Evaluation of Associated Lymphomas and Their Risk Factors in Patients with Lymphomatoid Papulosis: A Retrospective Single-Center Study from Turkey

Objective: Lymphomatoid papulosis (LyP) is an indolent skin disease with variable clinical features classified among the primary cutaneous CD30+ T-cell lymphoproliferative disorders. It may show association with cutaneous and systemic lymphomas. We aimed to identify the frequency and characteristics of associated lymphomas among Turkish patients with LyP and to determine the risk factors for secondary lymphomas. Materials and Methods: The files of patients diagnosed with LyP between 1998 and 2018 in a tertiary dermatology clinic were retrospectively analyzed. Univariate and multivariate models were used to assess the possible risk factors for secondary lymphomas, such as demographic and clinical characteristics of the patients. Results: Among 61 patients (47 adults, 14 children) with LyP, a total of 22 secondary lymphomas were observed in 20 patients. Nineteen of them were adults. Mycosis fungoides (MF) was the major associated lymphoma (n=19) followed by systemic anaplastic large cell lymphoma (ALCL) (n=2) and primary cutaneous ALCL (n=1). The most common stage in patients with accompanying MF was stage IB (n=11). While 18 patients showed the classical type of MF, one patient had folliculotropic MF. When the risk factors for association between LyP and other lymphomas were evaluated, only older age was found to be a significant risk factor and existence of ulcerated lesions was found to be a negative indicator. Conclusion: LyP is not rare in the pediatric population. MF is the most common associated lymphoma in patients with LyP. Adult LyP patients are more commonly associated with secondary lymphomas than pediatric patients. Older age at the time of diagnosis of LyP is a significant risk factor for associated lymphomas.

Calidad de vida en pacientes con linfomas cutáneos de células T / Quality of Life in Patients with Cutaneous T-Cell Lymphoma

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Registro de linfomas cutáneos primarios de la AEDV: primer año de funcionamiento / The First Year of the AEVD Primary Cutaneous Lymphoma Registry

ANTECEDENTES Y OBJETIVO: Los linfomas primarios cutáneos son enfermedades poco frecuentes. Este artículo describe el Registro de linfomas cutáneos primarios de la AEDV y sus primeros resultados. PACIENTES Y MÉTODOS: Registro de enfermedad de pacientes con linfomas cutáneos primarios. Los centros participantes recogieron datos prospectivamente de todos los pacientes, incluyendo datos del diagnóstico, de los tratamientos, de las pruebas realizadas y del estado actual del paciente. Se realizó un análisis descriptivo. RESULTADOS: En diciembre del 2017 el registro tenía datos de 639 pacientes pertenecientes a 16 hospitales universitarios. Un 60% eran hombres y los diagnósticos, por orden de frecuencia, fueron: micosis fungoide/síndrome de Sézary (MF/SS) (348 casos; 55%), linfoma cutáneo primario de células B (LCCB) (184; 29%), trastorno linfoproliferativo de células T CD30+ (LTCD30+) (70; 11%) y otro tipo de linfoma T (OLT) (37; 5%). El número de casos incidentes recogidos durante el primer año fue de 105 (16,5%). En los pacientes con MF/SS, el diagnóstico más frecuente fue MF clásica (77,3%). La mitad de estos casos se diagnosticaron en estadio IA. La mayoría de los pacientes estaban en remisión parcial (32,5%) o enfermedad estable (33,1%). Los tratamientos más usados fueron los corticoides tópicos (90,8%) seguidos de fototerapia. En los pacientes con LCCB el diagnóstico más frecuente fue el linfoma de la zona marginal (50%). Casi todos los pacientes tuvieron afectación exclusivamente cutánea y casi la mitad fue T1a. La mayoría (76,1%) estaba en remisión completa. Los tratamientos más utilizados fueron la cirugía (55,4%) y la radioterapia (41,9%). En los pacientes con LTCD30+, el diagnóstico más frecuente fue la papulosis linfomatoide (68,6%). La mayoría fueron clasificados T3b (31,4%). La mitad de los casos estaban en remisión completa. Los tratamientos más frecuentes fueron los esteroides tópicos (68,6%), seguidos de la quimioterapia sistémica (32,9%). CONCLUSIÓN: Las características del paciente con linfoma cutáneo primario en España no difieren de otras series descritas en la literatura. El registro facilitará al grupo de linfomas de la AEDV realizar investigación clínica

BACKGROUND AND OBJECTIVE: Primary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. PATIENTS AND METHODS: Disease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. RESULTS: In December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30+ T-cell lymphoproliferative disorder (CD30+ CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical coricosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30+ CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). CONCLUSION: The characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate clinical research by the AEDV's lymphoma group

[Primary cutaneous lymphoma-a case series of 163 patients]. / Primär kutane Lymphome ­ eine Fallserie von 163 Patienten.

BACKGROUND: In addition to a broad and clinically diverse spectrum of known primary cutaneous lymphomas, for which an incidence of 1-3:100,000 is postulated, each year further entities are specified and defined. The goal is the presentation of a case series from daily clinical routine. METHODS: Over a period of 6 years and 2 months, patients consulting the Department of Dermatology, Medical Center University of Freiburg, were registered. Subsequently, collectives of mycosis fungoides (MF), Sezary syndrome (SS), CD30+ lymphoproliferative diseases, single cases with rare primary cutaneous lymphomas, and subcollectives of B­cell lymphomas were examined. The high number of MF cases allowed the additional quantitative analyses of the types of therapies used in this group. RESULTS: Yearly 16-25 new diagnoses of primary cutaneous lymphoma are made. The evaluation of 163 primary cutaneous lymphoma revealed 111 cases with MF (68.1%), including 9 particular variants, 15 primary cutaneous CD30+ lymphoproliferative diseases (9.2%) dominated by 10 lymphomatoid papulosis (LyP), in addition to 5 primary cutaneous anaplastic large cell lymphoma (PCALCL), 6 SS (3.68%), and 24 cutaneous B­cell lymphomas (14-72%). Three cases with rare primary cutaneous T/NK cell lymphomas are addressed in detail. In all, 82% of MF cases were stage IA and IB. The descending use of therapies for stage I-III included steroids and diverse UV therapies followed by bexarotene, interferon-α, methotrexate, and extracorporal photophoresis. CONCLUSIONS: Diagnoses of cutaneous lymphomas belong to a vast spectrum of differential diagnoses. This registry describes frequent findings and shows rare variants. You can only diagnose what you know; accordingly, a collection of case reports, which we wish to encourage, can help in processing and specification of entities.

The First Year of the AEVD Primary Cutaneous Lymphoma Registry. / Registro de linfomas cutáneos primarios de la AEDV: primer año de funcionamiento.

BACKGROUND AND OBJECTIVE: Primary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. PATIENTS AND METHODS: Disease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. RESULTS: In December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30+ T-cell lymphoproliferative disorder (CD30+ CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical corticosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30+ CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). CONCLUSION: The characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate clinical research by the AEDV's lymphoma group.

Papulosis linfomatoide. Presentación de un caso / Lymphomatoid papulosis. Report of a case

La papulosis linfomatoide forma parte del espectro de los procesos linfoproliferativos cutáneos primarios de células T CD30+. Es una enfermedad rara de etiopatogenia incierta y compleja. El diagnóstico diferencial puede a veces resultar muy difícil. Se describió el caso de una mujer de 80 años con el diagnóstico, particularmente atípico desde la visión histopatológica, en el cual la correlación anatomoclínica ha sido un importante aspecto que lo hace interesante. El objetivo es comunicar un caso de presentación poco frecuente en la práctica médica (AU).

Lymphomatoid papulosis is part of the primary skin lymph proliferative processes of the T CD30+ cells. It is a rare disease of complex and uncertain etiopathogenesis. The differential diagnosis could be very difficult sometimes. The described case was the one of a female patient, aged 80 years with that diagnosis, particularly atypical from the histopathological point of view, where the anatomoclinical correlation has been an important aspect making it interesting. The objective is to inform a case of infrequent presentation in the medical practice (AU).

Papulosis linfomatoide. Presentación de un caso / Lymphomatoid papulosis. Report of a case

La papulosis linfomatoide forma parte del espectro de los procesos linfoproliferativos cutáneos primarios de células T CD30+. Es una enfermedad rara de etiopatogenia incierta y compleja. El diagnóstico diferencial puede a veces resultar muy difícil. Se describió el caso de una mujer de 80 años con el diagnóstico, particularmente atípico desde la visión histopatológica, en el cual la correlación anatomoclínica ha sido un importante aspecto que lo hace interesante. El objetivo es comunicar un caso de presentación poco frecuente en la práctica médica (AU).

Lymphomatoid papulosis is part of the primary skin lymph proliferative processes of the T CD30+ cells. It is a rare disease of complex and uncertain etiopathogenesis. The differential diagnosis could be very difficult sometimes. The described case was the one of a female patient, aged 80 years with that diagnosis, particularly atypical from the histopathological point of view, where the anatomoclinical correlation has been an important aspect making it interesting. The objective is to inform a case of infrequent presentation in the medical practice (AU).

Associated Hematolymphoid Malignancies in Patients With Lymphomatoid Papulosis: A Canadian Retrospective Study.

BACKGROUND: Lymphomatoid papulosis is one of the primary cutaneous CD30+ T-cell lymphoproliferative disorders. Although considered a benign disease, lymphomatoid papulosis has been associated potentially with an increased risk of secondary hematolymphoid malignancies. OBJECTIVE: The aim of this study was to assess the clinical characteristics and histologic subtypes of lymphomatoid papulosis, identify the prevalence and types of secondary hematolymphoid malignancies, and determine the potential risk factors for development of these hematolymphoid malignancies. METHODS AND MATERIALS: A retrospective chart review was performed for all histologically confirmed cases of lymphomatoid papulosis between 1991 and 2016. RESULTS: Seventy patients with lymphomatoid papulosis were identified. Thirty patients (43%) experienced a secondary hematolymphoid malignancy. Twenty-four (80%) of the hematolymphoid malignancies occurred after the onset of lymphomatoid papulosis. Older age at diagnosis of lymphomatoid papulosis, male sex, histology type B, and the presence of T-cell receptor gene rearrangement are associated with higher risk of developing hematolymphoid malignancy. CONCLUSION: Lymphomatoid papulosis is associated with increased risk of developing secondary hematolymphoid malignancies, particularly mycosis fungoides and cutaneous anaplastic large cell lymphoma.

Frequency and Risk Factors for Associated Lymphomas in Patients With Lymphomatoid Papulosis.

BACKGROUND: Lymphomatoid papulosis (LyP) is classified as an indolent cutaneous lymphoma, but outcome dramatically worsens if LyP is associated with lymphoma. The frequency of this association remains unclear in the literature. Here, we assess the frequency and risk factors of association between LyP and another lymphoma in an 11-year retrospective study conducted in 8 dermatology departments belonging to the French Study Group on Cutaneous Lymphoma (FSGCL). PATIENTS AND METHODS: Patients with LyP were identified and data extracted from the FSGCL registry between 1991 and 2006. Patients were followed up to January 2014. Age, sex, number of skin lesions, histologic subtype, and genotype were recorded at baseline. Risk factors were determined using univariate and multivariate analysis. Cumulative probability of association was calculated using the Kaplan-Meier method. RESULTS: We observed 52 cases of lymphomas (cutaneous, n = 38; systemic, n = 14) in 44 of 106 patients (41%). Lymphoma diagnosis was concomitant with or prior to LyP diagnosis in 31 cases and occurred during the course of LyP in 21 cases (cutaneous, n = 14; systemic, n = 7; median delay: 5 years; interquartile range: 1.5-7 years). In multivariate analysis, main prognostic factors for association between LyP and another lymphoma were older age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.01-1.08; p = .011) and presence of a T-cell clone in LyP lesions (OR: 7.55; 95% CI: 2.18-26.18; p = .001). CONCLUSION: Older age and presence of a T-cell clone in LyP lesions are risk factors for associated lymphomas in patients with LyP. These findings should help to identify patients who require close management in clinical practice. IMPLICATIONS FOR PRACTICE: The management of lymphomatoid papulosis (LyP) is that of an indolent cutaneous lymphoma, based on its excellent prognosis. However, this good prognosis is altered if LyP is associated with lymphoma. Furthermore, risk factors for and frequency of this association remain unclear in the literature. The results presented here demonstrate a high rate of association between LyP and other lymphomas (41%) as well as a long median delay of occurrence (5 years), which emphasizes the need for prolonged follow-up of patients with LyP. Moreover, two main risk factors (i.e., older age and presence of a T-cell clone in LyP lesions) are highlighted, which should help clinical practitioners to identify patients who require close management.

Lymphomatoid papulosis: is a second lymphoma commoner among East Asians?

BACKGROUND: Lymphomatoid papulosis (LyP) is a low-grade cutaneous lymphoma, which lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Around 10-20% of LyP cases are associated with a second lymphoma. AIM: To analyse a cohort of Asian patients with LyP, diagnosed from 1987 to 2007 at the National Skin Centre (NSC), Singapore, in terms of epidemiology, treatment and association with a second lymphoma. METHODS: Patients were identified through the NSC clinical and histological databases. RESULTS: During this period, 13 patients were diagnosed with LyP based on clinicopathological criteria. The mean age at diagnosis was 41 years, the male : female ratio was 2.3 : 1, and 92% of the patients were Chinese. Recurrent papulonecrotic lesions were present for a mean of 3 years before diagnosis. Treatment of LyP comprised monotherapy (n = 4) or combination therapy (n = 9) using corticosteroids, oral antibiotics, methotrexate and/or phototherapy. Mean duration of follow-up was 6.4 years. Eight patients (61.5%) were diagnosed with a second lymphoma, either before (n = 2), concurrently with (n = 1) or after (n = 5) the diagnosis of LyP. Mycosis fungoides (MF) was the commonest lymphoma (78%, n = 7), followed by primary cutaneous anaplastic large-cell lymphoma (12%, n = 2). There was one death (mortality rate 7.7%), which occurred in a patient who had developed stage IIA MF after LyP, which subsequently progressed to systemic T-cell lymphoma. CONCLUSIONS: LyP is a chronic, relapsing disease with considerable morbidity, but an overall good prognosis. A strikingly large proportion of our Asian patients (61.5%) had a second lymphoma, compared with previous studies. This emphasizes the importance of regular lifetime surveillance for associated lymphomas in all patients with LyP.

Contact hypersensitivity in patients with primary cutaneous lymphoproliferative disorders.

BACKGROUND: One of the suggested causes of primary cutaneous lymphoproliferative disorders is persistent antigenic stimulation. OBJECTIVE: To study the prevalence of contact hypersensitivity in patients with primary cutaneous lymphoproliferative disorders other than mycosis fungoides (MF). MATERIALS AND METHODS: Thirty consecutive patients with primary cutaneous lymphoproliferative disorders other than MF were patch tested to a European Standard & partial metal series. The results were compared with those of 792 consecutive patients with other skin diseases referred to our clinic and a large published series of 9760 healthy individuals from North America. RESULTS: Twenty-two patients with primary cutaneous lymphoma other than MF and eight patients with pseudolymphomas were included in the study. Altogether there were 23 positive patch tests in 13 patients. Only the prevalence of positive patch tests to cobalt (5/30 patients = 17%) was found to be significantly higher in the studied group than in the two control groups (P<0.01 and P=0.05, respectively). The contact hypersensitivity to cobalt and the other allergens, however, could not be related causally to the pathogenesis of the lesions. CONCLUSIONS: The relative prevalence of contact hypersensitivity to cobalt only was found to be increased in a group of primary cutaneous lymphoproliferative disorders, but a causal relationship to the lymphoproliferative disorders could not be established.

[Lymphomatoid papulosis in children: report of 9 cases and review of the literature]. / Papulosis linfomatoide en la infancia: presentación de 9 casos y revisión de la literatura.

BACKGROUND: Lymphomatoid papulosis is a rare lymphoproliferative T cell CD30+ disease with excellent prognosis which affects almost exclusively adult patients, being rarely in the childhood; thus the clinic and pathologic spectrum and the risk of evolution to another type of lymphoma are not well defined in the pediatric group. OBJECTIVE: The aim of this article is to analyze the characteristics of infantile lymphomatoid papulosis and review the literature. MATERIAL AND METHOD: A retrospective study analyzing the characteristics of 9 patients aged up to 18 diagnosed of lymphomatoid papulosis attended in our department from 1995 to 2009 was performed. RESULTS: The study included 7 boys and 2 girls aged between 2 and 17. Pityriasis lichenoides acuta's lesions appeared associated before and after lymphomatoid papulosis' development in 2 and 1 cases respectively. The lesions resolved spontaneously, leaving a postinflammatory hyperpigmentation (77%) or hypopigmentation (23%). The development of varioliform scars occurred in over 77% of cases. Histologically, all cases showed features compatible with type A of lymphomatoid papulosis. Molecular studies showed monoclonality in the 3 cases in which this technique was done. CONCLUSIONS: Infantile lymphomatoid papulosis is a rare entity clinically manifested as the adult form. This lymphoproliferative disease, which is occasionally associated with pityriasis lichenoides acuta, shows features compatible with the type A or histiocytoid pattern in the histological analysis. The development of other lymphoproliferative disorders is less frequent in the infantile form than in the adulthood. The prevalent association among pityriasis lichenoides and lymphomatoid papulosis observed in our analysis, as well as the difficulties which supposed to differentiate between these two pathologies in various cases, suggest that those entities could be part of a common clinical and pathological spectrum.

Lymphomatoid papulosis in children: a retrospective cohort study of 35 cases.

BACKGROUND: Lymphomatoid papulosis (LyP) is a rare entity, considered to be part of the spectrum of the CD30(+) cutaneous lymphoproliferative disorders. About 10% to 20% of the adult LyP patients will develop an associated lymphoid malignancy. Only a few cases of LyP have been described in children, and the risk of associated lymphoid malignancies in these patients is not known. OBJECTIVES: To study the association between childhood onset of LyP and other malignancies and to determine the clinical characteristics in this subgroup of patients. DESIGN: Retrospective cohort study. SETTING: Referral center at a university hospital. Retrospective registry for patients with LyP of childhood onset (< or =18 years). Patients Thirty-five patients with childhood-onset LyP (19 boys and 16 girls) were interviewed by telephone using a standardized questionnaire. The median duration of follow-up was 9.0 years. All included patients were confirmed by histologic examination. RESULTS: The age distribution was significantly different, with boys having an earlier onset of LyP (P =.03). Of the 35 LyP patients, 3 (9%) developed a malignant lymphoma; all were diagnosed as having non-Hodgkin lymphoma. Compared with the general population, patients with childhood-onset LyP have a significantly increased risk of developing non-Hodgkin lymphoma (relative risk, 226.2; 95% confidence interval, 73.4-697.0). More than two thirds of the patients reported being atopic, which is significantly more than the expected prevalence of atopy (relative risk, 3.1; 95% confidence interval, 2.2-4.3). CONCLUSIONS: Lymphomatoid papulosis presents similarly in children and adults, including the risk of lymphoid malignancies. Therefore, all LyP patients should be closely monitored throughout their lives.

Relative frequency of various forms of primary cutaneous lymphomas.

BACKGROUND: Data on the relative frequency of the various forms of primary cutaneous lymphomas (PCLs) are largely limited to European institutions. OBJECTIVE: Our purpose was to document the relative frequencies of various PCLs seen at 3 US institutions with active cutaneous lymphoma programs and to compare those with the European data. METHODS: Included in this study are newly registered patients seen at MCP Hahnemann University, New York University, and the University of California, San Francisco from July 1, 1995 to June 30, 1998. RESULTS: A total of 755 patients were seen. The frequency distribution of the major diagnostic groups was as follows: mycosis fungoides/Sézary syndrome, 82.3%; lymphomatoid papulosis, 12.6% (including patients with associated mycosis fungoides/Sézary syndrome); CD30(+) anaplastic large-cell lymphoma, 0.9%; peripheral T-cell lymphomas, 2.9%; B-cell lymphoma, 4.5%. CONCLUSION: The most striking finding is the much lower relative frequency of primary cutaneous B-cell lymphomas at US institutions (4.5%) versus the approximately 20% reported by European groups. The reason for this difference requires further study.

Lymphomatoid papulosis: a clinical and histopathologic review of 53 cases with leukocyte immunophenotyping, DNA flow cytometry, and T-cell receptor gene rearrangement studies.

BACKGROUND: Lymphomatoid papulosis (LyP) is a recurrent hemorrhagic papular skin eruption with a clinically benign course and histopathologic features of lymphoma. OBJECTIVE AND METHODS: To better characterize this disease, we studied 53 patients seen since 1965. RESULTS: A lymphoproliferative malignancy developed within 2 to 36 years after onset of LyP in eight patients. Histologically, the dermis in LyP showed an infiltrate of large (type A) or small (type B) atypical lymphocytes. The large atypical cells (type A) stained with CD30 (Ber-H2). Seven of the patients in whom lymphoma developed had type A histologic features. DNA flow cytometry showed mainly a diploid pattern, except for two cases that showed aneuploidy. Five of 11 patients showed T-cell receptor (TCR) clonal gene rearrangements; lymphoma has not developed in these patients. One patient had a TCR rearrangement in a plaque of mycosis fungoides but not in the LyP lesion. CONCLUSION: LyP is either a reactive skin condition or a localized lymphoid malignancy. Neither DNA flow cytometry nor TCR gene rearrangement can predict the 15% to 19% of patients in whom a lymphoma will develop. Continued observation of all patients is essential.