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878 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 879

secretion by the tumor. This assumption has been supported by the Normal hepatocytes, and to a lesser degree nonparenchymal liver cells,
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presence of erythropoietin mRNA in tumor cells. Wilms tumors produce small amounts of erythropoietin, both constitutively and in
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and paraganglioma are also occasionally associated with an erythro- response to hypoxia.
cytosis. Many of these cases may have a somatic VHL gene mutation Congenital Polycythemia and Pheochromocytoma Pheo-
that, in combination with a germline mutation of another allele, may chromocytomas have been described in association with congenital
constitute an unrecognized VHL syndrome. A patient with congenital erythrocytosis. In a growing number of reports, several individuals
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erythrocytosis and recurrent paraganglioma with a PHD2 mutation was with congenital polycythemia have developed recurrent pheochromo-
described. Tumor tissue exhibited a loss of heterozygosity of PHD2 in cytomas, paragangliomas, and sometimes somatistatinomas. 141–143 The
the tumor, suggesting that PHD2 could be a tumor-suppressor gene. 34 tumors in these patients are heterozygous for gain-of-function muta-
Partial obstruction of the renal artery would be expected to cause tions of the EPAS1 gene (encoding HIF-2α), and an erythropoietin tran-
renal tissue hypoxia and a physiologic stimulation of erythropoietin script is present in tumor tissues (Chaps. 32 and 57). Even though these
production. Nevertheless, it has proved quite difficult to induce erythro- tumors may be recurrent, they bear the same heterozygous mutations
cytosis in laboratory animals by placing a Goldblatt clamp on the renal of the EPAS1 gene. However, these mutations are generally not found in
arteries. Only a few of the many patients who have arteriosclerotic nontumor tissues, so the etiology of the association of these tumors with
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narrowing of the renal arteries have been reported to be polycythemic. 126 polycythemia is not certain; it is also possible that they may be associ-
Post–Renal Transplantation Erythrocytosis Although the full ated with postgonadal genetic mosaicism, wherein the EPAS1 mutation
molecular basis of post–renal transplant erythrocytosis remains predisposes to tumor development. 141–143 However, in one family the
unknown, angiotensin II (Chaps. 32 and 34) plays an important role in EPAS1 mutation was inherited and also associated with the develop-
its pathogenesis. Increased activity of the angiotensin II–angiotensin ment of recurrent pheochromocytomas/paragangliomas. 116
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receptor 1 pathway makes the erythroid progenitors hypersensitive to Endocrine Disorders Chapter 38 has additional discussion.
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angiotensin II. 128,129 Furthermore, angiotensin II can modulate release of Aldosterone-producing adenomas, Bartter syndrome, and
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erythropoiesis stimulatory factors (Chap. 32) including erythropoietin dermoid cyst of the ovary have been described in association with
and insulin-like growth factor (IGF)-1. 130,131 Studies of venous effluents erythrocytosis. Erythropoietin levels were found to be elevated in the
have determined that the native rather than the transplanted kidneys serum and returned to normal after extirpation of the tumors. A num-
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are the source of the inappropriate production of erythropoietin, and ber of pathogenetic mechanisms have been suggested (Chaps. 32 and
in some patients, removal of the native kidneys has led to rapid res- 38), including decreased plasma volume; mechanical interference with
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toration of normal hematocrit values. The condition is rarely seen in renal blood supply; hypertensive damage to renal parenchyma; func-
patients with nonrenal solid-organ allografts. The role of angiotensin II tional interaction between aldosterone, renin, and erythropoietin; and
in augmenting erythropoiesis was confirmed by anemia in angiotensin- inappropriate secretion of erythropoietin by the tumors. Mild poly-
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converting enzyme–knockout mice. Prior to the late 1990s when the cythemia may be present in patients with Cushing syndrome, but its
use of angiotensin-converting enzyme inhibitors increased as a means pathophysiologic basis is not entirely clear (Chap. 38).
to reduce proteinuria, the incidence of erythrocytosis in renal trans- The erythropoietic effect of androgens is of considerable practi-
plant patients was approximately 8 to 10 percent within the first 2 years cal importance. For many years, it was assumed that the higher red
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after engraftment. cell count in males was caused by androgens because the hemoglobin
Polycythemia with Connective Tissue Tumors Occasionally, levels of boys and girls were identical up until the time of puberty. It
there is an association of erythrocytosis with large uterine myomas. was not until pharmacologic doses of testosterone were administered to
35
Usually, the tumor has been huge and extirpation has routinely been fol- women with carcinoma of the breast that the full erythropoietic potency
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lowed by a hematologic “cure.” The suggestion that the tumor interferes of androgens was appreciated. Since then, various androgen prepara-
with pulmonary ventilation has not been supported by the normal arte- tions have been used in the treatment of refractory anemia, occasionally
rial blood gas findings in the few patients so studied. Another possible causing dramatic erythropoiesis, with hemoglobin values climbing into
mechanism is that the large abdominal mass causes mechanical inter- the polycythemic range (Fig. 57–5).
ference with the blood supply to the kidneys, resulting in renal hypoxia The mechanism of androgen action on erythropoiesis appears to
and erythropoietin production. Inappropriate erythropoietin secretion be complex, related both to their capacity to stimulate erythropoietin
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by smooth muscle cells has been demonstrated both in uterine myomas production and their capacity to induce differentiation of marrow
and in one case of cutaneous leiomyoma. 35,135 Rare cases of polycythe- stem cells directly. These two effects have specific structural require-
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mia attributed to a myxoma of the atrium, hamartoma of the liver, ments. Androgens with the 5α-H configuration stimulate renal and
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and focal hyperplasia of the liver have been documented. extrarenal erythropoietin production, whereas androgens with the
Brain Tumors In adequately studied patients with erythrocytosis 5β-H configuration enhance the differentiation of stem cells. Testos-
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and cerebellar hemangiomas, arterial blood gas tensions have been nor- terone administration is associated with an increase in erythropoietin
mal. That the tumors are directly responsible for the polycythemia can levels and a decrease in hepcidin levels. Although erythropoietin lev-
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be surmised from the identification of erythropoietin in cyst fluid and els declined with continued testosterone administration, they remained
stromal cells and from a case in which erythropoietin mRNA was pres- inappropriately high despite improved hemoglobin levels, suggesting a
ent in the tumor. Although in these cases a mutation of the VHL gene new set point. 150
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was not sought, it is likely that these tumors were a manifestation of an Neonatal Polycythemia Polycythemia at birth is a normal physi-
underlying VHL syndrome as cerebellar hemangiomas are an integral ologic response to intrauterine hypoxia and to the high oxygen affinity
feature of VHL syndrome. of red cells containing very high proportions of hemoglobin F (Chap. 7).
Hepatoma In 1958, McFadzean and coworkers reported that It may become excessive and even symptomatic, especially in infants
almost 10 percent of patients in Hong Kong with hepatocellular carci- of diabetic mothers, or if the clamping of the cord is delayed, permit-
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noma developed erythrocytosis. Since then, this association has been ting placental blood to boost the blood volume of the infant. Because
recognized as an important clinical clue in the diagnostic consideration it is difficult to recognize symptoms of hyperviscosity in the neonate,
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of patients with liver disease. The cause of erythrocytosis is probably many pediatricians perform a partial plasma exchange transfusion if the
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inappropriate production of erythropoietin by the neoplastic cells. venous hematocrit is above 65 percent at birth. 152

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