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Haemangioendothelioma: a current perspective
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9 D][zlelgC0l,,'lN [qm PATHOLOGY M i n i - s y m p o s i u m : v a s c u l a r disease
Haemangioendothelioma: a current perspective
C. M o n t e a g u d o a n d A. L l o m b a r t - B o s c h
Introduction
Historical evolution
Frank B. Mallory could never have imagined when be first coined the term 'haemangioendothelioma', during the Middleton Goldsmith Lecture delivered at the New York Academy of Medicine on 4 April 1908] what a tremendous conlroversy this 'properly descriptive' term e would create to several generations of pathologists. It is a matter of fact that Mallory's proposition of diagnostic morphologic features which could serve to effectively distinguish benign from malignant vascular neoplasms on the one hand, as well as predict clinical behaviour on the other, has been a controversial issue lk)r more than a century. This controversy is well illustrated by the number of cases reported between [ 875 and 1940 as so-called 'benign metastasizing haemangioma '3,4 and which were then discredited by Arthur P. Stout in 1943, who considered them to be examples of underdiagnoscd malignant vascular tumours. 2 In an attempt to improve diagnostic accuracy, many modifications of the histologic classification of vascular neoplasms have been introduced, together with continuous and equivocal changes in nomenclature including the label haemangioendothelioma. These changes may explain the current use of confusing terms such as haemangioendothelioma in this field of soil tissue tumour pathology. In order to understand the current value, significance and potential of this term in diagnostic pathology, we will analyze its origin and conceptual evolution.
Mallory considered that there was no reason for making an artificial division between the slow-growing vasoIbrmative tumours (angiomata) and those in which the tumour cells grew rapidly and sometimes in solid masses (endothcliomata); he accordingly introduced the term 'haemangioendotheliomata' to include all 'tumours arising from blood vessel endothelium', j Thus in its original concept the term was not associated with any particular clinical behaviour. 35 years later, Stout described the histologic features of 'malignant tumours of blood vessels featuring vascular endothelial cells', 2 emphasizing the presence of an atypical endothelium and vascular anastomoses; he considered that 'they were best called by the name haemangioendothelioma'. In the same paper, Stout, as mentioned above, disapproved of the concept of 'benign metastasizing haemangioma' since, all cases of which photomicrographs or histologic material had been available to him were, in his opinion, typical examples of haemangioendothelioma. Therefore, in this classical paper, Stout linked the term haemangioendothelioma to a malignant behaviour. Later, Kauffman and Stout in 19615 referred to and compared benign and malignant baemangioendotheliomas in children; the former included 'benign juvenile haemangioendothelioma' as well as the turnout-like lesion called Masson's 'vegetant intravascular haemangioendothelioma'. In addition, these authors recognized a subgroup of malignant haemangioendotheliomas which had a limited potential to metastasize and a more benign histologic appearance consisting of prominent collagen deposition between vascular spaces, an almost complete absence of mitoses, and a less bizarre appearance of tumour cells. The authors 5 did however point out that the small number of cases in this malignant haemangio-
Carlos Monteagudo, MD and Antonio LIombart-Bosch, MD,
Department of Pathology, Medical School. University of Valencia, Spain. Reprint requests to: AL B: Dcpartamenlo de Patologia, Facultad de Medicina, Avd. Blasco Ibanez 17, 46010 Valencia, Spain , ( ( S ) 2 , 6 5 72 (" ~ r v l ) i ( ~, ~ . f i ' P I ~/o~v(I)) ~ 1905 ['caIsou Pnoic'~'dlmal l~al
(35
66 CURRENTDIAGNOSTICPATHOLOGY endothelioma subgroup prevented them from doing more than to suggest that these tumours had a different biology and they therefore recommended that their treatment should be the same as for the more aggressive examples of haemangioendotheliomas. In the meantime, though 2 groups of authors had criticized the equivocal use of the term haemangioendothelioma, 6'7 no convincing or widely accepted alternative term was established and a diagnosis of haemangioendothelioma continued to be familiar to pathologists. Interestingly, Wilson Jones 8 preferred the label 'malignant angioendothelioma' as opposed to that of 'angiosarcoma' for well and moderately differentiated malignant vascular tumours of the skin. In 1985, Angervall and co-workers, 9 and later Enzinger and Weiss, 1~ redefined haemangioendotheliomas as vascular tumours of intermediate, borderline or low malignancy, occupying a halfway position between haemangiomas and conventional angiosarcomas, a proposition which has been theoretically accepted worldwide. Present status In practise, the term haemangioendothelioma has continued to be used in recent years to designate a heterogeneous and almost daily increasing group of vascular neoplasms: 1~176epithelioid haemangioendothelioma (EH), malignant endovascular papillary angioendothelioma (MEPA or Dabska's tumour), spindle cell haemangioendothelioma (SCH), retiform haemangioendothelioma (RH), Kaposiform haemangioendothelioma of infancy and childhood (KHIC), and polymorphous haemangioendothelioma of lymph nodes (PHLN), in addition to the well recognized benign juvenile haemangioendothelioma (BJH). Although defined as having low malignant potential, it has to be noted that, with the exception of EH, of all the entities designated as 'endotheliomas' there are in the literature no more than 5 cases with documented metastatic dissemination. As a result the word benign has been added to some of these entities in order to identify their behaviour, and most data support a nonneoplastic reactive nature for others. Therefore, as several authors have previously stressed, the term haemangioendothelioma per se is currently devoid of any specific significance. The views expressed are not merely academic, philosophical, or useless discussions on nomenclature but a potential source of confusion to oncologists. 21 Because the equivocal significance of the term haemangioendothelioma might be followed by inappropriate or doubtful application of therapeutic protocols, it is important to allocate haemangioendothelioma to the correct subtype. Classification In our opinion, haemangioendotheliomas may be subclassified, in terms of clinical behaviour, as follows:
(A) Certainly benign: A 1 - BJH (juvenile cellular haemangioma) A2 - Masson's vegetant intravascular haemangioendothelioma (intravascular endothelial hyperplasia) (B) Probably benign: B 1 - SCH (C) Locally aggressive but uncertain malignancy: C 1 - KHIC (D) Potentially malignant (low grade): D1 - EH D2 - MEPA D3 - RH D4 - PHLN (E) Certainly malignant: E1 - Conventional angiosarcoma (malignant haemangioendothelioma, MH) Two additional entities which share a similar terminology are malignant angioendotheliomatosis (angiotropic lymphoma), and reactive angioendotheliomatosis (a selflimited endothelial proliferation). We will briefly discuss below the clinicopathologic features of haemangioendotheliomatous lesions (A-D). Conventional angiosarcoma and angioendotheliomatosis, whose study is beyond the scope of this review, will not be reviewed.
Benign juvenile haemangioendothelioma (BJH), juvenile cellular haemangioma In spite of its denomination and histologic appearance, the main interest of this benign lesion is its ability to simulate malignancy. Clinically, BJH usually appears during the first few weeks of life, grows in the first year, and slowly involutes during the next 5-8 years. 22 The essential histologic features are a lobulated growth pattern, the presence of solid cellular areas together with foci of capillary haemangioma and abundant mast cells. 23 Intercommunicating vascular anastomoses may be found but are not extensive. Immunohistochemistry and electron microscopy 23~5 have shown a heterogenous population in cellular areas; endothelial cells with dense crystalloid inclusionsy alpha-smooth-muscle actin positive pericytes, fibroblasts, and factor XIII positive interstitial cells. Worrisome atypical histologic features include infiltration of normal adjacent tissues, areas of high mitotic rate, and poorly defined lobulation: perineural invasion has also been reported. 26 The clue to arriving at the correct diagnosis lies in the fact that the atypical changes are focal and that the above mentioned characteristic features are readily found in their proximity. Moreover, it has to be remembered that malignant vascular tumours are extremely rare in infancy and childhood. The prognosis of BJH is excellent, though in some special anatomical sites difficult clinical situations may occur. 27 Figure 1 (A-C) illustrates a giant BJH in a newborn which spontaneously and progressively regressed without any therapeutic intervention.
HAEMANGIOENDOTHELIOMA:A CURRENTPERSPECTIVE 67
(B)
(A)
(C)
Fig. 1--(A) Giant benign infantile haemangioma. CLinical photograph of the tumour at presentation. (B) Histologic appearance of the lesion; notice the solid monotonous cellular proliferation with occasional capillary lumina and hemosiderin deposits (H&E, x 100). (C) Clinical photograph 18 months later showing that the lesion has almost completely regressed.
Masson 's vegetant intravascular haemangioendothelioma ( intravascular endothelial hypeq)lasia, 'endovasculite prohfe'rante thrombopoMtique ', pseudoangiosarcoma) In 1923 Pierre Masson described a previously unrecognized vascular lesion in infected haemorrhoidal veins, showing papillary endothelial proliferation associated with thrombi in its later stages of evolution5 s A few years later, Folke Hensehen described the same lesion in several other locations including nasal cavity and female urethra, and called it 'thrombopoietic proliferative cndovasculitis'. > The main histologic features of this lesion2S 31 are the presence of papillary fronds usually covered by a single layer of swollen endothelial cells
(Fig. 2A). Multiple endothelial layers, however, may be found. The stroma of these papillae are characteristically composed of fibrinous or hyalinized material (Fig. 2B). The endothelial cells have small nucleoli and few mitotic figures. No frank anaplasia or necrotic areas are found, Thrombi are usually present - although it is not a pre-requisite for this diagnosis - and inflammatory cells are scanty. As previously stated, 3~ the importance of recognizing this lesion resides in its capacity to simulate a malignant vascular tumour. Recognition of the intravascular location of this lesion, the association with other vascular lesions (haemangioma, pyogenic granuloma, haemorrhoids), and the absence of anaplasia should result in avoidance of a misdiagnosis of angiosarcoma.
68 CURRENTDIAGNOSTICPATHOLOGY
(A)
(A)
(B)
(B)
Fig. 2--Masson's intravascular endothelial hyperplasia
Fig, 3--Spindle cell haemangioendothelioma. (A) There is a
showing: (A) multiple thin papillary projections towards a vascular lumen, (B) papillary fronds covered by flat endothelial cells and containing abundant hyaline material. H&E (A) • 100, (B) x 400.
nodular configuration with cavernous vascular spaces together with solid, spindle cell areas. (B) At high power, spindle cells having bland nuclei are seen together with epithelioid cells in the solid areas. H&E (A) • 100, (B) x 400.
Spindle cell haemangioendothelioma (SCH)
that vascular-lining cells and epithelioid cells are immunoreactive for von Willebrand Factor (vWF) and vimentin (VIM), and also show Ulex Europaeus Aglutinnin-I (UEA-I) positive staining, whereas the spindle cells are in general negative for endothelial markers, and positive for VIM. Some spindle cells express macrophage markers, factor VIII, and alphasmooth-muscle actin (alpha-SMA); desmin immunoreactivity has been reported in only one case. 4~ At the ultrastmctural level, 32,34-36 the epithelioid cells show some features of endothelial cell differentiation as well as abundant cytoplasmic intermediate filaments? 6 Between the vascular channels, fibroblasts, pericytic-like cells and macrophages may be found. Furthermore, primitive vessel formation and partial endothelial differentiation have been found in the solid spindle cell areas. 34 The spindle cells therefore geem to be a heterogeneous population. This lesion may simulate Kaposi's sarcoma. The differential diagnosis is based on the presence of cavernous areas and epithelioid or vacuolated cells in addition to spindle cells, and the absence of PAS-positive hyaline globules as seen in Kaposi's sarcoma.
Though initially described in 1986 as a low grade angiosarcoma mimicking Kaposi's sarcoma, 32 this lesion was subsequently considered a borderline tumour. Currently, it is generally regarded as a benign, non-metastasizing (possibly non-neoplastic) malformative or reactive vasoformative lesion. 33 39 SCH may be solitary but more frequently occurs as multiple cutaneous or subcutaneous lesions. There is no age or sex predilection. A few cases have been associated with Maffucci's syndrome. 32,33,39 One of our cases (Figs 3A and 3B) developed in a patient with this syndrome. Associations with Ollier's disease, Klippel-Trenaunay syndrome, congenital lymphedema and early onset varicosities have been reported in i s o l a t e d c a s e s . 34,41
The histopathological features ensuring correct diagnosis are: (1) the presence of cavernous endothelial-lined vascular spaces (containing phleboliths in about half of the cases), (2) a spindle cell proliferation with bland nuclei and minimal mitotic activity and (3) epithelioid and vacuolated cells found together with the spindle cell population, immunohistochemical studies have shown
HAEMANGIOENDOTHELIOMA:A CURRENTPERSPECTIVE 69
Kaposiform haemangioendothelioma of infancy and childhood (KHIC) This neoplasm has been clinically recognized for more than 20 years. 42 Nonetheless, the histologic features have only recently been described in detail, z~ KHIC occurs as a solitary tumour in the first decade of life, is without any sex predilection and is usually located in the deep soft tissues and the retroperitoneum. It is commonly associated with systemic manifestations such as the Kasabach-Merritt syndrome and lymphangiomatosis. Histologically, infiltrating, lobulated nodules with spindle cell fascicles forming slit-like or round capillary lumina are found. Epithelioid and vacuolated cells are also present, as well as cytoplasmic haemosiderin deposits. Microthrombi may be occasionally seen within the vascular spaces. Nuclear atypia is minimal, and mitotic activity is low (less than 3 per 10 HPF). No association with HIV or HPV-16 infections has been described. Immunohistochemically, the spindle cell population is CD-34 positive, and usually vWF, UEA-I and SMA negative. At the ultrastructural level, endothelial-like cells forming poorly canalized structures and only partially surrounded by a basal lamina are seen. No Weibel-Palade bodies have been found in the turnout cells. The differential diagnosis with Kaposi's sarcoma is based both on the clinical data, such as the solitary rather than multicentric presentation and the absence of association with HIV and HPV-16 infections and on the histological features of a lobulated rather than diffuse growth pattern, the presence of round or epithelioid cells, and the absence of an inflammatory infiltrate. Another vascular lumour which may on occasion be difficult to distineuish histologically in some areas from KHIC is the acquired tufted angioma (angioblastoma of Nakagawa). The presence of an infiltrative spindle cell population in the former tumour is the clue lBr this differential diagnosis. 19 The clinical behaviour of KHIC is that of a locally aggressive, non-metastasizing neoplasm. 2~ The fact that Interferon alpha-2a is particularly effective in treating this tumour t9'21 is an additional reason for its recognition as an independent entity.
Epithelioid haemangioendothelioma (EH) This well characterized neoplasm, described by Enzinger and Weiss in 1982, 48 occupies an intermediate position in the spectrum of epithelioid (histiocytoid) vascular neoplasms lying between the benign epithelioid haemangioma and the more aggressive epithelioid angiosarcoma.m ~2,~,~,17 The clues to the differential diagnosis with the latter have not however, been properly defined and are a matter of degree. 1-~'49,s~ Although EH may occur in almost any site, the most common locations are soft tissues, lung, liver and bone. In the lung it has been also referred to as an intravascular bronchioloalveolar tumour (IVBAT). In the liver and lung it is frequently nmltifocal. EH is histologically
Fig. 4--Epithelioid haemangioendothelioma (usual 'low grade' subtype) showing a b u n d a n t m y x o i d and hyalinized stroma with few vacuolated epithelioid bland t u m o u r cells. H&E left, x 100; right, x 400.
characterized by the presence of nests and cords of large cellswith abundant eosinophilic, sometimes vacuolated, cytoplasm, which are embedded in a hyaline, myxoid, chondroid or collagenous stroma (Fig. 4). 10'12'17A8'50Red blood cells may be found within the cytoplasmic vacuoles, which are mucin negative. A low mitotic activity and mild to moderate pleomorphism are present. Abundant ostcoclast-like giant cells have been fBund in a few cases. 5L52 In about half of the cases the neoplasm grows centrifugally from a large-sized vessel. EH tumour cells are immunoreactive for vWF. UEA-1, CD-34, VIM and occasionally cytokeratin ( C A M - 5 . 2 ) . 12'i7'5~ Ultrastructural features include immature cell junctions, abundant cytoplasmic intermediate filaments, WeibelPalade bodies, and intracytoplasmic lumen formation with occasional red blood cells. Lung and liver turnouts from a case with multiple lesions differed in their base merit membrane profile, having a similar composition to that usually present in corresponding normal lung and liver tissue. 55 This difference has been interpreted as a proof for multicentric rather than metastatic origin of multifocal tumours, but this issue is still a matter of debate. 5s,55 In spite of a good overall prognosis, in one large series about 30% of cases developed metastases - half of them to regional lymph nodes. ~2 Although clinical behaviour cannot be predicted with certainty by histology, j2,s3 aggressive morphologic features are significant pleomorphism (Fig. 5), increased mitotic activity (>1 per 10 HPF), atypical mitoses and foci of necrosis. Based on these histologic criteria, a subgroup of 'malignant EH' with a higher incidence of metastases has been proposed. ~2 However, since metastases may also be found in the putative 'benign' or 'less aggressive' counterparts, this subclassification should not be regarded as a dogma. The cytokeratin positivity together with the epithelioid features and multifocal liver or lung infiltration may suggest a diagnosis of metastatic carcinoma. On the other hand, the presence of a hyaluronidase resistant alcian-blue positive chondroid or myxoid stroma may simulate a myxoid chondrosarcoma. Positive immuno-
70 CURRENTDIAGNOSTICPATHOLOGY previously supported by ultrastructural examination, 58 and the presence of a lymphocytic associated component. A potential differentiation of tumour cells towards high endothelial cells was suggested. Although lymph node extension of MEPA was found in two of the six original cases, and a few cases recurred, the prognosis of this tumour is good; some authors interpret the lymph node lesions as a consequence of the multifocality of the process rather than a metastatic growth. In fact no systemic turnout dissemination or tumour related deaths have been reported.
Fig. 5---Epithelioid haemangioendothelioma (aggressive subtype) showing higher cellularity, significant pleomorphism and frequent mitoses. H&E x 400,
reactivity for endothelial cell markers and absence of S-IO0 staining are helpful in the differential diagnosis.
Dabska's malignant endovascularpapillary angioendothelioma (MEPA) In 1969, Maria Dabska reported six cases of a peculiar vascular turnout of the skin in children. 56 Two clinical presentations were found: a diffuse swelling or an intradermal tumour. The essential histologic features were the presence of anastomosing vascular channels and papillary plugs of atypical endothelial cells projecting into the lumen (Fig. 6). Three cell types were originally described: lymphocyte-like cells, large atypical cells sometimes showing columnar or hobnail appearance, and flat endothelial cells. In some areas glomeruloid structures were present. Hyaline globules surrounded by proliferating endothelial cells have also been described. 6~ During the 25 years since the original description, only five new cases have been reported, 57-62 which is in fact a very unusual situation. In an immunohistochemical study, Manivel et al, in 1986, 59 confirmed the endothelial nature of tumour cells, which had been
Fig. 6--Dabska's malignant endovascular papillary angioendothelioma. Two fields are shown of prominent intravascular papillary formations covered by cuboidal or columnar cells together with a few lymphocytes. H&E x 400.
Retiform haemangioendothelioma (RH) RH is a recently described and hitherto unrecognized neoplasm considered by the authors to be a low grade angiosarcoma. 18 Histologically, the hallmark of these tumours is the presence of 'long arborising blood vessels arranged in a retiform pattern, reminiscent of normal rete testis' (Fig. 7). In most cases these vessels are lined by monomorphic hobnail endothelial cells. A very prominent lymphocytic infiltrate and papillae with hyaline collagenous cores, similar to those seen in MEPA (Dabska's tumour) are also found in some cases. Of the 14 cases reported, regional lymph node metastasis was found in only one, in which a biphasic pattern with typical retiform areas and a spindle cell component was present; the latter was the only component found in the lymph node. RH should be distinguished from conventional angiosarcoma. The reason for separating it from the latter is essentially the fact that there have been no tumour-related deaths in RE. At microscopic level, the absence of endothelial atypia, mitotic activity, and dermal collagen dissection are the clues for making the correct diagnosis. The precise relationship between RH and MEPA is uncertain, although the former has been considered as the adult counterpart of the latter. 19 On the other hand, in our opinion, some similarities of RH with the vascular tumour described by Ors6s in 1932 under the term 'gemmangioma' merit further analysis. 63
Fig. 7 - - L o w power magnification of a vascular lesion showing a retiform architectural pattern which is characteristic of RH. H&E x 100.
HAEMANGIOENDOTHELIOMA: A CURRENT PERSPECTIVE
Polymorphous haemangioendotheliomaof lymph nodes (PHLN) P H L N has r e c e n t l y b e e n d e s c r i b e d as a b o r d e r l i n e v a s c u lar t u m o u r o f l y m p h n o d e s , t6 H i s t o l o g i c a l l y it is c h a r a c terized b y the p r e s e n c e o f a variety o f p a t t e r n s w i t h i n the s a m e lesion: solid areas w i t h sheets o f p o l y g o n a l cells w i t h scanty c y t o p l a s m and no m a r k e d atypia; foci o f v a s c u l a r d i f f e r e n t i a t i o n ( c y t o p l a s m i c v a c u o l e s , clefts, c h a n n e l s , and papillary structures); a n d a n g i o m a t o u s areas w i t h v a s c u l a r s p a c e s l i n e d b y e n d o t h e l i u m w i t h or w i t h o u t a h o b n a i l a p p e a r a n c e . T h e t u m o u r cells are U E A - I p o s i t i v e but v W F negative. T h e d i f f e r e n t i a l d i a g n o s i s w i t h a n g i o s a r c o m a is b a s e d on the a b s e n c e of
anaplasia
and
dissecting
vascular
channels.
No
m e t a s t a s e s w e r e r e c o r d e d in the three original c a s e s reported.
Conclusions It w o u l d a p p e a r therefore, that the label h a e m a n g i o e n d o t h e l i o m a is currently u s e d as a sort o f q u a r a n t i n e c a t e g o r y for v a s c u l a r n e o p l a s m s o f d o u b t f u l or u n k n o w n clinical b e h a v i o u r . W h e t h e r this situation will r e m a i n as such, or w h e t h e r any kind o f c o n s e n s u s will be r e a c h e d in the future to clarify the status o f t h e s e t u m o u r s will d e p e n d u p o n all o f us. in
the
meantime,
our
recommendations
are
the
f o l l o w i n g : (1) the t e r m s h a e m a n g i o e n d o t h e l i o m a and m a l i g n a n t h a e m a n g i o e n d o t h e l i o m a should not be used w i t h o u t further clarification; (2) cellular h a e m a n g i o m a '
and
' j u v e n i l e (infantile)
~
endothelial
h y p e r p l a s i a ' are the t e r m s p r e f e r r e d to the original den o m i n a t i o n s w h i c h include the h a e m a n g i o e n d o l h e l i o m a label; (3) the term S C H should be retained until n e w data is available to c o n f i r m with certainty, as e x p e c t e d , its putative b e n i g n nature; (4) the term h a e m a n g i o endothelioma
should
be
used
for
the
epithelioid,
retiform, K a p o s i f o r m , and p o l y m o r p h o u s varieties, as well as for m a l i g n a n t e n d o v a s c u l a r papillary
angio-
e n d o t h e l i o m a since t h e s e are entities for w h i c h a b e n i g n or m a l i g n a n t clinical b e h a v i o u r c a n n o t be e s t a b l i s h e d with certainty and, h e n c e , m a y be c o n s i d e r e d as b o r d e r line m a l i g n a n c i e s ; (5) m a l i g n a n t v a s c u l a r t u m o u r s w i t h e n d o t h e l i a l d i f f e r e n t i a t i o n and w i t h o u t s p e c i f i c features o f the entities r e v i e w e d a b o v e are b e s t called c o n v e n tional a n g i o s a r c o m a or s i m p l y ' a n g i o s a r c o m a ' .
References 1. Mallory F B. The results of the application of special histological methods to the study of tmnors. J Exp Med 1908; 10:575 593. 2. Stout A P. Hemangio-endothelioma: A tumor of blood vessels featuring vascular endothelial cells. Ann Surg 1943; 118: 445~64. 3. Borrmann R. Metastasenbildung bei histologisch gutartigen Geschwulsten (Fall von metastasierendem Angiom). Beitr Pathol Anat 1907; 40: 372-392. 4. Robinson J M, Castlcman B. Benign metastasizing hemangioma. Ann Surg 1936; 104: 436M-53. 5. Kaufflnan S L, Stout A P. Malignant hemangioendothelioma in infants and children. Cancer 1961; 14:1186 1196. 6. McCarthy W D, Pack G T. Malignant blood vessel tumors: report of 56 cases of angiosarcoma and Kaposi's sarcoma. Surg Gynecol Obstet 1950; 91: 465~182.
71
7. Rosai J, Summer H W, Kostianovsky M, Perez-Mesa C. Angiosarcoma of the skin. A clinico-pathologic and fine structural study. Hum Pathol 1976; 7: 83-109. 8. Wilson-Jones E. Malignant angioendothelioma of the skin. Br J Dermatol 1964; 76: 21-39. 9. Angervall L, Kindblom L G, Karlsson K, Stever B. Atypical hemangioendothelioma of venous origin. A clinicopathologic, angiographic, immunohistochemical and ultrastructural study of two endothelial tumors within the concept of histiocytoid hemangioma. Am J Surg Pathol 1985; 9: 504-516. 10. Enzinger F M, Weiss S W. Soft tissue tumors. 2nd ed. St Louis, CV Mosby, 1988: 533-544. 11. Rosai J, Gold J, Landy R. The histiocytoid hemangiomas. A unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone and heart. Hum Pathol 1979; 10: 707-730. 12. Weiss S W, Ishak K G, Daft D H, Sweet D E, Enzinger F M. Epithelioid hemangioendothelioma and related lesions. Sere Diagn Pathol 1986; 3:259 287. I3. Tsang W Y W, Chan J K C, Fletcher C D M. Recently characterized vascular tumours of the skin and soft tissues. Histopathology 1991; 19:489 501. 14. Hunt S J, Santa Cruz D J. Acquired benign and 'borderline' vascular lesions. Dermatol Clin 1992; 10:97 115. 15. Allen P W, Ramakrishna B, MacCormac L B. The histiocytoid hemangiomas and other controversies. Pathol Annual 1992; 27 (2): 51 87. 16. Chan J K C, Frizzera G, Fletcher C D M, Rosai J. Primary vascular tumors of lymph nodes other than Kaposi's sarcoma: An analysis of 39 cases and delineation of two new entities. Ant J Surg Pathol 1992; 16: 335-350. 17. Tsang W Y W, Chan J K C. The family of epithelioid vascular tumors. Histol Histopathol 1993; 8:187 212. 18. Calonje E, Fletcher C D, Wilson-Jones E, Rosai J. Retiform hemangioendothelioma. A distinctive tbrm of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol 1994; 18:115 25. 19. Allen P W. Three new vascular tumors rafted angionm, Kaposiform infantile hemangioendotheliomu, and proliferative cutaneous angiomatosis, hat J Surg Pathol 1994; 2:63 72. 20. Zukcrberg L R, Nickoloff B J, Weiss S W. Kaposiform hcmangioendothelionm of inlancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. AmJ SurgPathol 1993; 17:321 328. 21. Orchard P J, Smith C M. Woods W Get al. Trealmcnt of hemangioendothelioma with alpha interferon. Lancet 1989; 2:565 567. 22. l.ister W A. The natural history of strawberry nevi. Lancet 1938: l: 1429 1434. 23. Gonzalez-Crussi F, Reyes-Mugica M. Cellular hemangiomas ('hemangioendotheliomas') in infants: light microscopic, immunohistochemical, and ultrastructural observations. Am J Surg Pathol 1991; 115:769 778. 24. IAombart-Bosch A, Peydro Olaya A, Pcllin A. Ultrastructure of vascular neoplasms. Pathol Res Pract 1982; 174: 1~41. 25. Pasyk K A, Grabb W C, Cherry W. Crystalloid inclusions in endothelial cells of cellular and capillary hemangiomas. Arch Dermatol 1983;119:134 137. 26. Perrone T. Vessel-nerve intermingling in benign infantile hemangioendothelioma. Hum Pathol 1985; 16: 198-200. 27. Messineo A, Wesson D E, Filler R M, Smith C R. Juvenile hemangiomas involving the thoracic trachea in children: report of two cases. J Pediatr Surg 1992; 27: 1291-1293. 28. Masson P. Hemangioendotheliome v6getant intra-vasculaire. Bull Soc Anat (Paris) 1923; 20:517 523. 29. Henschen F. L'endovasculite prolifdrante thrombopoidtique dans la lesion vasculairelocale. Ann Anat Pathoi 1932; 9:113 121. 30. Kuo T T, Sayers C P, Rosai J. Masson's 'vegetant intravascular hemangioendothelioma': A lesion often mistaken for angiosarcoma. Cancer 1976; 38:1227 1236. 31. Amerigo J, Berry C L. lntravascular papillary endothelial hyperplasia in the skin and subcutaneous tissue. Virchows Arch A Anat Pathol Histol 1980; 387: 81-90. 32. Weiss S W, Enzinger F M. Spindle cell hemangioendothelioma, a low grade angiosarcoma resembling a cavernous hemangioma and Kaposi's sarcoma. Am J Surg Pathol 1986; 10:521 530. 33. Scott G A, Rosai J. Spindle cell hemangioendothelioma: report of seven additional cases of a recently described vascular neoplasm. Am J Dermatopathol 1988; 10:281 288. 34. Fletcher C D, Beham A, Schmid C. Spindle cell
72
CURRENT DIAGNOSTIC PATHOLOGY
haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology 1991; 18: 291-301. 35. Imayama S, Murakamai Y, Hashimoto H, Hori Y. Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma. Am J Clin Pathol 1992; 97: 279-287. 36. Ding J, Hashimoto H, Imayama S, Tsuneyoshi M, Enjoji M. Spindle cell hemangioendothelioma: probably a benign vascular lesion not a low grade angiosarcoma. A clinicopathological, ultrastructural and immunohistochemical study. Virchows Arch A Pathol Anat Histopathol 1992; 420: 77-85. 37. Fletcher C D. The non-neoplastic nature of spindle cell hemangioendothelioma. Am J Clin Pathol 1992; 98: 545-546. 38. Battocchio S, Facchetti F, Brisigotti M. Spindle cell hemangioendothelioma: further evidence against its proposed neoplastic nature. Histopathology 1993; 22: 296-298. 39. Perkins P L, Weiss S W. Spindle cell hemangioendothelioma: A clinicopathologic analysis of 77 cases. Mod Pathol 1994; 7: 9A. 40. Terashi H, Itami S, Kurata S, Sonoda T, Takayasu S, Yokoyama S. Spindle cell hemangioendothelioma: report of three cases. J Dermatol 1991; 18: 104-11. 41. Murakami I, Sarker A B, Teramoto N, Horie Y, Taguchi K, Akagi T. Spindle cell hemangioendothelioma: a report of two cases. Acta Pathol Jpn 1993; 43: 529-534. 42. A1-Rashid R A. Cyclophosphamide and radiation therapy in the treatment of hemangioendothelioma with disseminated intravascular clotting. Cancer 1971; 27: 364-368. 43. Neidt G W, Greco M A, Wierczorek R, Blanc W A, Knowles D M. Hemangioma with Kaposi's sarcoma-like features: report of two cases. Pediatr Pathol 1989; 9: 567-575. 44. Lai F M, Alien P W, Yuen P M, Leung P C. Locally metastasizing vascular tumor. Spindle cell, epithelioid, or unclassified hemangioendothelioma? Am J Clin Pathol 1991; 96: 660~563. 45. Tsang W Y, Chan J K. Kaposi-like infantile hemangioendothelioma. A distinctive vascular neoplasm of the retroperitoneum. Am J Surg Pathol 1991; 15: 982-989. 46. Suster S. Epithelioid and spindle-cell hemangioendothelioma of the spleen. Report of a distinctive splenic vascular neoplasm of childhood. Am J Surg Pathol 1992; 16: 785-792. 47. Ekfors T O, Kujari H, Herva R. Kaposi-like infantile hemangioendothelioma. Am J Surg Pathol 1993; 17:314-317. 48. Weiss S W, Enzinger E M. Epithelioid hemangioendothelioma. A vascular tumor often mistaken for a carcinoma. Cancer 1982; 50: 970-981.
49. Fletcher C D M, Beham A, Bekir S, Clarke A M T, Marley N J E. Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm. Am J Surg Pathol 1991; 15: 915-924. 50. Suster S, Morfin C A, Koss M N. Epithelioid hemangioendothelioma of the anterior mediastinum. Am J Surg Pathol 1994; 18: 871-881. 51. Larnovec J, Sobel H, Zidon A, Vern an I. Epithelioid hemangioendothelioma of the anterior mediastinum with osteoclast-like giant cells. Am J Clin Pathol 1990; 93: 813-817. 52. Williams S B, Butler B C, Gilkey F W, Kapadia S B, Burton D M. Epithelioid bemangioendothelioma with osteoclast-like giant cells. Arch Pathol Lab Med 1993; 117: 315-318. 53. Bollinger B K, Laskin W B, Knight C B. Epithelioid hemangioendothelioma with multiple site involvement. Literature review and observations. Cancer 1994; 73: 610-615. 54. Gray M H, Rosenberg A E, Dickersin G R, Bhan A K. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol 1990; 21: 212-217. 55. Nerlich A, Berndt R, Schleicher E. Differential basement composition in multiple epithelioid hemangioendotheliomas of liver and lung. Histopathology 1991; 18: 303-307. 56. Dabska M. Malignant endovascular papillary angioendothelioma of the skin in childhood. Cancer 1969; 24: 503-510. 57. De Dulanto F, Armijo-Moreno M. Malignant endovascular papillary hemangioendothelioma of the skin. Acta Dermatovenereol (Stockh) 1979; 53: 403-408. 58. Patterson K, Chandra R S. Malignant endovascular papillary angioendothelioma: cutaneous borderline tumor. Arch Pathol Lab Med 1985; 109: 671-673. 59. Manivel J C, Wick M R, Swanson P E, Patterson K, Dehner L P. Endovascular papillary angioendothelioma of childhood. Hum Pathol 1986; 17: 1240-1244. 60. Katz J A, Mahoney D H, Shukla L W, Smith C W, Gresik M V, Hawkins H L. Endovascular papillary angioendothelioma in the spleen. Pediatr Pathol 1988; 8: 185-193. 61. Maguin P H, Schroh R G, Barquin M A. Endovascular papillary angioendothelioma in children. Pediatr Dermatol 1987; 4: 332-335. 62. Morgan J, Robinson M J, Rosen L B, Unger H, Niven J. Malignant endovascular papillary angioendothelioma (Dabska tumor). Am J Dermatopathol 1989; 11: 64-68. 63. Ors6s F. Gefa-~spro[3geschwulst (Gemmangioma); Beitr Pathol Anat Physiol 1934; 93: 121-139.
9 D][zlelgC0l,,'lN [qm PATHOLOGY M i n i - s y m p o s i u m : v a s c u l a r disease
Haemangioendothelioma: a current perspective
C. M o n t e a g u d o a n d A. L l o m b a r t - B o s c h
Introduction
Historical evolution
Frank B. Mallory could never have imagined when be first coined the term 'haemangioendothelioma', during the Middleton Goldsmith Lecture delivered at the New York Academy of Medicine on 4 April 1908] what a tremendous conlroversy this 'properly descriptive' term e would create to several generations of pathologists. It is a matter of fact that Mallory's proposition of diagnostic morphologic features which could serve to effectively distinguish benign from malignant vascular neoplasms on the one hand, as well as predict clinical behaviour on the other, has been a controversial issue lk)r more than a century. This controversy is well illustrated by the number of cases reported between [ 875 and 1940 as so-called 'benign metastasizing haemangioma '3,4 and which were then discredited by Arthur P. Stout in 1943, who considered them to be examples of underdiagnoscd malignant vascular tumours. 2 In an attempt to improve diagnostic accuracy, many modifications of the histologic classification of vascular neoplasms have been introduced, together with continuous and equivocal changes in nomenclature including the label haemangioendothelioma. These changes may explain the current use of confusing terms such as haemangioendothelioma in this field of soil tissue tumour pathology. In order to understand the current value, significance and potential of this term in diagnostic pathology, we will analyze its origin and conceptual evolution.
Mallory considered that there was no reason for making an artificial division between the slow-growing vasoIbrmative tumours (angiomata) and those in which the tumour cells grew rapidly and sometimes in solid masses (endothcliomata); he accordingly introduced the term 'haemangioendotheliomata' to include all 'tumours arising from blood vessel endothelium', j Thus in its original concept the term was not associated with any particular clinical behaviour. 35 years later, Stout described the histologic features of 'malignant tumours of blood vessels featuring vascular endothelial cells', 2 emphasizing the presence of an atypical endothelium and vascular anastomoses; he considered that 'they were best called by the name haemangioendothelioma'. In the same paper, Stout, as mentioned above, disapproved of the concept of 'benign metastasizing haemangioma' since, all cases of which photomicrographs or histologic material had been available to him were, in his opinion, typical examples of haemangioendothelioma. Therefore, in this classical paper, Stout linked the term haemangioendothelioma to a malignant behaviour. Later, Kauffman and Stout in 19615 referred to and compared benign and malignant baemangioendotheliomas in children; the former included 'benign juvenile haemangioendothelioma' as well as the turnout-like lesion called Masson's 'vegetant intravascular haemangioendothelioma'. In addition, these authors recognized a subgroup of malignant haemangioendotheliomas which had a limited potential to metastasize and a more benign histologic appearance consisting of prominent collagen deposition between vascular spaces, an almost complete absence of mitoses, and a less bizarre appearance of tumour cells. The authors 5 did however point out that the small number of cases in this malignant haemangio-
Carlos Monteagudo, MD and Antonio LIombart-Bosch, MD,
Department of Pathology, Medical School. University of Valencia, Spain. Reprint requests to: AL B: Dcpartamenlo de Patologia, Facultad de Medicina, Avd. Blasco Ibanez 17, 46010 Valencia, Spain , ( ( S ) 2 , 6 5 72 (" ~ r v l ) i ( ~, ~ . f i ' P I ~/o~v(I)) ~ 1905 ['caIsou Pnoic'~'dlmal l~al
(35
66 CURRENTDIAGNOSTICPATHOLOGY endothelioma subgroup prevented them from doing more than to suggest that these tumours had a different biology and they therefore recommended that their treatment should be the same as for the more aggressive examples of haemangioendotheliomas. In the meantime, though 2 groups of authors had criticized the equivocal use of the term haemangioendothelioma, 6'7 no convincing or widely accepted alternative term was established and a diagnosis of haemangioendothelioma continued to be familiar to pathologists. Interestingly, Wilson Jones 8 preferred the label 'malignant angioendothelioma' as opposed to that of 'angiosarcoma' for well and moderately differentiated malignant vascular tumours of the skin. In 1985, Angervall and co-workers, 9 and later Enzinger and Weiss, 1~ redefined haemangioendotheliomas as vascular tumours of intermediate, borderline or low malignancy, occupying a halfway position between haemangiomas and conventional angiosarcomas, a proposition which has been theoretically accepted worldwide. Present status In practise, the term haemangioendothelioma has continued to be used in recent years to designate a heterogeneous and almost daily increasing group of vascular neoplasms: 1~176epithelioid haemangioendothelioma (EH), malignant endovascular papillary angioendothelioma (MEPA or Dabska's tumour), spindle cell haemangioendothelioma (SCH), retiform haemangioendothelioma (RH), Kaposiform haemangioendothelioma of infancy and childhood (KHIC), and polymorphous haemangioendothelioma of lymph nodes (PHLN), in addition to the well recognized benign juvenile haemangioendothelioma (BJH). Although defined as having low malignant potential, it has to be noted that, with the exception of EH, of all the entities designated as 'endotheliomas' there are in the literature no more than 5 cases with documented metastatic dissemination. As a result the word benign has been added to some of these entities in order to identify their behaviour, and most data support a nonneoplastic reactive nature for others. Therefore, as several authors have previously stressed, the term haemangioendothelioma per se is currently devoid of any specific significance. The views expressed are not merely academic, philosophical, or useless discussions on nomenclature but a potential source of confusion to oncologists. 21 Because the equivocal significance of the term haemangioendothelioma might be followed by inappropriate or doubtful application of therapeutic protocols, it is important to allocate haemangioendothelioma to the correct subtype. Classification In our opinion, haemangioendotheliomas may be subclassified, in terms of clinical behaviour, as follows:
(A) Certainly benign: A 1 - BJH (juvenile cellular haemangioma) A2 - Masson's vegetant intravascular haemangioendothelioma (intravascular endothelial hyperplasia) (B) Probably benign: B 1 - SCH (C) Locally aggressive but uncertain malignancy: C 1 - KHIC (D) Potentially malignant (low grade): D1 - EH D2 - MEPA D3 - RH D4 - PHLN (E) Certainly malignant: E1 - Conventional angiosarcoma (malignant haemangioendothelioma, MH) Two additional entities which share a similar terminology are malignant angioendotheliomatosis (angiotropic lymphoma), and reactive angioendotheliomatosis (a selflimited endothelial proliferation). We will briefly discuss below the clinicopathologic features of haemangioendotheliomatous lesions (A-D). Conventional angiosarcoma and angioendotheliomatosis, whose study is beyond the scope of this review, will not be reviewed.
Benign juvenile haemangioendothelioma (BJH), juvenile cellular haemangioma In spite of its denomination and histologic appearance, the main interest of this benign lesion is its ability to simulate malignancy. Clinically, BJH usually appears during the first few weeks of life, grows in the first year, and slowly involutes during the next 5-8 years. 22 The essential histologic features are a lobulated growth pattern, the presence of solid cellular areas together with foci of capillary haemangioma and abundant mast cells. 23 Intercommunicating vascular anastomoses may be found but are not extensive. Immunohistochemistry and electron microscopy 23~5 have shown a heterogenous population in cellular areas; endothelial cells with dense crystalloid inclusionsy alpha-smooth-muscle actin positive pericytes, fibroblasts, and factor XIII positive interstitial cells. Worrisome atypical histologic features include infiltration of normal adjacent tissues, areas of high mitotic rate, and poorly defined lobulation: perineural invasion has also been reported. 26 The clue to arriving at the correct diagnosis lies in the fact that the atypical changes are focal and that the above mentioned characteristic features are readily found in their proximity. Moreover, it has to be remembered that malignant vascular tumours are extremely rare in infancy and childhood. The prognosis of BJH is excellent, though in some special anatomical sites difficult clinical situations may occur. 27 Figure 1 (A-C) illustrates a giant BJH in a newborn which spontaneously and progressively regressed without any therapeutic intervention.
HAEMANGIOENDOTHELIOMA:A CURRENTPERSPECTIVE 67
(B)
(A)
(C)
Fig. 1--(A) Giant benign infantile haemangioma. CLinical photograph of the tumour at presentation. (B) Histologic appearance of the lesion; notice the solid monotonous cellular proliferation with occasional capillary lumina and hemosiderin deposits (H&E, x 100). (C) Clinical photograph 18 months later showing that the lesion has almost completely regressed.
Masson 's vegetant intravascular haemangioendothelioma ( intravascular endothelial hypeq)lasia, 'endovasculite prohfe'rante thrombopoMtique ', pseudoangiosarcoma) In 1923 Pierre Masson described a previously unrecognized vascular lesion in infected haemorrhoidal veins, showing papillary endothelial proliferation associated with thrombi in its later stages of evolution5 s A few years later, Folke Hensehen described the same lesion in several other locations including nasal cavity and female urethra, and called it 'thrombopoietic proliferative cndovasculitis'. > The main histologic features of this lesion2S 31 are the presence of papillary fronds usually covered by a single layer of swollen endothelial cells
(Fig. 2A). Multiple endothelial layers, however, may be found. The stroma of these papillae are characteristically composed of fibrinous or hyalinized material (Fig. 2B). The endothelial cells have small nucleoli and few mitotic figures. No frank anaplasia or necrotic areas are found, Thrombi are usually present - although it is not a pre-requisite for this diagnosis - and inflammatory cells are scanty. As previously stated, 3~ the importance of recognizing this lesion resides in its capacity to simulate a malignant vascular tumour. Recognition of the intravascular location of this lesion, the association with other vascular lesions (haemangioma, pyogenic granuloma, haemorrhoids), and the absence of anaplasia should result in avoidance of a misdiagnosis of angiosarcoma.
68 CURRENTDIAGNOSTICPATHOLOGY
(A)
(A)
(B)
(B)
Fig. 2--Masson's intravascular endothelial hyperplasia
Fig, 3--Spindle cell haemangioendothelioma. (A) There is a
showing: (A) multiple thin papillary projections towards a vascular lumen, (B) papillary fronds covered by flat endothelial cells and containing abundant hyaline material. H&E (A) • 100, (B) x 400.
nodular configuration with cavernous vascular spaces together with solid, spindle cell areas. (B) At high power, spindle cells having bland nuclei are seen together with epithelioid cells in the solid areas. H&E (A) • 100, (B) x 400.
Spindle cell haemangioendothelioma (SCH)
that vascular-lining cells and epithelioid cells are immunoreactive for von Willebrand Factor (vWF) and vimentin (VIM), and also show Ulex Europaeus Aglutinnin-I (UEA-I) positive staining, whereas the spindle cells are in general negative for endothelial markers, and positive for VIM. Some spindle cells express macrophage markers, factor VIII, and alphasmooth-muscle actin (alpha-SMA); desmin immunoreactivity has been reported in only one case. 4~ At the ultrastmctural level, 32,34-36 the epithelioid cells show some features of endothelial cell differentiation as well as abundant cytoplasmic intermediate filaments? 6 Between the vascular channels, fibroblasts, pericytic-like cells and macrophages may be found. Furthermore, primitive vessel formation and partial endothelial differentiation have been found in the solid spindle cell areas. 34 The spindle cells therefore geem to be a heterogeneous population. This lesion may simulate Kaposi's sarcoma. The differential diagnosis is based on the presence of cavernous areas and epithelioid or vacuolated cells in addition to spindle cells, and the absence of PAS-positive hyaline globules as seen in Kaposi's sarcoma.
Though initially described in 1986 as a low grade angiosarcoma mimicking Kaposi's sarcoma, 32 this lesion was subsequently considered a borderline tumour. Currently, it is generally regarded as a benign, non-metastasizing (possibly non-neoplastic) malformative or reactive vasoformative lesion. 33 39 SCH may be solitary but more frequently occurs as multiple cutaneous or subcutaneous lesions. There is no age or sex predilection. A few cases have been associated with Maffucci's syndrome. 32,33,39 One of our cases (Figs 3A and 3B) developed in a patient with this syndrome. Associations with Ollier's disease, Klippel-Trenaunay syndrome, congenital lymphedema and early onset varicosities have been reported in i s o l a t e d c a s e s . 34,41
The histopathological features ensuring correct diagnosis are: (1) the presence of cavernous endothelial-lined vascular spaces (containing phleboliths in about half of the cases), (2) a spindle cell proliferation with bland nuclei and minimal mitotic activity and (3) epithelioid and vacuolated cells found together with the spindle cell population, immunohistochemical studies have shown
HAEMANGIOENDOTHELIOMA:A CURRENTPERSPECTIVE 69
Kaposiform haemangioendothelioma of infancy and childhood (KHIC) This neoplasm has been clinically recognized for more than 20 years. 42 Nonetheless, the histologic features have only recently been described in detail, z~ KHIC occurs as a solitary tumour in the first decade of life, is without any sex predilection and is usually located in the deep soft tissues and the retroperitoneum. It is commonly associated with systemic manifestations such as the Kasabach-Merritt syndrome and lymphangiomatosis. Histologically, infiltrating, lobulated nodules with spindle cell fascicles forming slit-like or round capillary lumina are found. Epithelioid and vacuolated cells are also present, as well as cytoplasmic haemosiderin deposits. Microthrombi may be occasionally seen within the vascular spaces. Nuclear atypia is minimal, and mitotic activity is low (less than 3 per 10 HPF). No association with HIV or HPV-16 infections has been described. Immunohistochemically, the spindle cell population is CD-34 positive, and usually vWF, UEA-I and SMA negative. At the ultrastructural level, endothelial-like cells forming poorly canalized structures and only partially surrounded by a basal lamina are seen. No Weibel-Palade bodies have been found in the turnout cells. The differential diagnosis with Kaposi's sarcoma is based both on the clinical data, such as the solitary rather than multicentric presentation and the absence of association with HIV and HPV-16 infections and on the histological features of a lobulated rather than diffuse growth pattern, the presence of round or epithelioid cells, and the absence of an inflammatory infiltrate. Another vascular lumour which may on occasion be difficult to distineuish histologically in some areas from KHIC is the acquired tufted angioma (angioblastoma of Nakagawa). The presence of an infiltrative spindle cell population in the former tumour is the clue lBr this differential diagnosis. 19 The clinical behaviour of KHIC is that of a locally aggressive, non-metastasizing neoplasm. 2~ The fact that Interferon alpha-2a is particularly effective in treating this tumour t9'21 is an additional reason for its recognition as an independent entity.
Epithelioid haemangioendothelioma (EH) This well characterized neoplasm, described by Enzinger and Weiss in 1982, 48 occupies an intermediate position in the spectrum of epithelioid (histiocytoid) vascular neoplasms lying between the benign epithelioid haemangioma and the more aggressive epithelioid angiosarcoma.m ~2,~,~,17 The clues to the differential diagnosis with the latter have not however, been properly defined and are a matter of degree. 1-~'49,s~ Although EH may occur in almost any site, the most common locations are soft tissues, lung, liver and bone. In the lung it has been also referred to as an intravascular bronchioloalveolar tumour (IVBAT). In the liver and lung it is frequently nmltifocal. EH is histologically
Fig. 4--Epithelioid haemangioendothelioma (usual 'low grade' subtype) showing a b u n d a n t m y x o i d and hyalinized stroma with few vacuolated epithelioid bland t u m o u r cells. H&E left, x 100; right, x 400.
characterized by the presence of nests and cords of large cellswith abundant eosinophilic, sometimes vacuolated, cytoplasm, which are embedded in a hyaline, myxoid, chondroid or collagenous stroma (Fig. 4). 10'12'17A8'50Red blood cells may be found within the cytoplasmic vacuoles, which are mucin negative. A low mitotic activity and mild to moderate pleomorphism are present. Abundant ostcoclast-like giant cells have been fBund in a few cases. 5L52 In about half of the cases the neoplasm grows centrifugally from a large-sized vessel. EH tumour cells are immunoreactive for vWF. UEA-1, CD-34, VIM and occasionally cytokeratin ( C A M - 5 . 2 ) . 12'i7'5~ Ultrastructural features include immature cell junctions, abundant cytoplasmic intermediate filaments, WeibelPalade bodies, and intracytoplasmic lumen formation with occasional red blood cells. Lung and liver turnouts from a case with multiple lesions differed in their base merit membrane profile, having a similar composition to that usually present in corresponding normal lung and liver tissue. 55 This difference has been interpreted as a proof for multicentric rather than metastatic origin of multifocal tumours, but this issue is still a matter of debate. 5s,55 In spite of a good overall prognosis, in one large series about 30% of cases developed metastases - half of them to regional lymph nodes. ~2 Although clinical behaviour cannot be predicted with certainty by histology, j2,s3 aggressive morphologic features are significant pleomorphism (Fig. 5), increased mitotic activity (>1 per 10 HPF), atypical mitoses and foci of necrosis. Based on these histologic criteria, a subgroup of 'malignant EH' with a higher incidence of metastases has been proposed. ~2 However, since metastases may also be found in the putative 'benign' or 'less aggressive' counterparts, this subclassification should not be regarded as a dogma. The cytokeratin positivity together with the epithelioid features and multifocal liver or lung infiltration may suggest a diagnosis of metastatic carcinoma. On the other hand, the presence of a hyaluronidase resistant alcian-blue positive chondroid or myxoid stroma may simulate a myxoid chondrosarcoma. Positive immuno-
70 CURRENTDIAGNOSTICPATHOLOGY previously supported by ultrastructural examination, 58 and the presence of a lymphocytic associated component. A potential differentiation of tumour cells towards high endothelial cells was suggested. Although lymph node extension of MEPA was found in two of the six original cases, and a few cases recurred, the prognosis of this tumour is good; some authors interpret the lymph node lesions as a consequence of the multifocality of the process rather than a metastatic growth. In fact no systemic turnout dissemination or tumour related deaths have been reported.
Fig. 5---Epithelioid haemangioendothelioma (aggressive subtype) showing higher cellularity, significant pleomorphism and frequent mitoses. H&E x 400,
reactivity for endothelial cell markers and absence of S-IO0 staining are helpful in the differential diagnosis.
Dabska's malignant endovascularpapillary angioendothelioma (MEPA) In 1969, Maria Dabska reported six cases of a peculiar vascular turnout of the skin in children. 56 Two clinical presentations were found: a diffuse swelling or an intradermal tumour. The essential histologic features were the presence of anastomosing vascular channels and papillary plugs of atypical endothelial cells projecting into the lumen (Fig. 6). Three cell types were originally described: lymphocyte-like cells, large atypical cells sometimes showing columnar or hobnail appearance, and flat endothelial cells. In some areas glomeruloid structures were present. Hyaline globules surrounded by proliferating endothelial cells have also been described. 6~ During the 25 years since the original description, only five new cases have been reported, 57-62 which is in fact a very unusual situation. In an immunohistochemical study, Manivel et al, in 1986, 59 confirmed the endothelial nature of tumour cells, which had been
Fig. 6--Dabska's malignant endovascular papillary angioendothelioma. Two fields are shown of prominent intravascular papillary formations covered by cuboidal or columnar cells together with a few lymphocytes. H&E x 400.
Retiform haemangioendothelioma (RH) RH is a recently described and hitherto unrecognized neoplasm considered by the authors to be a low grade angiosarcoma. 18 Histologically, the hallmark of these tumours is the presence of 'long arborising blood vessels arranged in a retiform pattern, reminiscent of normal rete testis' (Fig. 7). In most cases these vessels are lined by monomorphic hobnail endothelial cells. A very prominent lymphocytic infiltrate and papillae with hyaline collagenous cores, similar to those seen in MEPA (Dabska's tumour) are also found in some cases. Of the 14 cases reported, regional lymph node metastasis was found in only one, in which a biphasic pattern with typical retiform areas and a spindle cell component was present; the latter was the only component found in the lymph node. RH should be distinguished from conventional angiosarcoma. The reason for separating it from the latter is essentially the fact that there have been no tumour-related deaths in RE. At microscopic level, the absence of endothelial atypia, mitotic activity, and dermal collagen dissection are the clues for making the correct diagnosis. The precise relationship between RH and MEPA is uncertain, although the former has been considered as the adult counterpart of the latter. 19 On the other hand, in our opinion, some similarities of RH with the vascular tumour described by Ors6s in 1932 under the term 'gemmangioma' merit further analysis. 63
Fig. 7 - - L o w power magnification of a vascular lesion showing a retiform architectural pattern which is characteristic of RH. H&E x 100.
HAEMANGIOENDOTHELIOMA: A CURRENT PERSPECTIVE
Polymorphous haemangioendotheliomaof lymph nodes (PHLN) P H L N has r e c e n t l y b e e n d e s c r i b e d as a b o r d e r l i n e v a s c u lar t u m o u r o f l y m p h n o d e s , t6 H i s t o l o g i c a l l y it is c h a r a c terized b y the p r e s e n c e o f a variety o f p a t t e r n s w i t h i n the s a m e lesion: solid areas w i t h sheets o f p o l y g o n a l cells w i t h scanty c y t o p l a s m and no m a r k e d atypia; foci o f v a s c u l a r d i f f e r e n t i a t i o n ( c y t o p l a s m i c v a c u o l e s , clefts, c h a n n e l s , and papillary structures); a n d a n g i o m a t o u s areas w i t h v a s c u l a r s p a c e s l i n e d b y e n d o t h e l i u m w i t h or w i t h o u t a h o b n a i l a p p e a r a n c e . T h e t u m o u r cells are U E A - I p o s i t i v e but v W F negative. T h e d i f f e r e n t i a l d i a g n o s i s w i t h a n g i o s a r c o m a is b a s e d on the a b s e n c e of
anaplasia
and
dissecting
vascular
channels.
No
m e t a s t a s e s w e r e r e c o r d e d in the three original c a s e s reported.
Conclusions It w o u l d a p p e a r therefore, that the label h a e m a n g i o e n d o t h e l i o m a is currently u s e d as a sort o f q u a r a n t i n e c a t e g o r y for v a s c u l a r n e o p l a s m s o f d o u b t f u l or u n k n o w n clinical b e h a v i o u r . W h e t h e r this situation will r e m a i n as such, or w h e t h e r any kind o f c o n s e n s u s will be r e a c h e d in the future to clarify the status o f t h e s e t u m o u r s will d e p e n d u p o n all o f us. in
the
meantime,
our
recommendations
are
the
f o l l o w i n g : (1) the t e r m s h a e m a n g i o e n d o t h e l i o m a and m a l i g n a n t h a e m a n g i o e n d o t h e l i o m a should not be used w i t h o u t further clarification; (2) cellular h a e m a n g i o m a '
and
' j u v e n i l e (infantile)
~
endothelial
h y p e r p l a s i a ' are the t e r m s p r e f e r r e d to the original den o m i n a t i o n s w h i c h include the h a e m a n g i o e n d o l h e l i o m a label; (3) the term S C H should be retained until n e w data is available to c o n f i r m with certainty, as e x p e c t e d , its putative b e n i g n nature; (4) the term h a e m a n g i o endothelioma
should
be
used
for
the
epithelioid,
retiform, K a p o s i f o r m , and p o l y m o r p h o u s varieties, as well as for m a l i g n a n t e n d o v a s c u l a r papillary
angio-
e n d o t h e l i o m a since t h e s e are entities for w h i c h a b e n i g n or m a l i g n a n t clinical b e h a v i o u r c a n n o t be e s t a b l i s h e d with certainty and, h e n c e , m a y be c o n s i d e r e d as b o r d e r line m a l i g n a n c i e s ; (5) m a l i g n a n t v a s c u l a r t u m o u r s w i t h e n d o t h e l i a l d i f f e r e n t i a t i o n and w i t h o u t s p e c i f i c features o f the entities r e v i e w e d a b o v e are b e s t called c o n v e n tional a n g i o s a r c o m a or s i m p l y ' a n g i o s a r c o m a ' .
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