an immunoperoxidase method described previously.!! RESULTS
Clinical findings The clinical findings are summarized in Table II. The mean age of the patients was 21 years (range 6 to 39 years). Four were female; two were male. The
sites of cutaneous disease at presentation were the scalp (three patients), forehead (two patients), right malar region (one patient), anterior aspect of the trunk (one patient), neck (one patient), and breast (one patient). Two patients had two or more sites of cutaneous disease at time of presentation. Four patients had additional sites of disease found during staging studies. These included lymph nodes (one cervical, one submental, one axillary), mediastinum, conjunctiva, breasts, liver, bone marrow, and stomach. The clinical stage (Ann Arbor system 12) at time of diagnosis was stage IE for one patient, stage lIE for one patient, and stage IV for four patients. Five patients (one lost to follow-up) were known to have been treated with multiagent chemotherapy. At time of last follow-up, disease in three patients was in complete remission; one patient had two separate relapses of disease, each treated with bone marrow transplantation, and subsequently died of sepsis without evidence of lymphoma; and one patient died of disease (after complete remission and subsequent relapse).
Histologic findings In every skin biopsy specimen there was a monotonous infiltrate of small lymphoid cells that diffusely replaced regions of the dermis (Fig. 1). In three patients the neoplasm was distributed in a patchy fashion. In the remaining three patients the neo-
Volume 25 Number 6, Part 1 December 1991
Cutaneous lymphoblastic lymphoma 1027
Fig. 1. Case 5. Pre-B cell LBL. At low power the neoplasm replaces reticular dermis and extends into subcutaneous tissue. (Hematoxylin-eosin stain; X25.)
Fig. 2. Case 5. Pre-B cell LBL. Neoplastic cells are nonconvoluted with "blastic" nuclear chromatin and small or inconspicuous nucleoli. (Hematoxylin-eosin stain; X630.)
plasm diffusely replaced the dermis, with infiltration into the subcutaneous tissue. A grenz zone was present in five patients. The neoplastic cells in every skin specimen had minimal cytoplasm and finely distributed nuclear chromatin; the nucleoli were small or absent in five patients (Fig. 2), whereas in one specimen (case 4)
the nucleoli were clearly distinct although not large (Fig. 3). In three cases the neoplastic cells were convoluted; in three they were nonconvoluted (see Figs. 2 and 3). Mitotic figures were found in every case and ranged from one to three per high-power field (X400). Five patients had noncutaneous sites involved by lymphoma. In each case the neoplastic
Journal of the American Academy of Dermatology
1028 Sander et al.
Fig. 3. Case 4. Pre-B cell LBL. Neoplastic cells have central, clearly visible small nucleoli. (Hematoxylin-eosin stain; X400.)
Table III. Immunologic determinants of LBL: Frozen section studies Immunophenotype
Case No.
1 (skin) 2 (skin) 3 (lymph node) 4 (skin)
+ +
+
+
+
+
+ +
+
+
+
+
+ +
ND ND
+
+ + +
+
+ + +
Late cortical T + myeloid Midcortical T Pre-B Pre-B
Table IV. Immunologic determinants of LBL: Paraffin-section studies Case No.
5 (skin) 6* (skin)
UCHL-l
+
+
+
Lysozyme
Immunophenotype
Pre-B Pre-B
*TdT+, EAC+, E rosette- assay with the use of cytospins of fresh tissue.
cells were identical to those seen in the skin specimens. A "starry-sky" pattern was noted in two of three lymph nodes replaced by lymphoma. Foci of necrosis were found within the mediastinal mass.
Immunophenotypic results The immunophenotypic results are summarized in Tables III and IV. Two neoplasms had a T cell immunophenotype. Case 1 had a mixed late cortical T cell and myeloid irnmunophenotype (CD2+, CD3-, CDS-, CD7+, CDl-, CD4+, CD8-, CD13+). Case
2 had a midcortical T cell immunophenotype (CD2+, CD3+, CDS+, CD7+, CDl+, CD4+, CD8+). Four had a pre-B cell irnmunophenotype. Cases 3 and 4 were studied with microscopic examination of frozen sections. In both cases neither cytoplasmic nor surface immunoglobulin was present and the neoplastic cells expressed the pan-B cell antigen CD 19 (Fig. 4, A). Case 3 was also CD22+. The neoplastic cells in both cases were negative for cell antigens (Fig. 4, B). Cases 5 and 6 were analyzed with fixed, paraffin-embedded sections. In both the
Volume 25 Number 6, Part 1 December 1991
Cutaneous lymphoblastic lymphoma 1029
Fig. 4. Case 4. Pre-B cell LBL. The neoplastic cells express the pan-B cell antigen CD 19 (A) and were negative for all pan-T cell antigens. CDS is illustrated (B). (Immunoperoxidase stain with frozen sections; X400.)
neoplastic cells reacted with the B cell antibody LN-2 (Fig. 5) and did not stain with the LN-l, UCHL-l, Leu-22, LCA, and antilysozyme anti~ bodies consistent with a pre-B cell immunophen~ type. Case 5was also positive with the L26 antibody, while case 6, with use of functional markers, was positive for the EAC but not the E rosette assays. Of five neoplasms assayed for TdT, all were positive.
Four tumors were studied with the CDIO antigen (common acute lymphoblastic leukemia antigen); two T cell and two pre-B cell neoplasms were positive for this antigen. DISCUSSION
In this study we describe the clinical and pathologic findings in six patients with LBL that involved
1030
Sander et al.
Fig. 5. Case 6. Pre-B cell LBL. In this case (as well as in case 5) neoplastic celIs react with B cell antibody LN2 and do not stain with T cell antibodies Leu-22 and UCHL-l, consistent with a pre-B cell immunophenotype. (Immunoperoxidase with fixed, paraffin-embedded sections; X200.)
the skin at the time of presentation. This is an unusual occurrence. Approximately 3.5% to 7% of all malignant lymphomas of the skin are of the lymphoblastic type. 13 Furthermore, in the International Working Formulation study less than 20% of all cases of LBL involved cutaneous sites at time of presentation. 7 In addition, two patients (cases 5 and 6) inthis study probably had LBL arising in the skin. There are few reports in the literature of primary cutaneous LBL, and the majority of cases were reported before the development of monoclonal antibodies and immunophenotypic studies. Four of six cases in this study had a pre-B cell immunophenotype. The high prevalence of pre-B cell tumors is unusual because the vast majority of LBLs have an immature T cell immunophenotype.4-6 In addition, the two tumors that may have arisen in the skin in all three cases had a pre-B cell immunophenotype. Thus pre-B cell LBLs may have a predilection for cutaneous sites or for arising in the skin, or both. This hypothesis has been suggested by others. 14, 15 Link et al. 14 reported two children with
Journal of the American Academy of Dermatology
pre-B cell LBLs of skin. Vaillant et a1,l6 and Bernard et aL 15 have also described cases of cutaneous LBL of the "non-B, non-T cell irnmunophenotype" (the cases of Bernard et al. 15 were reported before the availability of monoclonal antibodies). These cases are also likely to be pre-B cell LBLs because LBL and acute lymphoblastic leukemia have many features in common, and "non-T, non-B" acute lymphoblastic leukemias usually have immunoglobulin gene rearrangements. 17 This study also suggests that LBL, when it involves cutaneous sites, has a predilection for the head and neck. All six patients had lesions of the scalp, forehead, or face, although two patients also had other cutaneous sites of disease. Other types of B cell lymphoma, as well as cutaneous hyperplasias, also have a predilection for the head and neck. 18-20 The prognosis of patients with cutaneous LBL does not appear to be different from that of other patients with LBL without cutaneous involvement. Patients with cutaneous LBL are commonly found to have generalized lymphoma during the staging workup. The neoplasm is high grade, and thus patients often respond to intensive chemotherapy, irrespective of immunophenotype. Nevertheless, determining the immunophenotype of the cutaneous lesion(s) may be useful because patients with pre-B cell LBL rarely have a mediastinal mass and may often have involvement of unusual sites such as bone. 4 All cases in this study were immunophenotyped with a large panel of antibodies. Two T cell and two pre-B cell LBLs were studied for CDIO antigen expression; both were positive for this antigen. These results confirm those of others4• 5, 21-23 who have found that the CDIO antigen is expressed by both T cell and pre-B cell LBLs. Biopsy material from two patients in this study was imrnunophenotyped in fixed, paraffin-embedded sections. In both cases the neoplastic cells reacted with the LN-2 antibody, and one LBL was also positive for L26 antibody. In both cases cells were negative for LN-l and T cell and histiocyte-associated markers. Although thesemethods yield incomplete immunophenotyping data compared with frozen section or flow cytometric analysis of fresh or frozen tissue, recent studies have demonstrated the value of immunophenotypic studies in fixed, paraffin-embedded histologic sections in the diagnosis of pre-B cell and T cell acute lymphoblastic leukemia. 24,25 Thus these methods also appear to be helpful in the assessment of LBLs.
Volume 25 Number 6, Part 1 December 1991 REFERENCES 1. Nathwani BN, Kim H, Rappaport H. Malignant lym-
phoma, lymphoblastic. Cancer 1976;38:964-83. 2. Jaffe ES, Berard CWo Lymphoblastic lymphoma, a term rekindled with new precision. Ann Intern Med 1978;89:41517. 3. Picozzi VJ, Coleman CN. Lymphoblastic lymphoma. Semin Oncol 1990;17:96-103. 4. Cossman J, Chused TM, Fisher RI, et a1. Diversity of immunological phenotypes oflymphoblastic lymphoma. Cancer Res 1983;43:4486-90. 5. Weiss LM, Bindl 1M, Picozzi V1, et a1. Lymphoblastic lymphoma: an immunophenotype study of 26 cases with comparison to T cell acute lymphoblastic leukemia. Blood 1986;67:474-8. 6. Sheibani K, Nathwani BN, Winberg CD, et a1. Antigenically defined subgroups of lymphoblastic lymphoma: relationship to clinical presentation and biologic behavior. Cancer 1987;60:183-90. 7. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 1982;49:2112-35. 8. Medeiros LJ, Rizzi R, Lardelli P, et al. Malignant lymphoma involving a Warthin's tumor: a case with immunophenotypic and gene rearrangement analysis. Hum PathoI1990;21:974-7. 9. Jaffe ES, Braylan RC, Nanba K, et al. Functional markers: a new perspective on malignant lymphomas. Cancer Treat Rep 1977;61:953-62. 10. Hsu S-M, JaffeES. LeuMI and peanut agglutinin stain the neoplastic cells of Hodgkin's disease. Am J Clin Pathol 1984;82:29-32. II. Braziel RM, Keneklis T, Donlon JA, et a1. Terminal deoxynucleotidyl transferase in non-Hodgkin's lymphoma. Am J Clin PathoI1983;80:655-9. 12. CarbonePP, Kaplan HS, MusshoffK, et a1. Report of the Committee on Hodgkin's disease staging classification. Cancer Res 1971;31:1860-1. 13. Burg G, Braun-Falco O. Cutaneous lymphomas, pseudolymphomas and related disorders. Berlin: Springer, 1983;296-303.
Cutaneous lymphoblastic lymphoma 1031 14. Link MP, Roper M, Dorfman RF, et a1. Cutaneous lymphoblastic lymphoma with pre-B markers. Blood 1983; 61:838-41. 15. Bernard A, Murphy SB, Melvin S, et a1. Non-T, non-B lymphomas are rare in childhood and associated with cutaneous tumor. Blood 1982;59:549-54. 16. Vaillant L, Lorette G, Colombat P, et a1. Primary cutaneous lymphoblastic lymphoma ofnon-B, non-T phenotype. Arch DermatoI1990;126:400-2. 17. Korsmeyer SJ, Arnold A, Bakhshi A, et a1. Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias ofT cell and B cell precursor origins. J Clin Invest 1983;71:301-13. 18. BurkeJS, HoppeRT, Cibull ML, et a1. Cutaneousmalignant lymphoma: a pathologic study of 50 cases with clinical analysis of 37. Cancer 1981;47:300-10. 19. Medeiros LJ, Picker LJ, Abel EA, et at Cutaneous lymphoid hyperplasia: immunologic characteristics and assessment of criteria recently proposed as diagnostic of malignant lymphoma. J AM ACAD DERMATOL 1989;21:92942. 20. Garcia CF, Weiss LM, Warnke RA, et a1. Cutaneous follicular lymphoma. Am J Surg PathaI1986;10:454-63. 21. Ritz J, Nadler LM, Bhan AK, et a1. Expression of common acute lymphoblastic leukemia antigen (CALLA) by lymphomas of B-cell and T-cell lineage. Blood 1981 ;58:648-52. 22. Bernard A, Boumsell L, Reinherz EL, et al. Cell surface characterization of malignant T cells from lymphoblastic lymphoma using monoclonal antibodies: evidence far phenotypic differences between malignant Tcells from patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. Blood 1981;57:1105-10. 23. Hollema H, Poppema S. T-Iymphoblastic and peripheral T -cell lymphomas in the northern part of The Netherlands. Cancer 1989;64: 1620-8. 24. Taubenberger JK, Cole DE, Raffeld M, et a1. Immunophenotypic analysis of acute lymphoblastic leukemia using routinely processed bone marrow specimens. Arch Pathol Lab Med 1991;115:338-42. 25. Kubic VL, Brunning RD. Immunohistochemical evaluation of neoplasms in bone marrow biopsies using monoclonal antibodies reactive in paraffin-embedded tissue. Mod Pathol 1989;2:618-29.
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