DI GUGLIELMO AND HIS SYNDROMES
The name of Giovanni Di Guglielmo is inscribed in the
cells of the erythroid and megakaryocytic lineages could be
involved in a process that was analogous to the involve-
ment of the granulocytic lineage in leukaemia. Further-
more, he recognized bilineage and trilineage involvement in
these processes, foreshadowing the later descriptions of
various myeloproliferative disorders. Di Guglielmo gave his
name to Di Guglielmo’s disease (acute erythraemia, acute
erythraemic myelosis or pure erythroid leukaemia) and Di
Guglielmo’s syndrome (encompassing pure erythroid neo-
plasms and their transition to a mixed erythroid–granulo-
proliferation). Although these terms are now little used,
the concepts ﬁrst formulated by Di Guglielmo in 1917 were
prescient and now, more than 80 years later, their validity
Brazilian-born Italian haematologist who, during the course
of his career, made a number of signiﬁcant original
observations. Those for which he is best remembered are
his descriptions, in 1917, 1923 and 1942, respectively, of
erythroleukaemia and acute and chronic erythraemic
Giovanni Di Guglielmo was born in 1886 in Sao˜ Paolo,
Brazil. His parents, of southern Italian origin, had recently
migrated to the New World in search of a better life (Di
Guglielmo, 1998). When he was 6, the family returned to
Italy but, two years later, his parents re-emigrated to Brazil,
leaving the young child in the care of his aunt and uncle in
Andretta. He continued his schooling there and subse-
quently completed it in Avellino, later enrolling in the
School of Medicine at the University of Naples. After
graduation, in 1911, he returned to Brazil to practise
medicine. However, ﬁnding himself insufﬁciently prepared
for this career, he remained there less than a year before
returning to Italy again. On his return, he chanced to meet,
and became the ﬁrst pupil and later the principal collabor-
ator of, ‘the father of Italian haematology’, Adolfo Ferrata
(1880–1946). Di Guglielmo worked as Ferrata’s unpaid
assistant in the University of Naples from 1912 to 1916. His
research was interrupted by the First World War. In 1916,
he was drafted as a tenente medico, ‘medical lieutenant’, at
ﬁrst to a ﬁeld hospital and then with the troops to the front
line, at Monte Piana in the southern Tyrol (Alto Adige).
During this period of military service, he published his ﬁrst
signiﬁcant original observations, on a case of erythroleu-
kaemia (Di Guglielmo, 1917). Later, when criticized for the
lack of a citation in this paper, he defended himself, pointing
out that, as he was in the front line with the infantry, he did
not have the opportunity to consult bibliographic material
(Di Guglielmo, 1925). With the end of the war, he returned
to his research under the direction of his teacher and
mentor, Adolfo Ferrata, initially in Naples (between 1919
and 1921) and subsequently (between 1921 and 1922) in
Messina, where Ferrata had been appointed director of the
Institute of Medical Pathology. In the early post-war years,
Di Guglielmo contributed to a textbook on acute leukaemia
and, under the guidance of Ferrata, published several papers
relating to megakaryocytes and platelets (Di Guglielmo,
1920, 1923a). In 1920, he published more details of the
patient ﬁrst described in 1917, including a description of
circulating, platelet-producing megakaryocytes (Di Gugli-
elmo, 1920). In that same year, he returned brieﬂy to Brazil
where he presented a paper ‘Func¸ao piastrinoblastico dos
megacaryocytos no circolo sanguineo’ to the Sociedade di
Medicina a Cirurgia de Sao˜ Paolo. In 1922, Di Guglielmo
accompanied Ferrata to Siena; their collaboration continued
there until 1924. In 1923, at a conference in Rome, he
reported the ﬁrst case thought to represent eritremia acute or
acute erythraemia (Di Guglielmo, 1923b). In 1924, he
followed Ferrata again, this time to Pavia where Ferrata had
been appointed director of the Clinica Medica della Regia
Universita` di Pavia. There he remained until 1927, publish-
ing further signiﬁcant papers on eritremia acute. By 1926, Di
Guglielmo had become Professore Incaricato di Semeiotica e
Diagnostica Medica within Professor Ferrata’s department. In
1927, he moved to the University of Modena where he
became director of the Institute of Medical Pathology. In
1928, he won a concorso, the traditional Italian method of
gaining an academic position, and was called to the Chair of
Medical Pathology in Pavia. Here he remained until 1931,
subsequently also becoming the director of the University’s
Institute of Clinical Paediatrics. He published the ﬁrst Italian
case of Gaucher’s disease to be diagnosed by biopsy, rather
than after splenectomy or at autopsy, and reported the
presence of circulating Gaucher cells (Di Guglielmo, 1931).
That same year, he left northern Italy for Sicily where he
held chairs in pathology and medicine at the University of
Catania. During these years, his research interests included
Correspondence: Dr Barbara J. Bain, Department of Haematology,
St Mary’s Hospital Campus, Imperial College Faculty of Medicine,
London W2 1NY, UK. E-mail: email@example.com
British Journal of Haematology, 2003, 120, 939–943
Ó 2003 Blackwell Publishing Ltd
out extensive research on the treatment of brucellosis by
intravenous vaccination. In 1938, Di Guglielmo moved
again, to Naples, where he remained until 1952, occupy-
ing chairs in pathology and medicine. In 1941, he
published a description of the erythroid island, previously
described by Heilmeyer & Scho¨ner, recognizing it as an
anatomical and functional unit. Finally, at the age of
65 years, he became Professor of Clinical Medicine at La
Sapienza, the University of Rome, a post he was to occupy
for another 5 years (until 1956). In his retirement, he
continued with scholarly activities, until a few days before
his death, driven by ‘an insatiable desire to learn new
things but at the rapid pace of one who has little time left
to live’ (Di Guglielmo, 1962). After his death, his last
manuscript was gathered together for publication by his
sons, Renato and Lucio. This book, Le Malattie Eritremiche
ed Eritroleucemiche, which runs to some 300 pages of text
and 100 pages of illustrations and cites 747 references in
10 European languages (Di Guglielmo, 1962), is a
summary of his life’s work.
The name of Di Guglielmo is linked to a range of
involvement, speciﬁcally erythroleukaemia and acute and
chronic erythraemia or erythraemic myelosis. In 1917, he
described, under the designation ‘eritroleucemia’, a patient
with proliferation of abnormal erythroid cells, myeloblasts
and megakaryocytes (Di Guglielmo, 1917, 1920, 1923b,
1962). He conceived the idea that the erythroblastic
proliferation was analogous to leukaemia rather than being
a secondary phenomenon. This patient had immature cells
of erythroid, granulocytic and megakaryocytic lineages in
the peripheral blood, and the circulating megakaryocytes
were producing platelets. Di Guglielmo used the term
‘eritroleucopiastrinaemia’ to indicate this trilineage involve-
ment. Although Demel (1924) questioned whether Di
Guglielmo had been the ﬁrst to make the observation of
circulating platelet-producing megakaryocytes, Di Gugli-
elmo ﬁercely defended his priority, pointing out that Demel,
in 1915, in a case of chronic myeloid leukaemia, had
described giant platelets rather than intact platelet-produ-
cing megakaryocytes (Di Guglielmo, 1925). The ideas
formulated by Di Guglielmo at this time were so prescient
that they deserve to be quoted. They can be translated as
follows: ‘There can be haemopathies in which the altera-
tions in all the morphological elements in the peripheral
blood are so profound as to suggest a process involving the
whole haemopoietic tissue rather than merely a process of
one system with reactive changes in other systems
diagnosis of erythroleukaemia, since it showed the simul-
taneous presence of quantitative and qualitative changes
both in the red cell and the white cells; furthermore it can be
deduced that this process is the expression of a primitive
lesion of the haemopoietic tissue striking its diverse activities
– the red cell series, the white cell series and the platelets’.
The trilineage involvement was indicated by the name
suggested, ‘eritroleucopiastrinaemia’, which could be trans-
lated as ‘erythroleucothrombocythaemia’. In this early
publication, Di Guglielmo also drew attention to the
dynamic nature of this disease, referring to a phase of
erythraemia followed by a phase of leukaemia. It can be
seen that, even as early as 1917, Di Guglielmo had formed
the concepts of a panmyelosis or a global myeloproliferative
disorder, which were expounded further by William Dame-
shek (1900–69) more than 30 years later (Dameshek,
medical congress in Rome, the ﬁrst case that he considered
to have eritremia acuta (acute erythraemia), a pure
erythroid proliferation analogous to acute leukaemia (Di
Guglielmo, 1923b). He had already postulated the exist-
ence of such an entity in 1919. In 1926, he reported three
cases, including the patient of 1923 (Di Guglielmo,
Fig 1. Giovanni Di Guglielmo. Kindly provided
by Professor Lucio Di Guglielmo from his
further paper published in the same year, although the
title of the article does not reveal the nature of the
condition being discussed (Di Guglielmo, 1926b). All three
were reviewed in a further publication two years later (Di
Guglielmo, 1928). In 1936, Ferdinando Michele (1872–
1937; probably the ﬁrst person to practise splenectomy for
hereditary spherocytosis) suggested, at the second Con-
gress of the Italian Society for Haematology in Turin, that
acute erythraemic myelosis should be designated il morbo
Di Guglielmo, i.e. Di Guglielmo’s disease (Storti, 1998).
This terminology was used in the same year by Nolli &
Benario in an article in which they sought to distinguish
the morbo di Vaquez (polycythaemia vera) from Cooley’s
anaemia (beta thalassaemia major) and from eritremia ad
andamento acuto (acute erythraemia, acute erythraemic
myelosis or Di Guglielmo’s disease) (Nolli & Benario, 1936;
Di Guglielmo, 1937). Two years later, Angelo Baserga
(1908–95) used the same terminology in the title of a
small book on the subject published in Pavia (Baserga,
1938). Much later, William Dameshek used the term ‘Di
Guglielmo’s syndrome’ to refer to polyphasic erythroleu-
kaemia (see below). There must be some doubt as to
whether all three of Di Guglielmo’s cases of eritremia acuta
actually had a neoplastic disorder. Schwartz & Critchlow
(1952) accepted only the third case. The ﬁrst patient, a
young girl ﬁrst reported in 1923, was described by Di
Guglielmo as having eritremia acuta a tipo perniciosa or
eritremia acuta megaloblastica e megalocitica, i.e. ‘acute
erythraemia of pernicious type’ or ‘acute megaloblastic
and macrocytic erythraemia’. It is possible that she
actually suffered from a megaloblastic anaemia. The
second case was a deeply jaundiced neonate, and it seems
likely that he suffered from haemolytic disease of the
newborn with erythroblastosis fetalis. In both these
patients, Di Guglielmo was able to examine only the
peripheral blood. The third case was a 50-year-old man,
called Giovanni Albini, who presented with hepatomegaly,
splenomegaly, fever, pancytopenia and circulating primit-
ive erythroblasts; bone marrow examination showed
primitive erythroblasts with very few cells of granulocyte
lineage. Figure 2 shows characteristic cells, as illustrated
in Di Guglielmo (1928). The clinical course was acute.
The features of this case appear to be consistent with
acute erythraemic myelosis and, if this diagnosis is
accepted, Di Guglielmo was the ﬁrst to recognize this
condition. Di Guglielmo himself claimed priority for the
ﬁrst description of acute erythraemia on the basis of this
third patient, amply studied and documented and ﬁrst
published in 1926, rather than on the basis of either of
the other two patients (Di Guglielmo, 1962). At a
conference in Rome in 1948, Di Guglielmo recorded that
adequate documentation of this third patient was possible
only because of the persuasiveness of his assistant, Dr A.
Esposito. The patient’s relatives had been so anxious about
his condition that they had taken him home. They were
persuaded to bring him back to the hospital where he died
a few days later. A post-mortem examination was thus
Cases of chronic erythraemic myelosis were published by
Duesberg in 1940 and Heilmeyer & Scho¨ner in 1941
(Michiels, 1992). Further cases were published by Di
Guglielmo & Quattrin (1942), under the name myelosi
eritremica cronica. However, priority in describing this
condition may belong to another Italian, Copelli who, in
1912, reported a patient who presented with anaemia and
splenomegaly but without circulating erythroid cells and
was found to have foci of large primitive erythroid cells in
liver, spleen, lymph nodes and bone marrow (Copelli,
after his presentation on this subject at the Sixth Congress of
Fig 2. An illustration from Di Guglielmo
(1928) showing an artist’s impression of
circulating erythroblasts (1–11) and charac-
teristic bone marrow cells (12–22) in a patient
with acute erythraemia (Di Guglielmo’s
disease). The peripheral blood shows erythroid
cells of all stages of maturation, but the
author noted that acidophilic erythroblasts
soon disappeared from the peripheral blood
ﬁlm. The lack of mature erythroblasts in the
bone marrow is apparent.
Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 939–943
1956. The term ‘Di Guglielmo’s syndrome’ was popularized
in the anglophone haematological community by Dame-
shek, although Maxwell Wintrobe (1901–86) commented
that, when Dameshek spoke on Di Guglielmo’s syndrome at
the plenary session of the congress of the International
Society of Haematology in Rome in 1958, ‘his picture of Di
…. was so different from that of the
man after whom it had been named that Professor Di
Guglielmo was puzzled and surprised’ (Wintrobe, 1985).
Somewhat closer to the event, Di Guglielmo himself had said
that, ‘the introduction of the new term ‘‘Di Guglielmo’s
syndrome’’ created a certain perplexity’ (Di Guglielmo,
1962). Dameshek emphasized the natural progression from
erythraemic myelosis (with a dominant erythroid prolifer-
ation) through erythroleukaemia (a mixture of myeloblasts
and abnormal erythroid cells) to myeloblastic leukaemia
(dominant myeloblasts) (Dameshek, 1958; Dameshek &
Baldini, 1958). Di Guglielmo was afraid that, with the
emphasis on the transition from one disorder to another, the
existence of pure acute erythraemia might be doubted (Di
Guglielmo, 1962). After Di Guglielmo’s death, Dameshek
again proposed that the term ‘Di Guglielmo’s syndrome’
should be used to cover this whole disease spectrum,
commenting that the term ‘being sufﬁciently vague
cover a large area, and being eponymic, it can be discarded
becomes available’ (Dameshek, 1969).
In the last 30 years, a diagnosis of ‘chronic erythraemic
myelosis’ has become increasingly infrequent. Cases that
would once have been so designated are now most likely
to be categorized as a myelodysplastic syndrome, usually
being assigned to the French–American–British (FAB)
categories (Bennett et al, 1976) of refractory anaemia or
refractory anaemia with ring sideroblasts. Erythroleukae-
mia, as described by Di Guglielmo (1917), would now
usually be classiﬁed as acute myeloid leukaemia of FAB
M6 type or, according to the World Health Organization
(WHO) classiﬁcation (Brunning et al, 2001), as erythro-
⁄ myeloid). Acute erythraemic myelo-
sis, as described by Di Guglielmo in 1926, is a neglected
disease, which does not ﬁt FAB criteria for either a
myelodysplastic syndrome or acute myeloid leukaemia.
Although rare, its existence should be acknowledged. It is
probably most appropriately regarded as a variant of acute
myeloid leukaemia. If using the FAB classiﬁcation, the
designation M6 variant would seem appropriate (Garand
et al, 1995; Hasserjian et al, 2001). Kowal-Vern et al
(1992) suggested assigning this category to cases that
did not meet the FAB criteria for M6 AML but that had at
least 50% erythroid cells with at least 30% of erythroid
recognizes this entity, designating it ‘pure erythroid
leukaemia’. It is deﬁned as ‘a neoplastic proliferation of
immature cells committed exclusively to the erythroid
lineage (> 80%) with no evidence of a signiﬁcant myelob-
lastic component’. This is eritremia acuta rebaptised.
Fashions in nomenclature change, but Di Guglielmo’s
concepts, unlike those of many of his contemporaries, have
endured. He maintained a life-long interest in ‘his’ disease,
his major monograph, which he saw as his scientiﬁc and
spiritual testament being published posthumously (Di
Guglielmo, 1962). His careful observations of individual
patients over a period of more than 40 years contributed
greatly to advancing knowledge of this group of diseases.
His concept that erythroid cells might undergo prolifer-
ation analogous to the proliferation of granulocytic cells in
leukaemias was greatly in advance of his time, and the
clarity of his vision should be acknowledged.
B a r b a r a J . B a i n
Department of Haematology, St
Mary’s Hospital Campus, Imperial
College Faculty of Medicine,
I am grateful to Professor Lucio Di Guglielmo for providing
me with a photograph of his father and with copies of two
books, which would otherwise have been unavailable – a
biography of his father and his ﬁnal monograph.
Baserga, A. (1938) La Mielosi Eritremica Acuta (Malattia Di Gugli-
elmo). Biblioteca ‘Hematologica’ Pavia, Tipograﬁa gia` Coopera-
Bennett, J.M., Catovsky, D., Daniel, M.T., Flandrin, G., Galton,
D.A.G., Gralnick, H.R. & Sultan, C. (1976) Proposals for the
classiﬁcation of the acute leukaemias (FAB cooperative group).
British Journal of Haematology, 33, 451–458.
Brunning, R.D., Matutes, E., Flandrin, G., Vardiman, J., Bennett, J.,
Head, D. & Harris, N.L. (2001) Acute myeloid leukaemia
not otherwise categorised. In: World Health Organization Clas-
siﬁcation of Tumours, Pathology and Genetics of Tumours of
Haematopoietic and Lymphoid Tissues (ed. by E.J. Jaffe, N.L.
Harris, H.E. Stein & J.W. Vardiman), pp. 91–105. IARC Press,
iperplasia eritroblastica (eritromatosis). Patologica, 4, 460.
Dameshek, W. (1958) Pernicious anemia, megaloblastosis and the
Di Guglielmo syndrome. Blood, 13, 1085–1088.
Dameshek, W. (1969) The Di Guglielmo syndrome revisited. Blood,
Dameshek, W. & Baldini, M. (1958) The Di Guglielmo syndrome.
Blood, 13, 192–194.
Demel, A.C. (1924) Fatti ed ipotesi sulla origine delle piastrine.
Haematologica, 5, 104–146.
Di Guglielmo, G. (1917) Richerche di ematologia. I. Un caso di
eritroleucemia. Megacariociti in circolo e loro funzione piastri-
nopoietico. Folia Medica (Pavia), 13, 386.
Di Guglielmo, G. (1920) Megacariociti e piastrine. Haematologica, 1,
Di Guglielmo, G. (1923a) I megacariociti nel sangue periferico (1).
Haematologica, 4, 182–205.
Di Guglielmo, G. (1923b) Eritremie acute, Atti XXIX Congr. Italiano
Medical International, Roma.
Di Guglielmo, G. (1925) Sul sistema delle cellule giganti midollari.
Haematologica, 6, 156–195.
Di Guglielmo, G. (1926a) Eritremie acute. Bolletino della Societa` di
Medicina e Chirugia di Pavia, 40, 665.
reticuloendoteliale. Haematologica, 7, 481–518.
Di Guglielmo, G. (1928) L’eritremie. Haematologica, 9, 301–347.
Di Guglielmo, G. (1931) La cellula di Gaucher nel sangue periferico.
Haematologica, 12, 615–634.
Di Guglielmo, G. (1937) A proposito del ‘Morbo di Vaquez’ di Nolli e
Benario. Haematologica, 18, 113–119.
Di Guglielmo, G. (1962) Le Malattie Eritremiche ed Eritroleucemiche.
Il Pensiero Scientiﬁco, Rome.
Di Guglielmo, G. & Quattrin, N. (1942) Myelosi eritremica cronica.
Haematologica, 24, 1–58.
Di Guglielmo, N. (ed.) (1998) Giovanni Di Guglielmo, l’Uomo, lo
Scienziato, il Maestro: una Vita per Scienza. Associazione Pro Loco
Garand, R., Duchayne, E., Blanchard, D., Robilard, N., Kuhlein, E.,
Fenneteau, O., Salomon-Nguyen, F., Grange, M.J., Rousselot, P.
& Demur, C. (1995) Minimally differentiated erythroleukaemia
(AML M6 ‘variant’). A rare subset of AML, distinct from AML
M6. British Journal of Haematology, 90, 868–875.
Hasserjian, R.P., Howard, J., Wood, A., Henry, K. & Bain, B. (2001)
Acute erythremic myelosis (true erythroleukaemia): a variant of
AML FAB-M6. Journal of Clinical Pathology, 54, 205–209.
Kowal-Vern, A., Cotelingam, J. & Schumacher, H.R. (1992) The
prognostic signiﬁcance of proerythroblasts in acute erythro-
leukemia. American Journal of Clinical Pathology, 98, 34–40.
Michiels, J.J. (1992) Erythroleukemia and myelodysplastic syn-
dromes. an historical appraisal and a personal view. Leukemia and
Lymphoma, 9, 27–34.
Nolli, N. & Benario, O. (1936) Il morbo di Vaquez (policitemia
rubra). Haematologica, 17, 645–735.
Schwartz, S.O. & Critchlow, J. (1952) Erythremic myelosis
(Guglielmo’s disease). Critical review with report of four cases,
and comments on erythroleukemia. Blood, 7, 765–798.
Storti, E. (1998) Eritremia acuta nell’emopatologia animale. In:
Giovanni Di Guglielmo, l’Uomo, lo Scienziato, il Maestro: una Vita
per la Scienza (ed. by N. Di Guglielmo), pp. 63–68. Associazione
Pro Loco Andretta, Avellino.
Wintrobe, M.M. (1985) Hematology, the Blossoming of a Science, Lea
& Febiger, Philadelphia.
Keywords: Giovanni Di Guglielmo, Di Guglielmo’s syn-
drome, erythroleukaemia, acute myeloid leukaemia.