British jourml of Dermatology (1992) 127, 403-406,
Phenytoin-induced pseudolymphoma. A report of a case and review of the literature D,W.S,HARRIS. L.OSTLERE. C.BUCKLEY, S.WHITTAKER,* P,SWENYt AND M,H.A.RIJST1N Departments of Dermatoiogy and ^Nephrohgi), Tiie Royal Free Hospital and School of Medicine. London NW3 2QG, U.K. *St lohn's Dermatology Centre. St Thomas's Hospital, London SEI 7EH. U,K, Accepted for publication 1 May 1992
Summary
We report a patient with phenytoin-induced pseudolymphoma mimicking cutaneous T-cell lymphoma (CTCL), Despite withdrawal of phenytoin, there was persistence ofthe cutaneous eruption and lymphadenopathy. Southern hlot analysis of immunoglobulin and T-cell receptor genes was therefore used to assess whether there was a clonal lymphoid expansion. However, no rearrangement ofthe beta T-cell receptor gene or immunoglohulin heavy-chain gene was detected in tissue DNA from skin and lymph nodes. One year later the patient became asymptomatic, although he is still at risk of developing a true malignant lymphoma in the future, a condition known as pseudo-pseudolymphoma. It is suggested that genotypic studies may help in the initial diagnosis and the subsequent management of such patients.
Phenytoin-induced pseudolymphoma is a rare condition comprising cutaneous and systemic features which resolve within 2-6 weeks of drug withdrawal. The majority of reported cases have occurred in Black patients. The dermatological manifestations include morbilliform. pustular, vesiculo-papular and follicular rashes which may affect the face, trunk and limbs, especially acraily. Rarely, the eruption can present as an erythroderma or toxic epidermal necrolysis. The systemic features comprise a triad of fever, lymphadenopathy and hepatitis.
Case report A 25-year-old Black man presented in August 1990 with a 1-week history of fever and an itchy eruption, associated with marked facial oedema. On examination he was pyrexial {temperature 40°C) and had generalized erythroderma with pin-point pustulation over the face and trunk. There was marked facial swelling. He had generalized firm, grape-sized lymphadenopathy and 3 cm splenomegaly. Over the next 5 days desquamation occurred, but the rash persisted. He had a complex past medical history following the discovery of posterior urethral valves and hydroureter at the age of 2 years. This abnormality had resulted in chronic renal failure Correspondence: Dr D.W.S.Harris.
for which he had undergone two unsuccessful cadaveric renal transplants. It was following a native left nephrectomy and subsequent removal of a renal angle haematoma that the patient was treated with phenytoin 100 mg b.d, because he suffered a grand-mal fit postoperatively. The rash appeared 5 weeks later. Abnormal investigations at the time of presentation included; haemoglobin 7 • 8 g/dl. white cell count 1 3-8 X lO**/!, with an eosinophilia of 46%. aspartate transaminase 66 U/l (5-40 U/1). alanine transaminase 240 U/l (35-130 U/l). urea 28-7 mmol/l. creatinine 1068 /xmol/1. potassium 5-5 mmol/I, Culture of a swab from a pustule produced a scanty growth oi Staphylococcus aureus. The following tests were normal or negative: throat swabs, monospot. ASO titre. blood cultures and serology for HTLV-1 and HIV-1, A skin biopsy from the chest showed a diffuse lymphohistiocytic infiltrate in the superficial and papillary dermis in a perivascular and periadnexal distribution, Epidermotropism. with absence of Pautrier's microabscesses. was noted (Fig, 1), 'Ihere were occasional multilobular and hyperchromatic lymphocytes seen within the dermis, A lymph node biopsy showed destruction of lymph node architecture (Fig. 2) and an infiltrate which contained many cells with cerebriform nuclei and mitotic figures, Immunohistochemical staining with UCHL-1 confirmed that the majority ofthe infiltrate was composed of T lymphocytes. 403
404
D,W.S,HARRIS et al
I'igure 1. Skin biopsy showing a diffuse dfrmal tyinphohistiocytic iiiiillratc with a pt'rifidnexal and pt-rivascular distribution. Kpidermolropisni is .seen but there are no Pautrier's tnicroabscesses.
./.-..-
./^ V.- ».
t
f-.
••
Figure 2. I/iw-power view showing destruction ofthe normal lymph node architecture and its replacement by the lymphohistiocytic intiltrate.
Based upon the histological features a diagnosis of cutaneous T-cell iymphoma was made. However, it was felt that the clinical picture was more suggestive of a phenytoin-induced pseudolymphoma. Tissue DNA was extracted from skin and lymph node biopsies using conventional methods,' DNA was digested with restriction enzymes HcoR 1 and Hind 111, subjected to electrophoresis and Southern blot hybridization with probes for the constant region ofthe beta T-cell receptor gene and for the immunoglobulin heavy-chain gene under conditions of high stringency.^ These studies consistently revealed a germline configuration and no discrete
rearrangements of either the beta T-cell receptor or the immunoglobulin heavy-chain gene in tissue DNA from skin and lymph node biopsies. The rash progressed, and new areas of pustulation appeared on the abdomen, i'henytoin was stopped and prednisolone 50 mg daily commenced. The erythroderma improved over the next 2 weeks but the pruritus persisted, A reduction in steroid dose to 15 mg daily provoked a severe fiare of the rash. The patient was eventually weaned off steroids 11 months after presentation. During this period he was readmitted twice with septicaemia and signs of pustulation on his skin, from
PHENYTOIN-INDUCED PSEUDOLYMPHOMA
which a hospital-acquired multiresistant Staphylococctts
aureus was cultured. Discussion Phenytoin-induced pseudolymphoma is an uncommon syndrome with fewer than 2()() cases reported, despite world-wide use of the drug as an anticonvulsant. The first report of hydantoin-induced lymphadenopathy by Coope and Burrows* appeared in 1940. 2 years after phenytoin was introduced. The adenopathy and accompanying fever disappeared on cessation of therapy, but recurred upon rechallenge. In 19S9 Saltzstein and Ackerman*^ reviewed 7S cases and reported a further seven patients, two of whom subsequently died less than 5 years later of lymphoma. ln 1966 Hyman and Somers^ reported six patients on anticonvulsant therapy who developed a histologically proven Hodgkin's lymphoma or lymphosarcoma. All six patients were taking phenytoin in addition to other anticonvulsants. Withdrawal of phenytoin did not halt progression of the lympboma. Gams et al*" later reported a ease in which phenytoin-induced lymphadenopathy regressed after cessation of therapy. However, a fatal lymphoma developed 20 months later. This clinical course is known as pseudo-pseudolymphoma. Four major types of phenytoin-induced lymphadenopathy are recognized: benign iymphoid hyperplasia. pseudolymphoma. pseudo-pseudolymphoma and malignant lymphoma. Distinction between these is made by consideration of the clinical course of the illness and histological examination of lymphoid tissue. The clinical picture of the pseudolymphoma syndrome develops between 5 days and i months (with an average of about 3 weeks) after taking phenytoin. The onset of this hypersensitivity reaction is heralded by a high spiking fever and and intensely pruritic erythematous maculopapular rash, occasionally progressing to an exfofiative erythroderma. Pustulation, occasionally generalized.' is a frequent finding, as is oedema, particularly of the face. The eruption resolves with desquamation. Lymphadenopathy can be marked, often with grapesized nodes, and may be localized or generalized. There is evidence of hepatitis, with or without hepatomegaly. Splenomegaly is an occasional finding. Conjunctivitis, pharyngitis and a strawberry tongue may also be present. The peripheral blood shows a leucocytosis with eosinophilia. Haemolytic anaemia is a rarer finding. There is associated myalgia and arthralgia. These elinical features usually resolve over the same time period
405
after withdrawal of the drug, but persistence of the symptoms is recorded, as occurred in our patient. Repeat administration of the drug results in recurrence of the syndrome. Patients who are at high risk of developing such reactions include tbose known to react to phenytoin who are re-exposed to the drug.** those who develop unrecognized signs wbilst on the drug and who continue to take it.*^ and Black patients,'" Lymphoid hyperplasia and pseudolymphoma are clinically indistinguishable, but histological examination reveals normal lymph node architecture in the hyperplasia group. In the pseudolymphoma group, first described by van Wyk and Hoffman," loss of normal architecture, focal necrosis and infiltration with eosinophils is seen. As in our case this histology may suggest an erroneous diagnosis of malignant lymphoma. The pseudo-pseudolymphoma category applies to patients whose lymph node histology shows hyperplasia or malignant changes which regress upon stopping the drug. However, following an asymptomatic period they subsequently develop a malignant lymphoma. The lymphoma group have histological changes of a malignancy from the outset, and lack any sign of clinical regression. It appears unlikely that phenytoin is overtly carcinogenic in view of the large number of patients treated with this drug and the rarity of iymphomatous change. However. Li et al.' - and Anthony'' have shown an increased incidence of lymphoma occurring in patients on long-term phenytoin. The analysis of immunoglobulin and T-cell receptor genes represents a definitive method for establishing the lineage and clonality of lymphoproliferative disorders, including cutaneous T-cell lymphomas. This technique has also proved valuable in the assessment of dermatopathic lymphadenopathy.'"^ In order to clarify whether this patient had an underlying lympboma. gene rearrangement studies were performed on lymph node and skin biopsies. This is the first reported use of such a technique in this difficult diagnostic situation. Analysis of DNA from both skin and lymph node showed no evidence of rearrangement of the T-ceil receptor beta or immunoglobulin heavy-chain genes. This indicates that there was no evidence of a monoclonal lymphoid population, although the sensitivity of Southern blot analysis is such that a small lymphoid clone comprising 1% or less of the total cellular infiltrate could escape detection.- However, we suggest that this technique is the method of choice for assessing such patients and alerting the physician to the early transformation to lymphoma.
406
D.W.S.HARRIS et ai
References 1 Sambrook J. Fritsch E. Maniatis T. Molecular Cloning. A Laboratory Manual. 2nd edn. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1989. 2 Whittaker SJ. Smith NP. Russell Jones R. l.uzzatto 1., Analysis of beta, gamma and delta T-cell receptor genes in mycosis fungoides and Sezary syndrome. Cancer 1991; (>S: I 572-K2. 3 Coope R, Burrows RGR. Treatment of epilepsy with sodium diphenylhydantoinate, iMncet 1940: i: 490-2, 4 Salty-Stein SL. Ackerman I.V. Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically and pathologically malignant lymphomas. Cancer 1959: 12: l()4-82, 5 Hyman (iA, Sommers SC. The development of Hodgkin's disease and lymphoma during anticonvulsant therapy. Blood 1966: 28: 416-27, 6 Gams RA, Neal |A. Conrad h'd. Hydantoin-induced pseudopseudolymphoma. Ann Intern Med 196H: 69: 557-f>8. 7 Kleier RS. Breneman DL. Boiko S, Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome, ArchDermatol 1991; 127: 1361-4,
8 Schmidt D. Klugc W, Fatal toxic epidermal necrolysis following reexposure to phenytoin: A case report: F.pilepsia 198 i: 24:440- 5. 9 McCarthy LJ. Aguilar jC, Ransburg K. Fatal benign phenytoin lymphadenopathy. Arch Intern Med 1979: 1 i9: i(i7-8. 10 Rapp Rl', Norton JA. Young B, Tibbs PA, Cutaneous reactions in head-injured patients receiving phenytoin Tor seizure prophylaxis. Neurosurgery 198J: 13: 272-5. 11 van Wyk JJ. Hofiman CR. Periarterltis nodosa, A case of fatal exfoliative dermatitis resulting from 'dilantin sodium' sensitization. Arch Inlern Med 1948; 81: 605-11. 12 Li FP. Willard DR. Goodman R, Vawter G, Malignant lymphoma after diphenylhydantoin (Dilantin) therapy. Cancer 1975: 36: 1359-62, 1 i Anthony JJ. Malignant lymphoma associated with hydanloin drugs. Arch Neurol 1970: 22: 450-4, 14 Weiss LM, Hu W, Wood CIS et al, Cionai rearrangements ofT-cell receptor genes in mycosis fungoides and dermatopathic lymphadenopathy. N Eng//Med 1985: 313: 5J9-44,
Phenytoin-induced pseudolymphoma. A report of a case and review of the literature D,W.S,HARRIS. L.OSTLERE. C.BUCKLEY, S.WHITTAKER,* P,SWENYt AND M,H.A.RIJST1N Departments of Dermatoiogy and ^Nephrohgi), Tiie Royal Free Hospital and School of Medicine. London NW3 2QG, U.K. *St lohn's Dermatology Centre. St Thomas's Hospital, London SEI 7EH. U,K, Accepted for publication 1 May 1992
Summary
We report a patient with phenytoin-induced pseudolymphoma mimicking cutaneous T-cell lymphoma (CTCL), Despite withdrawal of phenytoin, there was persistence ofthe cutaneous eruption and lymphadenopathy. Southern hlot analysis of immunoglobulin and T-cell receptor genes was therefore used to assess whether there was a clonal lymphoid expansion. However, no rearrangement ofthe beta T-cell receptor gene or immunoglohulin heavy-chain gene was detected in tissue DNA from skin and lymph nodes. One year later the patient became asymptomatic, although he is still at risk of developing a true malignant lymphoma in the future, a condition known as pseudo-pseudolymphoma. It is suggested that genotypic studies may help in the initial diagnosis and the subsequent management of such patients.
Phenytoin-induced pseudolymphoma is a rare condition comprising cutaneous and systemic features which resolve within 2-6 weeks of drug withdrawal. The majority of reported cases have occurred in Black patients. The dermatological manifestations include morbilliform. pustular, vesiculo-papular and follicular rashes which may affect the face, trunk and limbs, especially acraily. Rarely, the eruption can present as an erythroderma or toxic epidermal necrolysis. The systemic features comprise a triad of fever, lymphadenopathy and hepatitis.
Case report A 25-year-old Black man presented in August 1990 with a 1-week history of fever and an itchy eruption, associated with marked facial oedema. On examination he was pyrexial {temperature 40°C) and had generalized erythroderma with pin-point pustulation over the face and trunk. There was marked facial swelling. He had generalized firm, grape-sized lymphadenopathy and 3 cm splenomegaly. Over the next 5 days desquamation occurred, but the rash persisted. He had a complex past medical history following the discovery of posterior urethral valves and hydroureter at the age of 2 years. This abnormality had resulted in chronic renal failure Correspondence: Dr D.W.S.Harris.
for which he had undergone two unsuccessful cadaveric renal transplants. It was following a native left nephrectomy and subsequent removal of a renal angle haematoma that the patient was treated with phenytoin 100 mg b.d, because he suffered a grand-mal fit postoperatively. The rash appeared 5 weeks later. Abnormal investigations at the time of presentation included; haemoglobin 7 • 8 g/dl. white cell count 1 3-8 X lO**/!, with an eosinophilia of 46%. aspartate transaminase 66 U/l (5-40 U/1). alanine transaminase 240 U/l (35-130 U/l). urea 28-7 mmol/l. creatinine 1068 /xmol/1. potassium 5-5 mmol/I, Culture of a swab from a pustule produced a scanty growth oi Staphylococcus aureus. The following tests were normal or negative: throat swabs, monospot. ASO titre. blood cultures and serology for HTLV-1 and HIV-1, A skin biopsy from the chest showed a diffuse lymphohistiocytic infiltrate in the superficial and papillary dermis in a perivascular and periadnexal distribution, Epidermotropism. with absence of Pautrier's microabscesses. was noted (Fig, 1), 'Ihere were occasional multilobular and hyperchromatic lymphocytes seen within the dermis, A lymph node biopsy showed destruction of lymph node architecture (Fig. 2) and an infiltrate which contained many cells with cerebriform nuclei and mitotic figures, Immunohistochemical staining with UCHL-1 confirmed that the majority ofthe infiltrate was composed of T lymphocytes. 403
404
D,W.S,HARRIS et al
I'igure 1. Skin biopsy showing a diffuse dfrmal tyinphohistiocytic iiiiillratc with a pt'rifidnexal and pt-rivascular distribution. Kpidermolropisni is .seen but there are no Pautrier's tnicroabscesses.
./.-..-
./^ V.- ».
t
f-.
••
Figure 2. I/iw-power view showing destruction ofthe normal lymph node architecture and its replacement by the lymphohistiocytic intiltrate.
Based upon the histological features a diagnosis of cutaneous T-cell iymphoma was made. However, it was felt that the clinical picture was more suggestive of a phenytoin-induced pseudolymphoma. Tissue DNA was extracted from skin and lymph node biopsies using conventional methods,' DNA was digested with restriction enzymes HcoR 1 and Hind 111, subjected to electrophoresis and Southern blot hybridization with probes for the constant region ofthe beta T-cell receptor gene and for the immunoglobulin heavy-chain gene under conditions of high stringency.^ These studies consistently revealed a germline configuration and no discrete
rearrangements of either the beta T-cell receptor or the immunoglobulin heavy-chain gene in tissue DNA from skin and lymph node biopsies. The rash progressed, and new areas of pustulation appeared on the abdomen, i'henytoin was stopped and prednisolone 50 mg daily commenced. The erythroderma improved over the next 2 weeks but the pruritus persisted, A reduction in steroid dose to 15 mg daily provoked a severe fiare of the rash. The patient was eventually weaned off steroids 11 months after presentation. During this period he was readmitted twice with septicaemia and signs of pustulation on his skin, from
PHENYTOIN-INDUCED PSEUDOLYMPHOMA
which a hospital-acquired multiresistant Staphylococctts
aureus was cultured. Discussion Phenytoin-induced pseudolymphoma is an uncommon syndrome with fewer than 2()() cases reported, despite world-wide use of the drug as an anticonvulsant. The first report of hydantoin-induced lymphadenopathy by Coope and Burrows* appeared in 1940. 2 years after phenytoin was introduced. The adenopathy and accompanying fever disappeared on cessation of therapy, but recurred upon rechallenge. In 19S9 Saltzstein and Ackerman*^ reviewed 7S cases and reported a further seven patients, two of whom subsequently died less than 5 years later of lymphoma. ln 1966 Hyman and Somers^ reported six patients on anticonvulsant therapy who developed a histologically proven Hodgkin's lymphoma or lymphosarcoma. All six patients were taking phenytoin in addition to other anticonvulsants. Withdrawal of phenytoin did not halt progression of the lympboma. Gams et al*" later reported a ease in which phenytoin-induced lymphadenopathy regressed after cessation of therapy. However, a fatal lymphoma developed 20 months later. This clinical course is known as pseudo-pseudolymphoma. Four major types of phenytoin-induced lymphadenopathy are recognized: benign iymphoid hyperplasia. pseudolymphoma. pseudo-pseudolymphoma and malignant lymphoma. Distinction between these is made by consideration of the clinical course of the illness and histological examination of lymphoid tissue. The clinical picture of the pseudolymphoma syndrome develops between 5 days and i months (with an average of about 3 weeks) after taking phenytoin. The onset of this hypersensitivity reaction is heralded by a high spiking fever and and intensely pruritic erythematous maculopapular rash, occasionally progressing to an exfofiative erythroderma. Pustulation, occasionally generalized.' is a frequent finding, as is oedema, particularly of the face. The eruption resolves with desquamation. Lymphadenopathy can be marked, often with grapesized nodes, and may be localized or generalized. There is evidence of hepatitis, with or without hepatomegaly. Splenomegaly is an occasional finding. Conjunctivitis, pharyngitis and a strawberry tongue may also be present. The peripheral blood shows a leucocytosis with eosinophilia. Haemolytic anaemia is a rarer finding. There is associated myalgia and arthralgia. These elinical features usually resolve over the same time period
405
after withdrawal of the drug, but persistence of the symptoms is recorded, as occurred in our patient. Repeat administration of the drug results in recurrence of the syndrome. Patients who are at high risk of developing such reactions include tbose known to react to phenytoin who are re-exposed to the drug.** those who develop unrecognized signs wbilst on the drug and who continue to take it.*^ and Black patients,'" Lymphoid hyperplasia and pseudolymphoma are clinically indistinguishable, but histological examination reveals normal lymph node architecture in the hyperplasia group. In the pseudolymphoma group, first described by van Wyk and Hoffman," loss of normal architecture, focal necrosis and infiltration with eosinophils is seen. As in our case this histology may suggest an erroneous diagnosis of malignant lymphoma. The pseudo-pseudolymphoma category applies to patients whose lymph node histology shows hyperplasia or malignant changes which regress upon stopping the drug. However, following an asymptomatic period they subsequently develop a malignant lymphoma. The lymphoma group have histological changes of a malignancy from the outset, and lack any sign of clinical regression. It appears unlikely that phenytoin is overtly carcinogenic in view of the large number of patients treated with this drug and the rarity of iymphomatous change. However. Li et al.' - and Anthony'' have shown an increased incidence of lymphoma occurring in patients on long-term phenytoin. The analysis of immunoglobulin and T-cell receptor genes represents a definitive method for establishing the lineage and clonality of lymphoproliferative disorders, including cutaneous T-cell lymphomas. This technique has also proved valuable in the assessment of dermatopathic lymphadenopathy.'"^ In order to clarify whether this patient had an underlying lympboma. gene rearrangement studies were performed on lymph node and skin biopsies. This is the first reported use of such a technique in this difficult diagnostic situation. Analysis of DNA from both skin and lymph node showed no evidence of rearrangement of the T-ceil receptor beta or immunoglobulin heavy-chain genes. This indicates that there was no evidence of a monoclonal lymphoid population, although the sensitivity of Southern blot analysis is such that a small lymphoid clone comprising 1% or less of the total cellular infiltrate could escape detection.- However, we suggest that this technique is the method of choice for assessing such patients and alerting the physician to the early transformation to lymphoma.
406
D.W.S.HARRIS et ai
References 1 Sambrook J. Fritsch E. Maniatis T. Molecular Cloning. A Laboratory Manual. 2nd edn. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1989. 2 Whittaker SJ. Smith NP. Russell Jones R. l.uzzatto 1., Analysis of beta, gamma and delta T-cell receptor genes in mycosis fungoides and Sezary syndrome. Cancer 1991; (>S: I 572-K2. 3 Coope R, Burrows RGR. Treatment of epilepsy with sodium diphenylhydantoinate, iMncet 1940: i: 490-2, 4 Salty-Stein SL. Ackerman I.V. Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically and pathologically malignant lymphomas. Cancer 1959: 12: l()4-82, 5 Hyman (iA, Sommers SC. The development of Hodgkin's disease and lymphoma during anticonvulsant therapy. Blood 1966: 28: 416-27, 6 Gams RA, Neal |A. Conrad h'd. Hydantoin-induced pseudopseudolymphoma. Ann Intern Med 196H: 69: 557-f>8. 7 Kleier RS. Breneman DL. Boiko S, Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome, ArchDermatol 1991; 127: 1361-4,
8 Schmidt D. Klugc W, Fatal toxic epidermal necrolysis following reexposure to phenytoin: A case report: F.pilepsia 198 i: 24:440- 5. 9 McCarthy LJ. Aguilar jC, Ransburg K. Fatal benign phenytoin lymphadenopathy. Arch Intern Med 1979: 1 i9: i(i7-8. 10 Rapp Rl', Norton JA. Young B, Tibbs PA, Cutaneous reactions in head-injured patients receiving phenytoin Tor seizure prophylaxis. Neurosurgery 198J: 13: 272-5. 11 van Wyk JJ. Hofiman CR. Periarterltis nodosa, A case of fatal exfoliative dermatitis resulting from 'dilantin sodium' sensitization. Arch Inlern Med 1948; 81: 605-11. 12 Li FP. Willard DR. Goodman R, Vawter G, Malignant lymphoma after diphenylhydantoin (Dilantin) therapy. Cancer 1975: 36: 1359-62, 1 i Anthony JJ. Malignant lymphoma associated with hydanloin drugs. Arch Neurol 1970: 22: 450-4, 14 Weiss LM, Hu W, Wood CIS et al, Cionai rearrangements ofT-cell receptor genes in mycosis fungoides and dermatopathic lymphadenopathy. N Eng//Med 1985: 313: 5J9-44,
