In the Greek and Roman mythology, Priapos—the son of Aphrodite and Dionysos—was the god of fertility, vegetables, garden, and male generative power. He is depicted by his permanent oversized penile erection which gave rise to the term priapism. Priapism is already mentioned in Ebers’ ancient Egyptian papyrus (16th century BC). The Greek physician Galen of Pergamon (216–129 BC) and the medieval physician G. de Chauliac (1300–1368) both thought that the condition was due to dilatation of the arteries ^[1][71]. Traumatic causes of priapism associated with spinal cord injury also had been empirically recognized since ancient Egyptian times and comprise, e.g., the description of anatomic findings in priapism of public hanging victims by Leonardo da Vinci ^[1][71]. The first modern descriptions of non-traumatic priapism were given by the French physician T. De Héry in 1552, by the German physician H. Petraens in 1616 ^[2][3][72,73], and the first account appearing in the English literature by J. W. Tripe in 1845 ^[4][74]. The present pathophysiological concept of vascular stasis and reduced venous outflow (‘congestion and slowing of the blood stream’) was firstly delineated by F. Hinman in 1914 and further expanded by his son ^[5][6][75,76].

In patients with hyperleukocytosis due to leukemia, leukostasis by aggregation of blood cells in the corpora cavernosa and the penile dorsal veins is considered the most important factor to cause priapism. In such cases with CML, compression of intra-abdominal veins and consecutive venous congestion of the corpora cavernosa due to massive splenomegaly may contribute as an additional factor ^[7][25]. CML was first described in 1845 in autopsy cases by J.H. Bennett in Glasgow and by R. Virchow in Berlin ^[8][9][77,78]. This was followed by the first diagnosis of CML in a patient while still alive by H. W. Fuller in Manchester already one year thereafter ^[10][11][79,80]. The first report of priapism in association with CML was given by Lissauer who described a 20-year-old patient treated near the town of Kassel/Germany in 1865 (see Case Vignette #1) ^[12][81]. Already in 1879, F. Salzer from Berlin discussed a hindered blood circulation in the smaller penile vessels of the corpora cavernosa in conjunction with the formation of thrombi as a possible pathophysiological mechanism of priapism in leukemia ^[13][82].

In pediatric patients, CML is very rare and evidently priapism associated with this condition is even rarer. To the best of our knowledge the first case describing a 10-year-old Italian boy was published by G. Maciotta in 1934 ^[14][83]. This was followed by reports on a prepubertal 12-year-old boy from France by A. Depaillat in 1954 ^[15][84], and presentations of an 8-year-old boy by D. Ritz in 1964 and of a 7-year-old boy by R.G. Graw in 1969 both from the USA ^[16][17][85,86]. The youngest patient so far described with priapism and a diagnosis of CML is a 7-week-old baby reported by L. Graivier in 1971 presenting with hepatosplenomegaly and blastic phase of atypical CML (moderate leukocytosis of 35.000 WBC per µL, 40% lymphoblasts, no detectable Philadelphia-chromosome) ^[18].

Case vignette #1

The first case of priapism associated with CML described in the German medical literature, Lissauer 1865, ^[12]

[German87]……betrifft einen jungen Mann von 20 Jahren aus der Nähe von Cassel [modern writing: Kassel] ….Oedem, namentlich der linken unteren Extremität … auch Zeichen von Anämie, sowie Verdauungsstörungen und Catarre waren vorhanden. Milz enorm vergrößert ….In der späteren Behandlung ….trat dann eine mehrere Tage anhaltende durch kein Mittel zu beseitigende Erection ein, ……

[English, author’s translation]. …..concerning a young, 20 year-old man living near Kassel…..presenting with edema, namely of the lower left extremity …. also signs of anemia, as well as disturbed digestion and catarrh. The spleen was enlarged enormously. Later during treatment ………an erection occurred persisting for several days and not resolving by any remedy……

Case vignette #1 The first case of priapism associated with CML described in the German medical literature, Lissauer 1865, [81] [German]……betrifft einen jungen Mann von 20 Jahren aus der Nähe von Cassel [modern writing: Kassel] ….Oedem, namentlich der linken unteren Extremität … auch Zeichen von Anämie, sowie Verdauungsstörungen und Catarre waren vorhanden. Milz enorm vergrößert ….In der späteren Behandlung ….trat dann eine mehrere Tage anhaltende durch kein Mittel zu beseitigende Erection ein, …… [English, author’s translation]. …..concerning a young, 20 year-old man living near Kassel…..presenting with edema, namely of the lower left extremity …. also signs of anemia, as well as disturbed digestion and catarrh. The spleen was enlarged enormously. Later during treatment ………an erection occurred persisting for several days and not resolving by any remedy……

Priapism is observed in all age groups from newborn to elderly and has an incidence of 1.5 per 100,000 ^[19][88]. While mostly seen in males with sickle cell disease, it may be the initial symptom of hyperleukocytosis in leukemias such as CML. During a 12-year period in a single tertiary center in Turkey, 71 patients presented with priapism and 24 (34%) out of these were affected with CML ^[20][89]. In a recent literature-based analysis covering the period from 1960 to 2020, E. Ali and coworkers analyzed 68 publications including case reports and case series on a total of 102 patients with priapism and CML ^[21][90]. The youngest patient was 7 weeks old, and the oldest was 60 years old. In this pooled data analysis priapism was observed more frequently in younger patients with CML. Depending on the upper age limit defining a ‘pediatric’ cohort, n = 41 (40%), n = 34 (33%), n = 21 (21%), and n = 17 (17%) patients, respectively, out of the 102 patients were children and adolescents in the age range 0–21, 0–18, 0–16, or 0–14 years, respectively. Evidently these data on pediatric CML and priapism are biased by the fact that only published reports were analyzed. A more systematic approach sourced from the CML Committee of the Japanese Pediatric Leukemia/Lymphoma Study Group. The authors report leukostasis as a complication of hyperleukocytosis in 23 out of 238 patients (9.7%) younger than 20 years when diagnosed with CML at 93 hospitals between 1996 and 2011 ^[22][59]. Priapism was seen in 4 cases (1.5%) of the total cohort. Also, a report from a trial on 40 French pediatric patients describes signs of leukostasis in 4 children (10%) and priapism in 1 boy (2.5%) only ^[23][9]. These findings—perhaps due to higher case numbers—differ considerably from a much higher reported 60% rate of leukostasis observed in 6 out of 10 pediatric CML patients described in the older literature ^[24][91].

In the, so far, largest pediatric cohort described and analyzed here, 16 out of 491 (3.2%) boys presented with priapism at diagnosis of CML, a proportion which is twice as high compared with the report from Japan. Priapism was not observed at a distinct age or in association with pubertal status but paralleled the incidence of CML which is higher in the second than in the first decade of life.

Ischemic priapism is an acute emergency with treatment delay resulting in irreversible damage of corporal tissue and the ultimate consequence of erectile dysfunction ^[25][92]. Blood stasis (low flow) causes progressive local hypoxia, hypercapnia, and acidosis ^[26][30]. Priapism-related pain is a cardinal feature of ischemia due to compartment syndrome. Interstitial edema of the corpora cavernosa develops by 12 h followed by endothelial destruction of sinusoids with thrombocyte adherence after 24 h ^[27][93]. Necrosis of cavernosal tissue and fibrosis have been observed by 48 h after onset of priapism ^[25][26][30,92].

History taking and physical examination are the first important steps when encountering cases of priapism. Assessment whether it is ischemic (low flow) or non-ischemic (high flow) in nature will determine the management pathway required.

Key questions when taking the history must focus on the duration of priapism (associated with the future risk of erectile dysfunction), on previous episodes of priapism (stuttering priapism), on underlying hematological disorders (e.g., sickle cell disease, which is the major cause of priapism in children), or a recent pelvic trauma (e.g., a straddle injury by a bicycle bar can cause high-flow priapism) ^[28][29][29,94]. Massive pain is typically associated with low-flow priapism. With a priapic penis, the patient may be writhing in pain; however, its absence is an unreliable indicator of ischemic priapism ^[30][24]. In contrast, high flow priapism never is associated with penile pain. Prescribed drugs causing priapism reported mostly in adults comprise antipsychotics (chlorpromazine, olanzapine, quetiapine, trazadone), PDE-5 inhibitors (sildenafil), anti-depressants, anti-hypertensives (including a-blockers), and depot testosterone, while illicit drugs also encountered in teenagers are cocaine, ecstasy, and marijuana ^[7][31][25,95].

Physical examination must not overlook any injury caused by a recent trauma to the patient’s pelvic, genital, or perineal areas possibly resulting in non-ischemic priapism. Also of note, the onset of non-ischemic priapism typically is delayed by a few days after the injury due to vessel spasm, formation of fistula, aneurysm, or a clot which is slowly resorbed ^[30][24]. Assessment of the penile rigidity may further help to discriminate the types of priapism. Unlike in a normal erection, the glans penis is typically not affected in either type of priapism and appears soft, while the corpora cavernosa are rigid in ischemic priapism compared to the less rigid state in non-ischemic priapism ^[7][25]. Concerning underlying hematological conditions, petechia due to thrombocytopenia and splenomegaly must not be overlooked (see Case Vignette #2) ^[32][41]. Besides priapism, the blood’s hyperviscosity in pediatric CML might cause visual impairment due to retinal papilledema and hemorrhages, hearing impairment, and pulmonary and CNS symptoms ^[33][52].

Among laboratory investigations, a full blood count and blood film will allow to identify underlying leukemias, sickle cell disease, and platelet disorders. A coagulation screen should identify patients with a hypercoagulable state. Urinalysis with toxicology screening may be helpful when searching for psychoactive drugs.

Penile blood aspiration (see next section) with blood gas testing and color duplex ultrasound are the two key techniques to discriminate high-flow (non-ischemic) from low-flow (ischemic priapism). Blood when aspirated from the corpus cavernosum in ischemic priapism has a dark color and blood gas testing exhibits values typical for hypoxia with low oxygen pressure, acidosis with low pH, and high carbon dioxide pressure (Figure 3). Non-ischemic values are similar to those of arterial blood (pO₂ > 90 mmHg, pCO₂ < 40 mmHg, pH 7.4). An animal study demonstrated that measuring glucose might aid in giving a prognosis of the reversibility of priapism as a low glucose predicts smooth muscle damage ^[26][30]. Whether this is appropriate in pediatric cases has not been investigated; however, in severe cases with a long duration of priapism, it may be considered and is easily performed if glucose values are part of the blood gas analysis tests.

Color duplex ultrasonography (CDU) is a non-invasive procedure detecting little or usually absent arterial flow through the cavernosal arteries in ischemic priapism, but high-flow in non-ischemic priapism ^[30][24]. CDU is a simple, reproducible, non-invasive, painless procedure which is helpful for guiding the management of priapism but requires expertise and may not be accessible in all emergency ambulances for 24 h per day. The up-front use of magnetic resonance imaging is time consuming, expensive, and not recommended; however, it can assess smooth muscle viability and predict erectile function restoration post-event ^[34][35][23,31]. Finally, elective pudenda arteriography can be diagnostic as well as therapeutic and, therefore, it should be reserved for the management of high-flow priapism when embolization is required ^[36][37].

Case vignette #2

Stuttering priapism in a 7-year-old boy with CML

Ongoingly over a period of 6–8 weeks[96, a 7-year-old prepubertal boy (Tanner stage 1) complained penile erections lasting for 7–8 h occurring once or twice weekly (stuttering priapism)100]. During this period the parents had presented the boy four times to different urologic and pediatric practitioners; however, when physically examined at the appointment, penile erection had resolved. No further diagnostics was initiated with the single exception of a urologist who recommended to contact a pediatric hemato-oncologist without delay. For unknown reasons, the parents did not follow this recommendation. Abdominal palpation was either not performed by the physicians, or had overlooked or not interpreted adequately the massive hepatosplenomegaly (liver 5 cm, spleen 7 cm below the costal arch) which the boy presented at hospital admission.

When another episode of priapism occurred, the boy was presented in the evening hours to the urology department at a university hospital where penile blood aspiration and irrigation without injection of sympathomimetics was performed and detumescence successfully achieved. The high WBC of 635 000/µL prompted the transfer to the department of pediatric hemato-oncology. Contact with the department of transfusion medicine was sought immediately and the apheresis equipment was transported to the pediatric intensity care unit (ICU). On the ICU following insertion of a catheter to the jugular vein, leukapheresis was initiated immediately with a flow rate of 3–5 mL per min over 4 h until midnight. A total blood volume of 2.1 L was processed (1.1-fold the calculated boy’s total blood volume of 1.9 L, bodyweight 23 kg), resulting in a decrease in the WBC to 450 000/µL. One unit of packed red cells was transfused in parallel to compensate the low Hb of 3.1 mmol/L (4.99 g/dL; Hct 14%) at presentation. No adverse events were observed. Cytarabine and hydroxyurea and allopurinol were started next morning and leukapheresis was repeated after 12 h with the intention to lower the risk of another episode of priapism. This brought down the WBC to 343/µL an no further episodes of priapism were noted.

After the diagnosis of pediatric CML was confirmed by FISH karyotyping showing the Major-BCR::ABL1 rearrangement, treatment with imatinib was initiated on the third day after admission When after one year of therapy, no optimal response according to the ELN recommendation was achieved, treatment was switched to the second generation TKI dasatinib which resulted in deep molecular response (MR4.5). In an interview performed with the patient when he was 20 years old, he indicated normal erectile function.

Case vignette #2 Stuttering priapism in a 7-year-old boy with CML Ongoingly over a period of 6–8 weeks, a 7-year-old prepubertal boy (Tanner stage 1) complained penile erections lasting for 7–8 h occurring once or twice weekly (stuttering priapism). During this period the parents had presented the boy four times to different urologic and pediatric practitioners; however, when physically examined at the appointment, penile erection had resolved. No further diagnostics was initiated with the single exception of a urologist who recommended to contact a pediatric hemato-oncologist without delay. For unknown reasons, the parents did not follow this recommendation. Abdominal palpation was either not performed by the physicians, or had overlooked or not interpreted adequately the massive hepatosplenomegaly (liver 5 cm, spleen 7 cm below the costal arch) which the boy presented at hospital admission. When another episode of priapism occurred, the boy was presented in the evening hours to the urology department at a university hospital where penile blood aspiration and irrigation without injection of sympathomimetics was performed and detumescence successfully achieved. The high WBC of 635 000/µL prompted the transfer to the department of pediatric hemato-oncology. Contact with the department of transfusion medicine was sought immediately and the apheresis equipment was transported to the pediatric intensity care unit (ICU). On the ICU following insertion of a catheter to the jugular vein, leukapheresis was initiated immediately with a flow rate of 3–5 mL per min over 4 h until midnight. A total blood volume of 2.1 L was processed (1.1-fold the calculated boy’s total blood volume of 1.9 L, bodyweight 23 kg), resulting in a decrease in the WBC to 450 000/µL. One unit of packed red cells was transfused in parallel to compensate the low Hb of 3.1 mmol/L (4.99 g/dL; Hct 14%) at presentation. No adverse events were observed. Cytarabine and hydroxyurea and allopurinol were started next morning and leukapheresis was repeated after 12 h with the intention to lower the risk of another episode of priapism. This brought down the WBC to 343/µL and no further episodes of priapism were noted. After the diagnosis of pediatric CML was confirmed by FISH karyotyping showing the Major-BCR::ABL1 rearrangement, treatment with imatinib was initiated on the third day after admission. When after one year of therapy, no optimal response according to the ELN recommendation was achieved, treatment was switched to the second generation TKI dasatinib which resulted in deep molecular response (MR4.5). In an interview performed with the patient when he was 20 years old, he indicated normal erectile function.

In adults with CML and priapism, initial therapeutic aspiration of blood for blood gas testing is combined with irrigation of heparinzed saline and/or intracavernous injection of phenyl-ephrine (adrenaline). After a tourniquet is applied to the base of the penis, a butterfly needle is inserted laterally through the penile skin in the middle of the shaft avoiding the urethra or dorsal neurovascular bundle. The procedure is outlined in more detail elsewhere ^[38][101]. In children and teenagers with CML presenting at the typical age of 4 -18 years old, these procedures should be performed under conscious sedation and with local anesthesia (penile block) ^[39][102]. If pediatric anesthetic expertise is readily available, dissociative sedation with low-dose ketamine, propofol, fentanyl, or morphine are the drugs of choice ^[40][103]. In particular, ketamine should be used preferentially as it may resolve priapism (see Supplement 1 ^{[41][42][43][44][45][46][47][48]}[104,105,106,107,108,109,110,111]).

To reduce skin bruising, passing the needle through the glans is recommended by some authors, although this may cause problems when subsequent distal shunt procedure is performed ^[30][24]. Unilateral aspiration is sufficient as the two penile corpora are interconnected. Using a three-way tap for repetitive flushing with saline allows to minimize needle passages. In pre-pubertal boys, a 21–23 gauge butterfly needle, and in adolescents, a bigger 19 gauge needle size is appropriate but problems may arise when clots have to be evacuated ^[39][49][102,112]. Aliquots of 3–5 mL of blood should be aspirated not exceeding a total volume of 30 mL (prepubertal) to 50 mL (adolescents) until the bright red color of oxygenated blood appears ^[30][49][24,112]. While some authors advocate repetitive aspirations with a maximum duration of one hour to achieve penile detumescence others recommend repeating irrigation only two or three times. On its own, aspiration has a success rate of approximately 30% ^[7][25]. If no permanent detumescence is achieved, immediate injection of adrenaline solution should follow ^[7][30][50][24,25,97]. In successful cases, applying pressure for several minutes after needle removal will reduce the hematoma rates ^[31][39][51][95,102,113]. Rare complications of cavernosal puncture include infection, urethral lesions, and non-ischemic priapism ^[30][24].

In the cohort described here, penile puncture was performed in 5 of 9 (55%) boys with analyzable data. Injection of sympathomimetics was required in four of the five patients. This is well in the range reported by other authors but evidently our cohort is too small for a more detailed comparison.

If ischemic priapism persists following aspiration and irrigation with saline, intracavernous injection of sympathomimetics should be performed. Cardiovascular monitoring (blood pressure, electrocardiogram) is strongly recommended as side effects due to peripheral vasoconstriction as well as positive inotropic and chronotropic effects on the heart may be possible. Rarely acute hypertension, reflex bradycardia, tachycardia, arrhythmias, and non-cardiologic side effects such as headache or dizziness have been observed ^[52][53][36,98]. As recommended by the American Urological Association guideline, phenylephrine—a selective alpha-1 adrenergic agonist which lacks beta-mediated cardiac ionotropic and chronotropic effects—is the sympathomimetic agent of choice due to its lower risk of cardiovascular side effects ^[54][55][114,115]. Other sympathomimetic agents that can be used are adrenaline or etilefrine, while metaraminol (a pure alpha-agonist) should not be used due to its high cardiovascular complication rate ^[56][116]. There are no direct comparative studies between these agents and there is no specific guidance on dosages for pediatric patients. As a pragmatic approach, JF Donaldson and coworkers recommend selection of the sympathomimetic to be used depending on what is readily available ^[30][24]. Suggested dosages, preparation of a saline solution, and the number of injections for different age groups until detumescence is achieved are listed as Supplemental Material (Supplement 2 [24,102,114]).

Repeated sympathomimetic injections with or without irrigation should always be undertaken prior to a decision for surgical intervention as they have a success rate of 43–81%. As outlined in a single center report, priapism in 71 adult patients was treated (among them 24 men with CML, mean duration of priapism 4.2 ± 1.4 days) with penile blood aspiration +/− phenylephrine irrigation. Operative shunt surgery had to be performed in 18 out of these 24 (75%) men ^[20][89]. In the cohort analyzed here, only one out of nine patients (Pat#2) with sufficient details reported on the management underwent operative shunt surgery after penile puncture and flushing had proven unsuccessful.