J Cutan Pathol 2015: 42: 858–862 doi: 10.1111/cup.12553 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
JAK2-positive cutaneous myelofibrosis presenting as sclerosing extramedullary hematopoietic tumors on the scalp: case presentation and review of the literature We report the second case of cutaneous myelofibrosis with a documented JAK2 activating mutation involving the scalp of a 67-year-old woman with primary myelofibrosis in her marrow. In contrast to the previous case, the biopsy revealed extensive lesional collagen deposition and closely mimicked a fibrohistiocytic proliferation. Similar rare lesions occurring in the setting of myeloproliferative neoplasms have been called sclerosing extramedullary hematopoietic tumors. These entities appear histomorphologically and etiologically distinct from extramedullary hematopoiesis, and their diagnosis should prompt the workup for a myeloproliferative neoplasm in the absence of an antecedent diagnosis. The presence of the JAK2 mutation in our case confirmed that the lesions represented skin involvement by a neoplastic myeloid proliferation and not compensatory extramedullary hematopoiesis. Our patient died of disease several months following the appearance of her lesions, which is in keeping with other reports that suggest that cutaneous myelofibrosis may serve as an independent poor prognostic sign in otherwise advanced primary myelofibrosis. A review of the literature further emphasizes the importance of distinguishing this entity from mesenchymal neoplasms and acute myeloid leukemia involving the skin. Keywords: cutaneous myelofibrosis, extramedullary hematopoiesis, JAK2, myeloproliferative neoplasia, sclerosing extramedullary hematopoietic tumor LeBlanc RE, Lester L, Kwong B, Rieger KE. JAK2-positive cutaneous myelofibrosis presenting as sclerosing extramedullary hematopoietic tumors on the scalp: case presentation and review of the literature. J Cutan Pathol 2015; 42: 858–862. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
858
Robert E. LeBlanc1 , Laura Lester1 , Bernice Kwong2 and Kerri E. Rieger1,2 1
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA and 2 Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
Kerri E. Rieger, MD, PhD, Department of Pathology, Stanford University School of Medicine, Room H2110, 300 Pasteur Drive, Stanford, CA 94305, USA Tel: +650 498 7398 Fax: +650 725 7409 e-mail: [email protected] Accepted for publication June 21, 2015
JAK2 positive cutaneous myelofibrosis Extramedullary hematopoiesis is defined as the production of one or more normal blood elements outside of the marrow. Whereas this occurs as a normal physiological process of embryogenesis, it occurs as a pathologic and compensatory physiologic phenomenon in limited settings. In neonates, extramedullary hematopoiesis most often occurs in response to a host of intrauterine viral infections and hemoglobinopathies. In these settings, it is not uncommon to witness skin involvement as scattered violaceous papules and nodules that evoke the nomenclature ‘blueberry muffin baby.’ In adults, extramedullary hematopoiesis occurs in chronic anemia in the settings of myeloid neoplasia and myelophthisic processes. It is commonly encountered in myeloproliferative neoplasms including primary myelofibrosis (PMF). When extramedullary hematopoiesis occurs in adults, the skin is an exceedingly rare site of involvement.1 In contrast to extramedullary hematopoiesis are rare reports of extramedullary dissemination of neoplastic myeloid proliferations in patients with known myeloproliferative diseases. These lesions resemble their neoplastic counterparts in the marrow instead of recapitulating normal trilineage hematopoiesis and maturation. Only in exceedingly rare case reports have molecular studies been performed on tissue biopsies to confirm their presumptive clonal neoplastic origins. A subset of these entities, termed sclerosing extramedullary hematopoietic tumors (SEMHT), is associated with stromal fibrosis that may be analogous to the myelofibrosis that occurs in advanced stage myeloproliferative neoplasms. Consequently, these extramedullary lesions may easily be mistaken for mesenchymal neoplasms. Whereas a majority of cases reported have involved visceral organs, mesentery, and retroperitoneum, there are rare reported cases in the skin including one that arose in the setting of undiagnosed chronic myelogenous leukemia.2 There has been one other report of documented JAK2 V617F mutated PMF involving the skin; however, this case lacked features of SEMHT.3 We present the first molecularly annotated case of cutaneous myelofibrosis presenting as SEMHT in a patient with PMF and harboring the JAK2 V617F activating mutation in both the marrow and skin lesions. Report of a patient A 67-year-old woman presented with increasing numbers of asymptomatic nodules on her scalp
Fig. 1. The scalp biopsy showed a cellular and fibrotic spindle cell proliferation filling the reticular dermis and infiltrating the subcutaneous adipose tissue.
that had arisen over the preceding months. She had a history of PMF with a confirmed JAK2 V617F activating genetic mutation diagnosed 2 years prior to the onset of her skin lesions. Her marrow biopsy from a month earlier had revealed grade 3 marrow fibrosis (MF-3) with no increase in blasts or associated karyotypic abnormalities. On examination she had numerous palpable, non-tender and mobile subcutaneous nodules measuring 8–10 mm over her frontal scalp. She had no other skin complaints and her remaining examination was unremarkable. A 4-mm punch biopsy was obtained from a nodule on her frontal scalp and sent for routine histologic evaluation with a clinical differential diagnosis of leukemia cutis and trichilemmal (pilar) cyst. Histologic sections through the scalp specimen revealed a poorly delineated, markedly cellular spindle cell proliferation filling the reticular dermis with extension to the subcutaneous fibroadipose tissue and splaying of adipocyte lobules (Fig. 1). The proliferation spared the epidermis, superficial dermis and intervening adnexal structures. Higher power magnification revealed a preponderance of large cells with abundant cytoplasm compressed between the dense, intervening collagen fibers. The large cells had pleomorphic, often bizarrely contoured nuclear membranes (Fig. 2). Rare multinucleated forms were appreciated. Accompanying the enlarged atypical cells were loose aggregates of immature myeloid cells and scattered erythroid precursors that were most noticeable in the vicinity of blood vessels (Fig. 3). Myeloperoxidase staining elaborated a majority of the cells comprising the infiltrate and
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LeBlanc et al.
Fig. 2. Higher power magnification revealed spindled cells set in a fibrotic stroma with occasional admixed plump cells. Myeloperoxidase (MPO) highlighted a majority of cells, confirming granulocytic lineage (inset).
Fig. 3. Numerous immature granulocytes (thick arrows) and nucleated red blood cells (thin arrows) were clustered around blood vessels. Glycophorin C highlighted the scattered erythroid forms (inset).
confirmed their myeloid origin (Fig. 2, inset). Glycophorin C highlighted scattered, immature erythroid cells (Fig. 3, inset). No well-formed erythroid islands were identified by immunohistochemistry. CD61 and Factor VIII stained the enlarged, markedly atypical cells confirming megakaryocytic differentiation (Fig. 4, inset). CD163 highlighted accompanying histiocytes but not the enlarged megakaryocytic forms. CD34 highlighted very rare cells comprising less than 1% of the total infiltrate, thus providing no evidence of acute myeloid leukemia. Mixed cytokeratin cocktail and S100 were both negative; and Factor XIIIa stained numerous background dermal dendritic cells and showed patchy, equivocal labeling of the large atypical cells. Trichrome staining revealed extensive dermal and subcutaneous collagen deposition (Fig. 5). The JAK2 V617F mutation was showed by real time polymerase chain reaction
860
Fig. 4. The atypical appearing giant cells were positive for Factor VIII (inset), a cytoplasmic stain for megakaryocytes.
Fig. 5. Trichrome staining illustrated extensive dermal and subcutaneous collagen deposition.
(PCR) performed on the formalin-fixed paraffin embedded scalp biopsy specimen. The histomorphology was diagnostic of SEMHT and represented cutaneous involvement by PMF given that it harbored the same mutation that was seen in the marrow. A month following her skin biopsy, the patient underwent repeat bone marrow biopsy revealing MF-3 fibrosis with 3% blasts. A concurrent peripheral blood examination with manual differential revealed a leukoerythroblastic smear with 5% circulating blasts. These findings provided no evidence of progression to an acute leukemia; however, the patient died of her disease approximately 4 months following her scalp biopsy and less than a year from the onset of her cutaneous involvement. Discussion The World Health Organization defines PMF as a clonal myeloproliferative neoplasm comprised of dysmorphic megakaryocytes and granulocytes
JAK2 positive cutaneous myelofibrosis within the bone marrow. PMF progresses from a prefibrotic phase with marrow hypercellularity and mildly left-shifted myelopoiesis that can evade diagnosis for decades to a fibrotic phase characterized by marked reticulin or collagen fibrosis and a median survival of 3–7 years.4 Other adverse prognostic indicators include age over 70 years, hemoglobin less than 10 g/dl, platelet count less than 100 × 106/l and an abnormal karyotype.4 Splenic involvement is not considered an adverse prognostic indicator although it is often an incidental finding that prompts systemic workup and diagnosis.4 Mortality is often attributable to infection and coagulopathy secondary to marrow failure, thrombotic events or progression to acute myeloid leukemia (AML).4 AML is diagnosed in 5–30% of cases.4 Whereas some of these cases are by definition therapy-related AML, leukemic progression has been seen in cases of PMF in patients who have not undergone cytotoxic therapies, suggesting that AML is part of the natural disease progression of PMF.4 A large subset of myeloproliferative neoplasms are associated with an acquired V617F JAK2 mutation.4 Whereas other mutations have been associated with small subsets of PMF including MPL 4 and recently CALR,5 JAK2 is seen in 50–60% of cases.4,6 This mutation is seldom present in leukemias and myelodysplastic syndrome.4,6 Although 30 cases of cutaneous extramedullary hematopoiesis have been reported in the setting of myeloproliferative neoplasms,7,8 beginning with the observations of Hickling9 only one case prior has been shown to possess the JAK2 mutation.3 In most of these other rare reported cases there have been dysmorphic megakaryocytes and myeloid progenitors with sparse immature erythroid elements elaborated with immunohistochemistry.3 The dysmorphic features present in these reported cases lend credence to the hypothesis that they represented neoplastic involvement of the skin and not compensatory extramedullary hematopoiesis despite the lack of molecular confirmation. The pathogenesis of splenomegaly in PMF has been attributed to the sequestration and proliferation of clonally involved circulating progenitor cells. The progenitor cells are mobilized from the bone marrow because of impaired adhesion to the marrow stroma and allowed to circulate and colonize extramedullary sites.10,11 The extramedullary hematopoietic cells of the spleen in PMF have been found to frequently carry the JAK2 V617F mutation and to have a
high rate of concordance with the genotype and karyotype of the disease in the marrow.12,13 The presence of the JAK2 V617F mutation in the cutaneous lesions of our patient and in a previously reported patient with PMF3 suggests that the cutaneous findings in PMF may also result from sequestration and proliferation of clonally involved circulating progenitor cells as occurs in the spleen. The reason for colonization of the skin by these progenitor cells remains to be elucidated. Given the evidence that extramedullary proliferations of hematopoietic cells in PMF represent dissemination of the neoplastic clone and not compensatory extramedullary hematopoiesis, there is debate over the appropriate nomenclature for when this phenomenon occurs in the skin. Hoss and McNutt proposed the term ‘cutaneous myelofibrosis’ arguing that ‘extramedullary hematopoiesis’ should be reserved for compensatory hematopoiesis in the absence of morphologic and molecular abnormalities.14 O’Malley et al. proposed ‘neoplastic myeloid proliferation’ for cutaneous myeloid proliferations driven by genetic mutation.13 Fraga and Caughron suggested that this same cutaneous finding be interpreted as metastatic disease.3 We favor the term cutaneous myelofibrosis as it would prompt workup for systemic disease in the absence of an antecedent diagnosis and could potentially impart prognostic information; this is the second report of shortened survival in a patient with cutaneous myelofibrosis, and non-splenic SEMHT in the setting of myelofibrosis are associated with death within months of diagnosis as compared to the median overall survival of 3–7 years of patients with fibrosis stage PMF.1,4 More data will be helpful in determining whether or not cutaneous clonal disease manifestations in PMF are indeed an independent poor prognostic sign. We report the first case of cutaneous myelofibrosis in the skin with a documented JAK2 mutation and SEMHT morphology. The single prior case of cutaneous myelofibrosis with a documented JAK2 mutation consisted of a nodular infiltrate of myeloid cells and megakaryocytes.3 While we consider both cases to be cutaneous myelofibrosis, our case is unique and challenging in that the morphology could have been easily misconstrued as a mesenchymal neoplasm. Histomorphologically, SEMHT are characterized by a proliferation of atypical megakaryocytes and variable proportions of granulocytic and erythroid precursors comprising a mass with pronounced accompanying fibrosis.15,16 These
861
LeBlanc et al. tumors arise in the setting of myeloproliferative neoplasms and are exceedingly rare in the skin, being more often reported in the retroperitoneum, mesentery, lymph nodes, lung, liver, breast, kidney, adrenal gland and lacrimal gland.15 – 18 As the bone marrow fibrosis in PMF has been found to occur in response to cytokines such as TGF-beta secreted by clonal megakaryocytes, it is not surprising that extramedullary hematopoiesis involving these same atypical megakaryocytes may induce a similar fibrotic stroma at other anatomic locations.16 The importance of SEMHT lies in the histologic differential diagnosis that includes sarcomas and fibrohistiocytic proliferations, spindle cell variant of squamous cell carcinoma, melanoma, poorly differentiated carcinomas, inflammatory and sclerosing diseases, Hodgkin lymphoma and leukemia cutis. The distinct immunophenotypes of these entities and clinicopathologic correlation should allow for a correct diagnosis. Although the megakaryocytes of PMF are often described as bulbous or cloud-shaped, fibrosis can result in cytologic distortion as illustrated in our case. Bare megakaryocytic nuclei are a common finding and numerous small forms can often be elucidated by immunohistochemistry with CD61 or Factor VIII. As in the marrow, acute leukemic involvement
should be excluded in cutaneous manifestations. This may be aided by CD34, CD117 and TdT immunostains to highlight blasts amidst fibrosis and the predominant megakaryocytic and early myeloid populations. Vimentin staining in SEMHT should be avoided as it will highlight the abundant accompanying fibroblasts, which have been shown to be polyclonal.19 Factor XIIIa staining may similarly highlight the accompanying dermal dendritic cells and contribute to a misdiagnosis of dermatofibroma or dermatofibrosarcoma protuberans. In summary, we reported an exceedingly rare case of cutaneous myelofibrosis exhibiting the JAK2 V617F activating mutation in a patient with a history of PMF. This is the second case to be reported and is unique in that it showed SEMHT morphology, raising a differential diagnosis that included mesenchymal neoplasms and AML. Recognition of these rare lesions is important to direct appropriate therapy, which entails the search for underlying systemic disease in the absence of an antecedent diagnosis. As in the previously reported case, our patient had a shortened survival following the appearance of her skin lesions despite an absence of other independent high-risk features, thus raising the possibility that cutaneous myelofibrosis may be a poor prognostic sign.
References 1. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003; 78: 1223. 2. Lane JE, Walker AN, Kulharya A, Marzec T. Cutaneous sclerosing extramedullary hematopoietic tumor in chronic myelogenous leukemia. J Cutan Pathol 2002; 29: 608. 3. Fraga GR, Caughron SK. Cutaneous myelofibrosis with JAK2 V617F mutation: metastasis, not merely extramedullary hematopoiesis!. Am J Dermatopathol 2010; 32: 727. 4. Vardiman JWMJ, Baccarani M, et al. Myeloproliferative neoplasms. In Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classification of tumours of haematopoietic and lymphoid tissues, 4th ed. Geneva: WHO Press, 2008. 5. Medinger M, Passweg J. Angiogenesis in myeloproliferative neoplasms, new markers and future directions. Memo 2014; 7: 206. 6. Muxi PJ, Oliver AC. Jak-2 positive myeloproliferative neoplasms. Curr Treat Options Oncol 2014; 15: 147. 7. Corella F, Barnadas MA, Bordes R, et al. A case of cutaneous extramedullary
862
8.
9. 10.
11.
12.
13.
hematopoiesis associated with idiopathic myelofibrosis. Actas Dermosifiliogr 2008; 99: 297. Miyata T, Masuzawa M, Katsuoka K, Higashihara M. Cutaneous extramedullary hematopoiesis in a patient with idiopathic myelofibrosis. J Dermatol 2008; 35: 456. Hickling RA. Chronic non-leukemic myelosis. Quart J Med 1937; 6: 253. Rosti VMM, Vannucchi AM, et al. The expression of CXCR4 is down-regulated on the CD34+ cells of patients with myelofibrosis with myeloid metaplasia. Blood Cell Mol Dis 2007; 38: 280. Xu MBE, Chao J, et al. Constitutive mobilization of CD34+ stem cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases. Blood 2005; 105: 4508. Hsieh PPOR, O’Malley DP, et al. The role of Jak Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders. Mod Pathol 2007; 20: 929. O’Malley DP, Orazi A, Wang M, Cheng L. Analysis of loss of heterozygosity and X chromosome inactivation in spleens with myeloproliferative disorders and acute myeloid leukemia. Mod Pathol 2005; 18: 1562.
14. Hoss DM, MuNutt NS. Cutaneous myelofibrosis. J Cutan Pathol 1992; 19: 221. 15. Gualco G, Ojopi EB, Chioato L, Cordeiro DL, Negretti F, Bacchi CE. Postsplenectomy sclerosing extramedullary hematopoietic tumor with unexpected good clinical evolution: morphologic, immunohistochemical, and molecular analysis of one case and review of the literature. Appl Immunohistochem Mol Morphol 2010; 18: 291. 16. Remstein ED, Kurtin PJ, Nascimento AG. Sclerosing extramedullary hematopoietic tumor in chronic myeloproliferative disorders. Am J Surg Pathol 2000; 24: 51. 17. Ghazi NG, Bowman AM, Shields MD. Bilateral lacrimal system involvement by sclerosing extramedullary hematopoietic tumor. Ophthal Plast Reconstr Surg 2006; 22: 296. 18. Yang X, Bhuiya T, Esposito M. Sclerosing extramedullary hematopoietic tumor. Ann Diagn Pathol 2002; 6: 183. 19. Castro-Malaspina H, Rabellino EM, Yen A, Nachman RL, Moore MA. Human megakaryocyte stimulation of proliferation of bone marrow fibroblasts. Blood 1981; 57: 781.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
JAK2-positive cutaneous myelofibrosis presenting as sclerosing extramedullary hematopoietic tumors on the scalp: case presentation and review of the literature We report the second case of cutaneous myelofibrosis with a documented JAK2 activating mutation involving the scalp of a 67-year-old woman with primary myelofibrosis in her marrow. In contrast to the previous case, the biopsy revealed extensive lesional collagen deposition and closely mimicked a fibrohistiocytic proliferation. Similar rare lesions occurring in the setting of myeloproliferative neoplasms have been called sclerosing extramedullary hematopoietic tumors. These entities appear histomorphologically and etiologically distinct from extramedullary hematopoiesis, and their diagnosis should prompt the workup for a myeloproliferative neoplasm in the absence of an antecedent diagnosis. The presence of the JAK2 mutation in our case confirmed that the lesions represented skin involvement by a neoplastic myeloid proliferation and not compensatory extramedullary hematopoiesis. Our patient died of disease several months following the appearance of her lesions, which is in keeping with other reports that suggest that cutaneous myelofibrosis may serve as an independent poor prognostic sign in otherwise advanced primary myelofibrosis. A review of the literature further emphasizes the importance of distinguishing this entity from mesenchymal neoplasms and acute myeloid leukemia involving the skin. Keywords: cutaneous myelofibrosis, extramedullary hematopoiesis, JAK2, myeloproliferative neoplasia, sclerosing extramedullary hematopoietic tumor LeBlanc RE, Lester L, Kwong B, Rieger KE. JAK2-positive cutaneous myelofibrosis presenting as sclerosing extramedullary hematopoietic tumors on the scalp: case presentation and review of the literature. J Cutan Pathol 2015; 42: 858–862. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
858
Robert E. LeBlanc1 , Laura Lester1 , Bernice Kwong2 and Kerri E. Rieger1,2 1
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA and 2 Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
Kerri E. Rieger, MD, PhD, Department of Pathology, Stanford University School of Medicine, Room H2110, 300 Pasteur Drive, Stanford, CA 94305, USA Tel: +650 498 7398 Fax: +650 725 7409 e-mail: [email protected] Accepted for publication June 21, 2015
JAK2 positive cutaneous myelofibrosis Extramedullary hematopoiesis is defined as the production of one or more normal blood elements outside of the marrow. Whereas this occurs as a normal physiological process of embryogenesis, it occurs as a pathologic and compensatory physiologic phenomenon in limited settings. In neonates, extramedullary hematopoiesis most often occurs in response to a host of intrauterine viral infections and hemoglobinopathies. In these settings, it is not uncommon to witness skin involvement as scattered violaceous papules and nodules that evoke the nomenclature ‘blueberry muffin baby.’ In adults, extramedullary hematopoiesis occurs in chronic anemia in the settings of myeloid neoplasia and myelophthisic processes. It is commonly encountered in myeloproliferative neoplasms including primary myelofibrosis (PMF). When extramedullary hematopoiesis occurs in adults, the skin is an exceedingly rare site of involvement.1 In contrast to extramedullary hematopoiesis are rare reports of extramedullary dissemination of neoplastic myeloid proliferations in patients with known myeloproliferative diseases. These lesions resemble their neoplastic counterparts in the marrow instead of recapitulating normal trilineage hematopoiesis and maturation. Only in exceedingly rare case reports have molecular studies been performed on tissue biopsies to confirm their presumptive clonal neoplastic origins. A subset of these entities, termed sclerosing extramedullary hematopoietic tumors (SEMHT), is associated with stromal fibrosis that may be analogous to the myelofibrosis that occurs in advanced stage myeloproliferative neoplasms. Consequently, these extramedullary lesions may easily be mistaken for mesenchymal neoplasms. Whereas a majority of cases reported have involved visceral organs, mesentery, and retroperitoneum, there are rare reported cases in the skin including one that arose in the setting of undiagnosed chronic myelogenous leukemia.2 There has been one other report of documented JAK2 V617F mutated PMF involving the skin; however, this case lacked features of SEMHT.3 We present the first molecularly annotated case of cutaneous myelofibrosis presenting as SEMHT in a patient with PMF and harboring the JAK2 V617F activating mutation in both the marrow and skin lesions. Report of a patient A 67-year-old woman presented with increasing numbers of asymptomatic nodules on her scalp
Fig. 1. The scalp biopsy showed a cellular and fibrotic spindle cell proliferation filling the reticular dermis and infiltrating the subcutaneous adipose tissue.
that had arisen over the preceding months. She had a history of PMF with a confirmed JAK2 V617F activating genetic mutation diagnosed 2 years prior to the onset of her skin lesions. Her marrow biopsy from a month earlier had revealed grade 3 marrow fibrosis (MF-3) with no increase in blasts or associated karyotypic abnormalities. On examination she had numerous palpable, non-tender and mobile subcutaneous nodules measuring 8–10 mm over her frontal scalp. She had no other skin complaints and her remaining examination was unremarkable. A 4-mm punch biopsy was obtained from a nodule on her frontal scalp and sent for routine histologic evaluation with a clinical differential diagnosis of leukemia cutis and trichilemmal (pilar) cyst. Histologic sections through the scalp specimen revealed a poorly delineated, markedly cellular spindle cell proliferation filling the reticular dermis with extension to the subcutaneous fibroadipose tissue and splaying of adipocyte lobules (Fig. 1). The proliferation spared the epidermis, superficial dermis and intervening adnexal structures. Higher power magnification revealed a preponderance of large cells with abundant cytoplasm compressed between the dense, intervening collagen fibers. The large cells had pleomorphic, often bizarrely contoured nuclear membranes (Fig. 2). Rare multinucleated forms were appreciated. Accompanying the enlarged atypical cells were loose aggregates of immature myeloid cells and scattered erythroid precursors that were most noticeable in the vicinity of blood vessels (Fig. 3). Myeloperoxidase staining elaborated a majority of the cells comprising the infiltrate and
859
LeBlanc et al.
Fig. 2. Higher power magnification revealed spindled cells set in a fibrotic stroma with occasional admixed plump cells. Myeloperoxidase (MPO) highlighted a majority of cells, confirming granulocytic lineage (inset).
Fig. 3. Numerous immature granulocytes (thick arrows) and nucleated red blood cells (thin arrows) were clustered around blood vessels. Glycophorin C highlighted the scattered erythroid forms (inset).
confirmed their myeloid origin (Fig. 2, inset). Glycophorin C highlighted scattered, immature erythroid cells (Fig. 3, inset). No well-formed erythroid islands were identified by immunohistochemistry. CD61 and Factor VIII stained the enlarged, markedly atypical cells confirming megakaryocytic differentiation (Fig. 4, inset). CD163 highlighted accompanying histiocytes but not the enlarged megakaryocytic forms. CD34 highlighted very rare cells comprising less than 1% of the total infiltrate, thus providing no evidence of acute myeloid leukemia. Mixed cytokeratin cocktail and S100 were both negative; and Factor XIIIa stained numerous background dermal dendritic cells and showed patchy, equivocal labeling of the large atypical cells. Trichrome staining revealed extensive dermal and subcutaneous collagen deposition (Fig. 5). The JAK2 V617F mutation was showed by real time polymerase chain reaction
860
Fig. 4. The atypical appearing giant cells were positive for Factor VIII (inset), a cytoplasmic stain for megakaryocytes.
Fig. 5. Trichrome staining illustrated extensive dermal and subcutaneous collagen deposition.
(PCR) performed on the formalin-fixed paraffin embedded scalp biopsy specimen. The histomorphology was diagnostic of SEMHT and represented cutaneous involvement by PMF given that it harbored the same mutation that was seen in the marrow. A month following her skin biopsy, the patient underwent repeat bone marrow biopsy revealing MF-3 fibrosis with 3% blasts. A concurrent peripheral blood examination with manual differential revealed a leukoerythroblastic smear with 5% circulating blasts. These findings provided no evidence of progression to an acute leukemia; however, the patient died of her disease approximately 4 months following her scalp biopsy and less than a year from the onset of her cutaneous involvement. Discussion The World Health Organization defines PMF as a clonal myeloproliferative neoplasm comprised of dysmorphic megakaryocytes and granulocytes
JAK2 positive cutaneous myelofibrosis within the bone marrow. PMF progresses from a prefibrotic phase with marrow hypercellularity and mildly left-shifted myelopoiesis that can evade diagnosis for decades to a fibrotic phase characterized by marked reticulin or collagen fibrosis and a median survival of 3–7 years.4 Other adverse prognostic indicators include age over 70 years, hemoglobin less than 10 g/dl, platelet count less than 100 × 106/l and an abnormal karyotype.4 Splenic involvement is not considered an adverse prognostic indicator although it is often an incidental finding that prompts systemic workup and diagnosis.4 Mortality is often attributable to infection and coagulopathy secondary to marrow failure, thrombotic events or progression to acute myeloid leukemia (AML).4 AML is diagnosed in 5–30% of cases.4 Whereas some of these cases are by definition therapy-related AML, leukemic progression has been seen in cases of PMF in patients who have not undergone cytotoxic therapies, suggesting that AML is part of the natural disease progression of PMF.4 A large subset of myeloproliferative neoplasms are associated with an acquired V617F JAK2 mutation.4 Whereas other mutations have been associated with small subsets of PMF including MPL 4 and recently CALR,5 JAK2 is seen in 50–60% of cases.4,6 This mutation is seldom present in leukemias and myelodysplastic syndrome.4,6 Although 30 cases of cutaneous extramedullary hematopoiesis have been reported in the setting of myeloproliferative neoplasms,7,8 beginning with the observations of Hickling9 only one case prior has been shown to possess the JAK2 mutation.3 In most of these other rare reported cases there have been dysmorphic megakaryocytes and myeloid progenitors with sparse immature erythroid elements elaborated with immunohistochemistry.3 The dysmorphic features present in these reported cases lend credence to the hypothesis that they represented neoplastic involvement of the skin and not compensatory extramedullary hematopoiesis despite the lack of molecular confirmation. The pathogenesis of splenomegaly in PMF has been attributed to the sequestration and proliferation of clonally involved circulating progenitor cells. The progenitor cells are mobilized from the bone marrow because of impaired adhesion to the marrow stroma and allowed to circulate and colonize extramedullary sites.10,11 The extramedullary hematopoietic cells of the spleen in PMF have been found to frequently carry the JAK2 V617F mutation and to have a
high rate of concordance with the genotype and karyotype of the disease in the marrow.12,13 The presence of the JAK2 V617F mutation in the cutaneous lesions of our patient and in a previously reported patient with PMF3 suggests that the cutaneous findings in PMF may also result from sequestration and proliferation of clonally involved circulating progenitor cells as occurs in the spleen. The reason for colonization of the skin by these progenitor cells remains to be elucidated. Given the evidence that extramedullary proliferations of hematopoietic cells in PMF represent dissemination of the neoplastic clone and not compensatory extramedullary hematopoiesis, there is debate over the appropriate nomenclature for when this phenomenon occurs in the skin. Hoss and McNutt proposed the term ‘cutaneous myelofibrosis’ arguing that ‘extramedullary hematopoiesis’ should be reserved for compensatory hematopoiesis in the absence of morphologic and molecular abnormalities.14 O’Malley et al. proposed ‘neoplastic myeloid proliferation’ for cutaneous myeloid proliferations driven by genetic mutation.13 Fraga and Caughron suggested that this same cutaneous finding be interpreted as metastatic disease.3 We favor the term cutaneous myelofibrosis as it would prompt workup for systemic disease in the absence of an antecedent diagnosis and could potentially impart prognostic information; this is the second report of shortened survival in a patient with cutaneous myelofibrosis, and non-splenic SEMHT in the setting of myelofibrosis are associated with death within months of diagnosis as compared to the median overall survival of 3–7 years of patients with fibrosis stage PMF.1,4 More data will be helpful in determining whether or not cutaneous clonal disease manifestations in PMF are indeed an independent poor prognostic sign. We report the first case of cutaneous myelofibrosis in the skin with a documented JAK2 mutation and SEMHT morphology. The single prior case of cutaneous myelofibrosis with a documented JAK2 mutation consisted of a nodular infiltrate of myeloid cells and megakaryocytes.3 While we consider both cases to be cutaneous myelofibrosis, our case is unique and challenging in that the morphology could have been easily misconstrued as a mesenchymal neoplasm. Histomorphologically, SEMHT are characterized by a proliferation of atypical megakaryocytes and variable proportions of granulocytic and erythroid precursors comprising a mass with pronounced accompanying fibrosis.15,16 These
861
LeBlanc et al. tumors arise in the setting of myeloproliferative neoplasms and are exceedingly rare in the skin, being more often reported in the retroperitoneum, mesentery, lymph nodes, lung, liver, breast, kidney, adrenal gland and lacrimal gland.15 – 18 As the bone marrow fibrosis in PMF has been found to occur in response to cytokines such as TGF-beta secreted by clonal megakaryocytes, it is not surprising that extramedullary hematopoiesis involving these same atypical megakaryocytes may induce a similar fibrotic stroma at other anatomic locations.16 The importance of SEMHT lies in the histologic differential diagnosis that includes sarcomas and fibrohistiocytic proliferations, spindle cell variant of squamous cell carcinoma, melanoma, poorly differentiated carcinomas, inflammatory and sclerosing diseases, Hodgkin lymphoma and leukemia cutis. The distinct immunophenotypes of these entities and clinicopathologic correlation should allow for a correct diagnosis. Although the megakaryocytes of PMF are often described as bulbous or cloud-shaped, fibrosis can result in cytologic distortion as illustrated in our case. Bare megakaryocytic nuclei are a common finding and numerous small forms can often be elucidated by immunohistochemistry with CD61 or Factor VIII. As in the marrow, acute leukemic involvement
should be excluded in cutaneous manifestations. This may be aided by CD34, CD117 and TdT immunostains to highlight blasts amidst fibrosis and the predominant megakaryocytic and early myeloid populations. Vimentin staining in SEMHT should be avoided as it will highlight the abundant accompanying fibroblasts, which have been shown to be polyclonal.19 Factor XIIIa staining may similarly highlight the accompanying dermal dendritic cells and contribute to a misdiagnosis of dermatofibroma or dermatofibrosarcoma protuberans. In summary, we reported an exceedingly rare case of cutaneous myelofibrosis exhibiting the JAK2 V617F activating mutation in a patient with a history of PMF. This is the second case to be reported and is unique in that it showed SEMHT morphology, raising a differential diagnosis that included mesenchymal neoplasms and AML. Recognition of these rare lesions is important to direct appropriate therapy, which entails the search for underlying systemic disease in the absence of an antecedent diagnosis. As in the previously reported case, our patient had a shortened survival following the appearance of her skin lesions despite an absence of other independent high-risk features, thus raising the possibility that cutaneous myelofibrosis may be a poor prognostic sign.
References 1. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003; 78: 1223. 2. Lane JE, Walker AN, Kulharya A, Marzec T. Cutaneous sclerosing extramedullary hematopoietic tumor in chronic myelogenous leukemia. J Cutan Pathol 2002; 29: 608. 3. Fraga GR, Caughron SK. Cutaneous myelofibrosis with JAK2 V617F mutation: metastasis, not merely extramedullary hematopoiesis!. Am J Dermatopathol 2010; 32: 727. 4. Vardiman JWMJ, Baccarani M, et al. Myeloproliferative neoplasms. In Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classification of tumours of haematopoietic and lymphoid tissues, 4th ed. Geneva: WHO Press, 2008. 5. Medinger M, Passweg J. Angiogenesis in myeloproliferative neoplasms, new markers and future directions. Memo 2014; 7: 206. 6. Muxi PJ, Oliver AC. Jak-2 positive myeloproliferative neoplasms. Curr Treat Options Oncol 2014; 15: 147. 7. Corella F, Barnadas MA, Bordes R, et al. A case of cutaneous extramedullary
862
8.
9. 10.
11.
12.
13.
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