Bloody nipple discharge in 2 infants with interesting cytologic findings of extramedullary hematopoiesis and hemophagocytosis

Bloody Nipple Discharge in 2 Infants With Interesting

Cytologic Findings of Extramedullary Hematopoiesis

and Hemophagocytosis

Arzu Pampal, MD,* Aytac Gokoz, MD,w Tansu Sipahi, MD,z Handan Dogan, MD,w and

Ayca Torel Ergur, MDy

Summary: Bloody nipple discharge in the infantile period is an uncommon finding. Despite its stressful course to the parents, it is generally a benign condition with a spontaneous resolution. The approach to bloody nipple discharge in the infantile period is well documented in the literature even though the number of these cases is limited. We report 2 infants with unilateral bloody nipple discharge. Their physical examination, laboratory, and ultrasound findings were normal but the cytologic examinations of the discharge revealed signs of extramedullary hematopoiesis and hemophagocytosis. These extraordinary findings made us brainstorm on the probable ongoing processes in the infantile breast tissue.

Key Words: bloody nipple discharge, extramedullary hematopoiesis, hemophagocytosis, infant

(J Pediatr Hematol Oncol 2012;34:229–231)

M

ilky nipple discharge in the infantile period is a

known entity and generally due to either maternal

(placental transmitted) or fetal hormonal activity. It is a

transient period unless it accompanies an intraductal

papilloma or ductal ectasia of the mammary gland. On

the contrary, bloody nipple discharge in infantile period is

rather exceptional and limited number of patients are

presented in the literature.

However scary, it is a benign

condition with a spontaneous resolution. Despite the

limited data on the topic, the diagnostic work-up algorithm

for bloody nipple discharge is well presented in the

literature.

The aim of this study is to present 2 new cases of

infantile bloody nipple discharge. In order to reveal the

etiology, we also followed the algorithm presented in

the literature. The physical examination, laboratory, and

ultrasound findings of the either infant were normal but the

cytologic examinations of their bloody discharge revealed

signs of extramedullary hematopoiesis (EMH) and

hemo-phagocytosis. The EMH in infantile breast tissue has been

reported previously.

Besides, the findings of

hemopha-gocytosis are novel and these findings made us contemplate

on the probable ongoing processes in the infantile breast.

CASE REPORTS

Case Report 1

A 5-month-old girl presented to the pediatric and pediatric surgery clinics with an ongoing right-sided bloody nipple discharge for 3 weeks. There was no history of a local trauma or drug intake. Her prenatal history revealed oligohydramnios at the last weeks of gestation, but natal and postnatal histories were unremarkable. The girl was both breast and formula fed. The family history was negative for bleeding diathesis, breast cancer, or any endocrine/metabolic disorders. Her physical examination was totally normal with no signs of fever, lymphadenopathy, hepatosplenomegaly, and macular rash. The palpation of the breast was also normal with no signs of enlargement and mass. Mild pressure to the right upper quadrant of right breast revealed a painless bloody discharge at the nipple (Fig. 1A). Complete blood count, coagulation tests (prothrombin time: 13.9 s, activated partial thromboplastin time: 37 s), the liver and kidney functions tests (aspartate amino-transferase: 40 U/L, alanine transaminase: 41 U/L, blood urea nitrogen: 5 mg/dL, creatinine: 0.26 mg/dL), electrolyte levels, ferritin, triglyceride, and fibrinogen levels were within normal limits. Blood hormone levels of prolactin (10.28 ng/mL), follicle stimulating hormone (12.13 pg/mL), estradiol (5.71 U/L), and progesterone (0.15 ng/mL) were normal within values for her age. Bacterial culture of the discharge was negative. The ultrasound of the breast region revealed neither glandular hypertrophy nor asymmetry. The cytologic evaluation of the bloody discharge was interesting with the signs of EMH and hemophagocytosis. The smears prepared from the discharge revealed early bone marrow cells like normoblasts, metamyelocytes, myelocytes, megakaryocytes, and mature histiocytes with hemophagocytosis of erytrocytes, lymphocytes, and platelets (Fig. 1B-D). The girl was followed without any further intervention and the nipple discharge resolved spontaneously within 2 weeks.

Case Report 2

A 3-month-old girl presented to the pediatric and pediatric surgery clinics with an ongoing right-sided bloody and left-sided milky nipple discharge for 4 weeks. There was no history of a local trauma or drug intake. Her prenatal, natal, and postnatal history were unremarkable. The girl was breast fed. The family history was negative for bleeding diathesis, breast cancer, or any endocrine/ metabolic disorders. Her physical examination was totally normal with no signs of fever, lymphadenopathy, hepatosplenomegaly, and macular rash. The palpation of the breast was also normal. Mild pressure to the upper right quadrant of right breast revealed a painless bloody discharge at the nipple (Fig. 2A). Complete blood count, coagulation tests (prothrombin time: 15.4 s, activated partial throm-boplastin time: 39.3 s), the liver and kidney functions tests (aspartate aminotransferase: 42 U/L, alanine transaminase: 37 U/L, blood urea nitrogen: 5.85 mg/dL, creatinine: 0.20 mg/dL), electrolyte levels, ferritin, triglyceride, and fibrinogen levels were within normal limits. Blood hormone levels of prolactin (19.9 ng/mL) was normal within values for her age. Bacterial culture of the discharge was negative. The ultrasound of the breast region was normal. The cytologic evaluation of the bloody discharge revealed signs of EMH and hemophagocy-tosis. The smears prepared from the discharge revealed early bone Received for publication February 26, 2011; accepted June 7, 2011.

From the *Department of Paediatric Surgery; wDepartment of Pathology; zDepartment of Pediatric Haematology; and yDepart-ment of Pediatric Endocrinology, Ufuk University, Faculty of Medicine, Ankara, Turkey.

The authors declare no conflict of interest.

Reprints: Arzu Pampal, MD, Ufuk Universitesi, Tip Fakultesi, Cocuk Cerrahisi Bolumu, Konya Yolu No:86-88 Balgat 06520 Ankara, Turkey (e-mail: ademirtola@yahoo.com).

Copyrightr_{2011 by Lippincott Williams & Wilkins}

C

LINICAL AND

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ABORATORY

O

BSERVATIONS

marrow cells and mature histiocytes with hemophagocytosis (Figs. 2B-D). The girl was followed without any further intervention.

DISCUSSION

The term, EMH refers to the proliferation of erythroid

and myeloid lineage precursors with megakaryocytes at the

sites of the body other than bone marrow. This production

is generally needed to replace the body’s demand. During

the fetal life, hematopoiesis takes place in yolk sac and liver

as a physiological process. As a pathologic process, it is

generally associated with either bone marrow replacement

diseases like myelofibrosis and leukemia or hematological

disorders like thalassemia, sickle cell anemia, and

heredi-tary spherocytosis.

EMH is reported to take place in liver, spleen, lymph

nodes, thymus, kidney, breast, and connective tissue like

meninges, mesentery, lymph plexus, and retroperitoneum.

The first data of EMH in the infant’s breast tissue exists in

the literature as early as 1921.

In 1988, McKiernan et al

FIGURE 1. A, Unilateral bloody nipple discharge of the first case. B, Megakaryocytes in the smear prepared from the nipple discharge representing extramedullary hematopoiesis. C and D, Hemaphagocytosis of erythrocytes, lymphocytes, and platelets in the smears prepared from the nipple discharge representing hemophagocytosis (stained with Giemsa,  100).

FIGURE 2. A, Unilateral bloody nipple discharge of the second case. B, Megakaryocytes in the smear prepared from the nipple discharge representing extramedullary hematopoiesis. C and D, Hemaphagocytosis of normoblast, erythrocytes, and platelets in the smears prepared from the nipple discharge representing hemophagocytosis (stained with Giemsa,  100).

Pampal et al J Pediatr Hematol Oncol _{Volume 34, Number 3, April 2012}

presented their necropsy findings and demonstrated

primi-tive red and white cells at the histologic specimens of breast

indicating EMH in the infantile breast tissue. In 1992,

Anbazhagan et al

_{documented the existence of EMH at}

the periductal connective tissue in infants’ breast tissue.

They demonstrated prominent foci of hematopoiesis

histo-logically in 31% of infants <3.5 months of age. These foci

were found to consist of both immature erythroid cells and a

few myeloid elements. Megakaryocytes were demonstrated

in only 3.4% of infants of the same age group. They also

explained the disappearance of these cells with degeneration

of the mature cells depending on the findings of nuclear

karyorrhexis of the hematopoetic cells. In our cases, the

cytologic examinations of the bloody nipple discharges

revealed erytroid and myeloid precursors with

megakaryo-cytes, supporting an ongoing EMH in the breast. It is

assumed that as the infant grows the sites for EMH regress

and the persistence of EMH at the infantile period is

associated with premature births or stressful pre/perinatal

period.

The prenatal history of oligohydramnios of the

first case could have served as a stress factor and could be

the reason of prolonged EMH in the breast.

Hemophagocytosis is the phagocytosis of

hematopoie-tic cells by histiocytes. It is an isolated phenomenon that

can be seen either primarily or in secondary

hemophago-cytic syndrome.

Secondary hemophagocytic syndrome is

associated with a variety of situations like infections,

malignancy, and autoimmune diseases. In our cases, the

cytologic examinations of the discharges also revealed

mature histiocytes with hemophagocytosis of erytrocytes,

lymphocytes, and platelets. Neither physical examination

nor laboratory findings of the patients revealed any of the

aforementioned pathologies in our cases and the

hemopha-gocytosis of these cells in the discharge is thought to be a

probable way to eliminate the remnants of EMH in the

breast.

The English literature review revealed 25 infant cases

with bloody nipple discharge. Most of them presented with

either ductal ectasia or breast enlargement. Only 7 (28%) of

these patients revealed normal physical examination,

laboratory, and ultrasound findings.

_{These cases were}

diagnosed as bloody nipple discharge with an unclear

etiology but probably due to hormonal stimuli. The bloody

discharge was evaluated cytologically only in 5 of these

cases and these findings were reported as the existence of

macrophages and red blood cells in the discharge in 2

patients, amorphous protein material with histiocytes in 1

patient, abundant red cells in 1 patient, and as benign

cytology in 1 patient.

The pathophysiology of the bloody nipple discharge in

the infant period is still a mystery. The ongoing EMH in the

breast tissue in the infant period brings the mind the way of

its elimination. As the degeneration of the mature cells is

accepted as 1 way for elimination of EMH in the breast, the

findings of these cases suggest “hemophagocytosis” as the

other way.

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J Pediatr Hematol Oncol _{Volume 34, Number 3, April 2012 Bloody Nipple Discharge with Rare Cytologic Findings}