Are You Confident of the Diagnosis?
What you should be alert for in the history
Extramedullary hematopoiesis (EMH) normally develops during embryogenesis; however, when it occurs after birth EMH may be associated with other clinical scenarios that can be of concern. The liver and spleen are the most common organs for extramedullary hematopoiesis; however the skin can also be the first site of EMH in certain conditions.The diagnosis of cutaneous extramedullary hematopoiesis [EMH] cannot be made easily with just a detailed history and physical examination.
There are certain alarming conditions which should make you think about this entity. Stressful bone marrow conditions in children and adults are the most frequent conditions encountered.
The clinical presentation is usually one of erythematous to violaceous papules and nodules (Figure 1), with occasional plaques or ulcers. Rarely, it can also present as nasal polyps. When widely disseminated, as is seen most frequently in neonates, it can lead to the classic “blueberry muffin baby.”
This neonatal condition can be seen as a consequence of congenital viral infections or severe prenatal anemias. Serologic titers for the TORCHT (toxoplasmosis, rubells, cytomegalovirus and herpes virus), HIV, Parvovirus B19 and syphilitic infections are useful in evaluating neonatal EMH. Biopsy-proven dermal hematopoiesis is most often seen with rubella and cytomegalovirus infections. In the absence of any such history or laboratory confirmation of EMH, one should consider other disorders in the differential diagnosis.
EMH in the adult life is usually associated almost exclusively with the hematological disorder myelofibrosis. It can often occur in several organs under certain pathological conditions including spleen, liver, and skin, which are normal sites for EMH during embryogenesis, the skin being very uncommon. Other unusual locations include kidney, adrenal glands, testicles, pleura, and gastrointestinal tract.
Characteristic findings on physical examination
The majority of patients with EMH have classical clinical features of bone marrow dysfunction, including pallor, bruising, petechia, spontaneous bleeding of gums, splenomegaly, hepatomegaly, and bone pain etc. Malignant entities like granulocytic sarcoma can also present as tumornodules (Figure 1).
Expected results of diagnostic studies
Laboratory studies should be directed at confirming the diagnosis of EMH by checking a complete blood count (CBC), blood culture, bone marrow biopsy, flow cytometry, molecular studies, and rarely skin biopsy if necessary. In clinically obvious diseases, the diagnosis is usually straightforward, with anemia or polycythemia,thrombocytopenia or thrombocytosis, leukopenia or leukocytosis.
A skin biopsy is usually not necessary as a first-line diagnostic measure in the majority of the cases, with the exception of a few neonatal conditions like the blueberry muffin baby” or granulocytic sarcoma in adults. However, sometimes we perform skin biopsies as part of a new lesion work-up in patients with a previous history of hematological malignancies such as chronic myeloproliferative neoplasms (MPN), myelofibrosis, or relapsed acute leukemia. It is important to get an adequate portion of dermis by a punch or incisional biopsy to ensure that other conditions in the differential diagnosis are completely ruled out .
Histologically, the differential diagnosis of EMH is relatively limited. The most important distinctions are between EMH and disseminated congenital leukemia cutis and small blue cell neoplasms involving skin, including neuroblastoma, lymphoblastic lymphomas, and rarely Merkel cell carcinoma.
In EMH, all three hematopoietic elements (erythrocytes, leukocytes, and megakaryocytes) are represented, whereas in leukemias the cutaneous infiltrate is composed predominantly of immature monomorphous appearing leukocytes, many of which are cytologically atypical. In patients with overwhelming marrow involvement by leukemia, EMH can occur simultaneously with the leukemic involvement of skin, further complicating the differential diagnosis.
The most common association is with myelofibrosis, particularly after splenectomy.
Morpholobiogically, the dermal infiltrate (Figure 2) predominantly consists of myeloid and erythroid elements; with occasional clusters of megakaryocytes. Cells in all stages of maturation usually can be found. A skin biopsy shows perivascular monomorphous cellular infiltrates.
A variant associated with numerous megakaryocytes is known as a sclerosing extramedullary hematopoietic tumor. In this lesion, there are proliferating fibroblasts and collagen as well as hematopoietic elements. It may resemble a fibrohistiocytic tumor. Myeloid elements can be demonstrated with a naphthol ASD chloroacetate esterase stain (Leder stain) (Figure 3).
Myeloid elements can also be demonstrated with immunoperoxidase stains for myeloperoxidase, erythrocyte precursors with hemoglobin, glycophorin A (CD235a), and megakaryocytes with factor XIII, and factor VIII-related antigen. Other immunohistochemical markers include CD45, CD117, CD34, CD4, CD56, CD123, and special stains like PAS, Giemsa and toludine blue.
Who is at Risk for Developing this Disease?
EMH is most commonly seen in neonates secondary to underlying bone marrow stress, such as infections. It may occur in adults secondary to myelofibrosis or other myeloproliferative disorders or after splenectomy. It may also be seen in patient with severe anemia (including B12 and folate deficiency, or aplastic anemia) and in patients with hemoglobinopathies (including sickle cell anemia, hereditary spherocytosis, and thalassemia).
What is the Cause of the Disease?
The etiology of EMH is unknown. Recently overexpression of TGF-beta was detected by immunohistochemistry in hematopoietic cells and fibroblastswithin the dermal EMH mass of skin biopsy specimen. TGF-beta has been implicated in the adhesion of hematopoietic cells in the dermis. TGF-beta dysregulation could also contribute to fibroblast proliferation in the cutaneous EMH.
EMH is the production of blood elements away from the bone marrow. Up until the the 20th week of embyonic development, this occurs in the yolk sac and reticuloendothelial system; the bone marrow becomes the predominant source after that time. When the marrow can no longer produce blood elements, due to a host of conditions such as myelofibrosis or following infections such as the TORCH group, other organs with the capability of producing blood elements may compensate, resulting in EMH.
Systemic Implications and Complications
The systemic implications of EMH involve determining the nature of the underlying pathologic process resulting in the condition – does the patient have an infection, drug-induced aplastic anemia, a hemoglobinopathy, hemato-lymphoproliferative disorder, or myelofibrosis? All patients with EMH must be assessed for these diseases based on their clinical circumstances.
Treatment of underlying etiology results in reversal of the cutaneous process. Some of the treatments options include targeted chemotherapy, bone marrow or stem cell transplant in patients with underlying hematological disorder. In children with viral infections, management of underlying infection will resolve the skin lesions. Spontaneous resolution can also occur in some cases based on the simple fact that treatment of triggering factors will eventually resolve skin manifestations.
Optimal Therapeutic Approach for this Disease
The therapeutic approcah to cutaneous EMH is quite simple. The most important thing is to diagonose EMH. Once you know the reason for EMH, treatment of underlying etiology, if successful, will resolve EMH. All patients diagnosed with EMH should be referred promptly to a hematologist.
Successful treatment of the underlying condition will resolve the EMH in commonly encountered situations, such as managing viral infections in children and myeloproliferative neoplasms in adults.
Unusual Clinical Scenarios to Consider in Patient Management
Remember that extramedullary hematopoiesis can also be found incidentally in numerous unusual circumstances, like pyogenic granulomas and leg ulcers including Marjolin ulcers. However the same approach is used to diagnose and treat these conditions.
EMH has also been reported in pilomatrixomas and cutaneous hemangiomas.
What is the Evidence?
Kawakami, T. “Transforming growth factor-beta overexpression in cutaneous extramedullary hemaopoiesis of a patient with myelodysplastic syndrome associated with myelofibrosis”. J Am Acad Dermatol. vol. 58. 2008. pp. 703-6. (This is good review article explaining the pathobiology and possible mechanism of extramedullary hematopoiesis.)
Fraga, GR. “Cutaneous myelofibrosis with JAK2 V617F mutation: metastasis, not merely extramedullary hematopoiesis”. J Am Acad Dermatol. vol. 58. 2008. pp. 703-6. (This article explains the the differential diagnosis of cutaneous extramedulalry hematopoiesis with underlying history of chronic myeloproliferative neoplasms like primary myelobibrosis or chronic myelogenous leukemia.)
Lane, JE, Walker, A. “Cutaneous sclerosing extramedullary hematopoeitic tumor in chronic myelogenous leukemia”. J Cutan Pathol. vol. 29. 2002. pp. 608-612. (Extramedullary hematopoiesis is a well documented manifestation of chronic myeloproferative disorders, most commonly seen in chronic idiopathic myelofibrosis (agnogenic myeloid metaplasia), but rarely in chronic myelogenous leukemia.)
Vega Harring, SM. “Extramedullary hematopoiesis in pyogenic granuloma”. J Cutan Pathol. vol. 31. 2004. pp. 555-7. (This is good review explaining the existence of extramedullary hematopoiesis in unusual situations such as a pyogenic granuloma.)
Haniffa, MA, Wilkins, BS, Balsdale, C. “Cutaneous extramedullary hematopoiesis in chronic myeloproliferative and myelodysplastic disorders”. J Cutan Pathol. vol. 31. 2004. pp. 555-7. (This is an excellent review article explaining the etiology of extramedullary hematopoiesis.)
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