Virchows Arch

DOI 10.1007/s00428-011-1075-0

REVIEW AND PERSPECTIVE

The Kaiser's cancer revisited: was Virchow totally wrong?

Antonio Cardesa & Nina Zidar & Llucia Alos &
Alfons Nadal & Nina Gale & Günter Klöppel

Received: 28 March 2011 / Accepted: 30 March 2011

# Springer-Verlag 2011

Abstract On 15 June 1888, the German Emperor, Kaiser benign. A fourth specimen coughed up by the patient was
Friedrich III, died of laryngeal cancer. Three biopsies of his considered by Virchow to be nondiagnostic. A further
laryngeal lesion had been taken by the British laryngolo- specimen expectorated by the patient 3 months before his
gist, Morel Mackenzie, in 1887 and diagnosed by Rudolf death was diagnosed as carcinoma by Wilhelm Waldeyer.
Virchow as “pachydermia verrucosa laryngis”, confirming The autopsy revealed squamous carcinoma in the larynx
Mackenzie's assessment that the Kaiser's disease was with a cervical lymph node metastasis. The discrepancies
between the initial diagnoses and the final outcome of the
Dedication This article is dedicated in memory of Mario A. Luna, a Kaiser's disease gave rise to a never-ending medical
distinguished member of the Head and Neck Working Group of the controversy. Our investigations on this historical case were
European Society of Pathology and one of the great pathologists who limited to the official German documents and publications
initially contributed to the knowledge of hybrid verrucous carcinoma.
and their English translations and to subsequent literature
A. Cardesa (*) : L. Alos : A. Nadal sources of the time, after having received confirmation that
Anatomia Patologica, Facultat de Medicina, Hospital Clinic,
the histological slides and Virchow's original reports had
Universitat de Barcelona, Institut D’Investigacions Biomediques
August Pi i Sunyer (IDIBAPS), been lost. Based on current surgical pathology knowledge, we
Villarroel 170, propose that the tumour that challenged the diagnostic skills of
08036 Barcelona, Spain the founder of pathology was hybrid verrucous carcinoma
e-mail: acardesa@clinic.ub.es
(HVC), an extremely rare, metastasizing variant of verrucous
L. Alos carcinoma (VC) composed of pure VC mixed with clusters of
e-mail: lalos@clinic.ub.es
conventional squamous cell carcinoma. As we see it now,
A. Nadal Virchow was therefore not totally wrong. Our retrospective
e-mail: anadal@clinic.ub.es
evaluation suggests that Virchow's detailed description of the
N. Zidar : N. Gale Kaiser's cancer preceded the paper that contributed to the full
Institute of Pathology, Faculty of Medicine, understanding of HVC of the larynx by 110 years.
University of Ljubljana,
Korytkova 2,
Keywords Kaiser's cancer . Larynx . Hybrid verrucous
1000 Ljubljana, Slovenia
carcinoma . Mixed verrucous and squamous cell carcinoma
N. Zidar
e-mail: nina.zidar@mf.uni-lj.si
N. Gale
Historical perspective
e-mail: nina.gale@mf.uni-lj.si

G. Klöppel On 15 June 1888, the German Emperor, Kaiser Friedrich III,

Department of Pathology, Consultation Center of Pancreatic
and Endocrine Tumors, Technical University of München,
Ismaningerstr. 22,
81675 Munich, Germany
e-mail: guenter.kloeppel@alumni.uni-kiel.de
died of laryngeal cancer at the New Palace in Potsdam. He
was 57 years old and had reigned for only 99 days. While still
Crown Prince Friedrich Wilhelm, he had been treated by
Morel Mackenzie, Britain's leading laryngologist, who
 Virchows Arch

outcome of the August patient (Figs. 1, 2) were not

understood at that time. They gave rise to a bitter and
continuous medical controversy, which has never been
brought to a satisfactory close [13]. In this paper, we present
a novel interpretation of the difficulties and potential
diagnostic pitfalls that may have been lurking behind the
case of the Kaiser's cancer and provide new insights based on
current surgical pathology knowledge [14, 15].
Information regarding the histological slides containing
the biopsy and autopsy specimens and the original reports
written by Virchow in German was requested from
Professor Manfred Dietel, director of the Department of
Pathology of the Charité in Berlin, Germany. He answered
as follows: “Unfortunately, the histological sections and the
autopsy protocol of the Kaiser's cancer were lost during the
war”. This statement was confirmed by the director of the
“Berliner Medizinhistorisches Museum” of the Charité,
Professor Thomas Schnalke. This unfortunate fate presum-
ably occurred during the last days of the Second World
War, when Virchow's Institute was almost entirely
destroyed.
Therefore, our sources of information were limited to the
German publications and the translations of Virchow's
original reports into English and to the additional docu-
Fig. 1 Crown Prince Friedrich Wilhelm chatting with Virchow who is ments available in the English medical literature on the
dressed in red robe and others during a court ball in 1878. Painting by subject. These were fortunately abundant, because Friedrich
Werner III was married to Crown Princess Victoria, the oldest
daughter of Queen Victoria of England. According to Lin
maintained for a long time, contrary to the opinion of
German laryngologists that the disease was a benign wart
and not a cancer [1–7]. Three biopsies of the Crown Prince's
laryngeal lesion were taken by Mackenzie in 1887 and
diagnosed by Rudolf Virchow, the founder of “cellular
pathology” and the world's foremost pathologist of the time,
as a benign lesion, “pachydermia verrucosa laryngis” [3, 8, 9].
A fourth specimen coughed up by the patient was considered
by Virchow to be nondiagnostic [10]. A further specimen,
spontaneously expectorated by the patient on 4 March 1888,
3 months before his death, was diagnosed as carcinoma
by Wilhelm Waldeyer [3], known for his description of
“Waldeyer's ring” and his work on the development of
carcinomas [11]. The autopsy was performed by Virchow
himself, assisted by Wilhelm Waldeyer and Paul Langerhans,
who first described the pancreatic islets and the specialized
dendritic cells of the skin that both bear his name. It revealed
squamous carcinoma in the larynx and a metastasis in one
cervical lymph node [12]. The early death of Kaiser Friedrich
III generated enduring political controversies, as it was
considered to have dramatically influenced the course of the
subsequent political development in Europe [5, 6], a topic that
was lucidly discussed and accurately put into perspective by
Ober [7]. Furthermore, the seeming discrepancies between the Fig. 2 Photograph of Kaiser Friedrich III, probably at the beginning
initial clinical and pathological diagnoses and the final of his 99-days reign
Virchows Arch
[16], all of Virchow's pathological reports were translated
into English and recorded in Mackenzie's book [3] or
published in the British Medical Journal or the Lancet.
Moreover, we correlated all of this documentation with the
histopathological descriptions of the various types of laryn-
geal carcinomas and their distinctive biological behaviours
according to the latest (2005) WHO classification of head and
neck tumours [14].
Among the English translations of the official German
documents of the time [2, 8–10, 12] and of contemporary or
subsequent historical literature sources [3–7, 13, 17], we
selected as leading reference for our approach the review
written by William B. Ober in 1970 [7]. In this compre-
hensive and historically well-documented article, the
medical records and the histopathological descriptions of
the Kaiser's laryngeal cancer are presented as case report in
such a straightforward manner that it most adequately suits
our purposes:
The patient, a 56-year-old man, pipe smoker [18],
previously in good health, contracted an upper
respiratory infection in the autumn of 1886. It
lingered unduly and was followed by mild hoarseness
in January 1887. He was treated by his Physician-in-
Ordinary (Dr. Wegner) with gargles and inhalations.
Hoarseness persisted, and laryngoscopy by a consult-
ing physician (Prof. Gebhardt) on March 6, 1887,
revealed a sessile nodule 4×2 mm on the left vocal
cord. Both vocal cords moved freely. Attempted
removal by snare, then by ring-knife, failed because
the nodule was flat, smooth and hard. Under cocaine
for local anesthesia, galvanocautery was applied 3 times
between March 8 and March 21, but re-examination
showed it had increased in size. Between March 29 and
April 7, galvanocautery was applied daily (10 times).
Following this treatment, the patient was sent to a spa
for convalescence; inhalations and douches were pre-
scribed. It was noted that the surface of the lesion did not
heal, and the suspicion of carcinoma was first voiced at
this time.
Reexamination by a clinical consultant, Professor von
Bergman, on May 16 revealed “a growth that cannot be
got at from inside the throat, as it may also exist under
the larynx in a fold, where it cannot be reached.”
Because the possibility of carcinoma was strongly
entertained, laryngofissure was recommended.
Prince Bismark intervened, and the proposed opera-
tion was deferred pending on consultation. A panel of
consultants, including Professor Tobold, the senior
laryngologist in Berlin, examined Friedrich on May
18. Tobold's opinion was that the lesion “could be
considered a cancer without any other diagnosis.” …
After some discussion among the attending physi-
cians Morel Mackenzie was selected to perform the
operation, and he was summoned from London (via
the Crown Princess to Queen Victoria by Sir James
Reid, the Queen's resident physician).
On May 20 Mackenzie consulted for the first time
with the German physicians, and then examined the
patient. There was no pain, no difficulty in swallowing,
and no obstruction to breathing. Laryngoscopy revealed
“a growth about the size of a split pea at the posterior
part of the left vocal cord . . . pale pink, slightly rough on
the surface, but not lobulated . . . a portion of the growth
disappeared from view . . . it was partly attached to the
under-surface as well as the side of the vocal cord . . .
partly subglottic in situation. There was no trace of
ulceration . . . to the naked eye it bore the look of a
simple wart or papilloma.”
Mackenzie suggested surgery be deferred until the
nature of the process was established by transoral
biopsy. On May 21 using an unfamiliar instrument,
his own being in London, he succeeded in removing a
small fragment of superficial tissue. Microscopic
examination by Virchow, reported two days later,
revealed a “very superficial piece of mucous mem-
brane . . . to which at one spot only a somewhat shred
of deeper tissue adhered. In a few spaces, nests of
epithelial cells had originated. Thus nothing was
found that contradicted a simple irritative process”.
Rebiopsy was scheduled for May 25, Mackenzie's
own instruments having arrived, but was not carried
out because of local congestion and edema. The
second biopsy was performed on June 8, and
Mackenzie succeeded in removing more than half
the growth from the vocal cord. Virchow's examina-
tion described two fragments of tissue, the larger 3×
2.5 mm, the smaller 2 mm in diameter. Microscopic
examination showed thickening of the squamous
epithelium with papillae formation, but there was no
invasion of the underlying connective tissue by
epithelial nests. The submucosa was richly vascular
and congested. Virchow's diagnosis was pachydermia
verrucosa and he concluded his report with a
favourable prognosis, but cautioned whether such an
opinion would be justified with respect to the entire
disease or could be certain from the two portions
removed. He added that there was nothing in the
biopsy likely to arouse suspicion of more widespread
or more serious disease.
Virchow lectured on “pachydermia laryngis” to the
Berlin Medical Society on June 27, letting it be
understood that the Crown Prince's illness was his

point of departure. In the mean time, following the
second biopsy, the Crown Prince's symptoms had
improved, and he was able to attend in London Queen
Victoria's Golden Jubilee on June 21. During this
period, he continued under treatment by Mackenzie.
Dr. Wegner, his Physician-in-Ordinary was also in
attendance.
On June 28, the patient's symptoms were much
relieved; laryngoscopy showed that local congestion
and oedema had subsided. Accordingly, using his
own instruments, in his own office, in the presence of
Wegner, Mackenzie performed a third biopsy which
was sent to Berlin for pathologic examination. It was
an apparently adequate biopsy, and Virchow's report
was translated and published in England [9]. It merits
extensive quotation: “The object was in absolute
alcohol, in one piece, and though somewhat shriv-
elled, was well preserved. It had a flat base of longish
oval form, 5 mm long and 3 mm broad, upon which
was a small semi-spherical granular surface about
2 mm high… Further examination showed that the
flattened base consisted of club-shaped, rounded
papillary outgrowths lying in juxtaposition… Micro-
scopic examination showed still more decisively than
the previous occasion that the surface of the excised
portion was almost wholly occupied by papillary
outgrowths of various size. Only in the immediate
neighbourhood of the surface of excision was there
found a small zone of perfectly smooth, superficial,
tissue. Within the papillae, the large and hard
epithelial cells, in layers and flattened towards the
outer parts, represented by far the chief portion of the
new formation; the connective tissue framework was
thin, soft and vascular. No peculiar cell-formation was
observed … No alveolar structure, or deposition, or
penetration of epithelial cell masses could anywhere
be perceived in this tissue … Nowhere did this
proliferation reach the character of an independent
centre or formation. Thus, this excised portion, in a
still higher degree than was the case with the portions
obtained in previous operations, has shown itself to be
a hard, warty growth, that has started from a
moderately irritated and thickened surface, and the
examination of its base has not afforded the least
support for the idea of a new formation penetrating
inwards”.
This report was reassuring and the Crown Prince's
symptoms remained silent. He continued his visit to
England until September 3, when on Mackenzie's
advice, he avoided returning to Berlin and went to the
milder climate of the Tyrol. … From there Friedrich
went to Venice, then Lake Maggiore, and finally to
Virchows Arch
San Remo where he arrived, accompanied by Mark
Howell, Mackenzie's assistant, on November 3, 1887.
From this point Friedrich's condition began to
deteriorate:
On November 4 Howell noticed increased subglottic
swelling and summoned Mackenzie. Laryngoscopy
on November 6 revealed the left arythenoid swollen
and bright pink. There was a subglottic tumour half
an inch below the left vocal cord and a smaller one
behind the right vocal cord.
The patient was informed that “a very unfavourable
change had taken place”. He asked: “Is it cancer?”
Mackenzie replied: “I am sorry to say, sir, it looks
very much like it, but it is impossible to be certain”.
Mackenzie requested immediate consultation with
von Schrötter, who arrived on November 9. At the
request of the patient's son, Dr. Moritz Schmidt of
Frankfurt, a prominent laryngologist, was also called
in consultation. Professors Gebhardt and von Berg-
man came from Berlin. The question of syphilis was
raised, and potassium iodide medication was sug-
gested, even given, but on November 10 von
Schrötter delivered the combined opinion to the
patient and his family that the disease was malignant.
Alternative methods of management were discussed.
The patient declined laryngectomy but agreed to
submit to tracheotomy should that become necessary.
A bulletin signed by Mackenzie, von Schrötter
and other physicians in attendance was issued on
November 13 stating: “On examining His Imperial
and Royal Highness the Crown Prince's larynx, the
assembled physicians have been able to establish the
fact that the disease is due to a malignant new
growth.” In January1888 a fever developed with
productive cough. The patient coughed up several
pieces of slough, which were sent to Virchow for
examination. Virchow reported that the majority of
the tissue was necrotic; a few viable tissue fragments
were present but they revealed no cancer [10].
Tracheotomy proved necessary and was done on
January 8, 1888 at San Remo. A fragment of tissue
spontaneously expectorated by the patient on March 4
was diagnosed by Wilhelm Waldeyer as carcinoma [3].
Kaiser Wilhelm I died on March 9, and Friedrich
acceded to reign for only 99 days before he died on
June 15, 1888. An autopsy, limited to the cervical and
thoracic organs was performed by Virchow, assisted
by Waldeyer and Langerhans. The larynx, except for
the epiglottis, had been destroyed and was a large
gangrenous ulcer. A nodule at the base of the
epiglottis contained nests of carcinoma, and a lymph
Virchows Arch
node from the left cervical region was extensively
replaced by metastatic squamous carcinoma. The
immediate cause of death was septic bronchopneumonia
without abscess formation. There were no pulmonary
metastases; the carcinoma had not extended below the
clavicles. In all probability bronchopneumonia was due
to aspiration.
Even today, over 120 years after the death of Kaiser
Friedrich III, the reasons for Virchow's presumed failure to
diagnose the Kaiser's cancer early enough, continue to be
an enigma and to intrigue historians and oncologists in
general, as well as surgical pathologists specialising in head
and neck, and laryngologists in particular, making this case
the most controversial laryngeal cancer in the history of
medicine.
In the second half of the nineteenth century, laryngology
and pathology were in their inception. In 1854, the Spanish
singing teacher Manuel Garcia first viewed his own vocal
cords by means of a laryngeal mirror, thus initiating the use
of indirect laryngoscopy for educating the voice, and
shortly thereafter as a diagnostic and therapeutic procedure
[19]. Although rudimentary, this instrument allowed one
polypoid nodule to be removed as early as 1860 [6].
Already in 1871, Morel Mackenzie published a book
advocating the use of the laryngoscope and reporting on
100 laryngeal biopsies of his own and 89 by other
colleagues [20]. The first total laryngectomy for cancer
was performed by Theodor Billroth in 1873; samples from
that tumour were studied microscopically and a diagnosis
of epidermoid carcinoma was rendered [21].
Histology began under Schleiden and Schwann in
1847 [22], and by 1863, Virchow had postulated the
principle of “omnis cellula e cellula” [23]. The use of
microscopy in medicine expanded after that, as Gerlach
demonstrated that tissues could be stained with natural
dyes [24]. Shortly thereafter, aniline dyes further im-
proved the quality of tissue staining. By 1889, Cajal had
established the individuality of the nerve cells in bird
embryos while working in Barcelona [25]. This discovery
supplied the last needed evidence for the validity of the
cellular doctrine in all tissues, providing full support for
its universal application in pathology at a crucial moment
at which its use for clinical diagnosis and prognosis was
being brought into question. Our retrospective interpreta-
tion is that at such an early stage of scientific medicine the
reasons for the discrepancies between the initial clinical
and pathological diagnoses and the fatal outcome of
Kaiser Friedrich III could not be understood, because the
natural history and the histopathology of the very unusual
type of carcinoma afflicting him were not perceived by
pathologists and laryngologists in their full significance
until 110 years later.
Head and neck cancer in general and laryngeal carcino-
ma in particular are common cancers today all over the
world, with high incidences in European countries. More
than 90% of these tumours are squamous cell carcinomas
(SCC) [26]. Among the nine different types of SCC of the
larynx recognized by the 2005 WHO classification of head
and neck tumours [14], the hybrid subtype of verrucous
carcinoma (VC) [27] is the one that in our view fits
Virchow's reports of the Kaiser's cancer very well. Hybrid
verrucous carcinoma (HVC) is a very unusual cancer,
accounting for about 0.17% of all laryngeal SCCs [28].
VC is a very well-differentiated SCC [29], occurring
predominantly in men in the sixth and seventh decades of
life [30]. Its aetiology has been related in 95% of the cases
to the use of tobacco and alcohol [31]. Human papilloma
virus genotypes 16 and 18, and also 6 and 11, have been
identified in some VC [32, 33]. Approximately 90% of all
head and neck VC arise in two main sites: the oral cavity
(55%) and the larynx (35%) [34]. In the larynx, 85% of VC
arise in the glottis, extending from there to the epiglottis,
subglottis or both in about 17% of cases [28]. VC of the
larynx accounts for 1–3.4% of all SCCs [35, 36] with an
average of 1.7% [28]. The glottis is the single most
commonly affected site, accounting for about 30% of all
the head and neck cases, being followed by the gums
(11.5%) and the buccal mucosa (10%) [34].
Clinically, hoarseness is the main presenting symptom of
laryngeal VC [28]. Grossly, VC of the larynx usually
presents as a broad-based exophytic tumour with a white
keratotic and warty surface. On cut surface, it is firm to
hard, tan to white, and may show keratin-filled surface
clefts. It can be large by the time of diagnosis and involve
contiguous structures, measuring up to 5–7 cm [28].
Microscopically (Fig. 3), VC consists of thickened club-
shaped papillae and blunt intrastromal invaginations of very
well-differentiated squamous epithelium with marked sur-
face keratinization and thin fibrovascular cores [28]. The
deceivingly bland appearance of the squamous epithelium
and its lack of atypia prototypically belay malignancy [37].
The cells in VC are larger than those seen in common SCCs
[38] and express TGFβ-R [39]. Mitoses are rare and are
only observed in the suprabasal layer; there are no
abnormal mitoses. VC invades the subjacent stroma with
well-defined pushing rather than infiltrative borders. A
lymphoplasmacytic inflammatory response is common in
the stroma. VC pursues a slow and locally invasive growth,
causing extensive destruction if inadequately treated. Bona
fide and unperturbed VC do not metastasize [28, 30, 36, 40].
VC therefore bears an excellent prognosis and the survival
rate for patients with pure VC ranges from 85% to 95%.
Although surgery appears to be a more effective treatment
for VC, radiotherapy seems an alternative option for patients
who are not good candidates for surgery [28, 34]. Early

Fig. 3 Panoramic view of verrucous carcinoma showing marked
surface keratinisation, very well-differentiated squamous epithelium
with blunt intrastromal invaginations and thin fibrovascular cores. The
upper part of this type of lesion is what Virchow presumably saw in
the second biopsy performed on June 8, 1887. H&E
Fig. 4 a Deep part of a verrucous carcinoma composed of blunt
intrastromal invaginations of very well-differentiated squamous
epithelium with large cells and thin fibrovascular cores, invading
with well-defined pushing borders. The preserved basement mem-
brane, the bland appearance of the squamous epithelium and its lack
of atypia do not reveal the malignancy of the tumour. This type of
lesion is what Virchow presumably saw at the bottom of the third
Virchows Arch
reports suggested anaplastic transformation of VC following
radiotherapy; however, more recent studies do not support
this notion [28, 40].
VC is characterised by a high frequency of initial
misdiagnosis. In a recent series of 53 VC of the larynx,
16 of 31 patients (52%) had received an incorrect diagnosis
of a benign lesion before referral to the consultation centre
[28], underlining the need for better knowledge of this
entity even today. VC has been controversial since its
beginning. As described by Ackerman: “The biopsy
material from this neoplasm is often confusing. Superficial
biopsies are often taken and a positive diagnosis of
carcinoma cannot be made. Even with deep biopsies, which
are recommended, diagnosis may be difficult (Fig. 4a)
because of the intact basement membrane and the well-
differentiated nature of the growth.” [29]. According to
Fechner [41], Ackerman's paper was a paradigm of the
failure to diagnose a tumour microscopically without knowing
its true clinical nature. Ackerman himself delighted in
recounting the events leading to the correct diagnosis. He
had received multiple biopsy specimens from a lesion of the
oral cavity that he had repeatedly called papilloma. The
surgeon insisted that Ackerman see the patient, who had a
tumour extending from the buccal mucosa into the skin of the
cheek. The surgeon asked pointedly: “Now what do you think
of THAT papilloma, doctor”? Ackerman replied: “Well,
biopsy removed on June 28, 1887. H&E. b Hybrid verrucous
carcinoma. In the upper part of the picture, there are residual
components of verrucous carcinoma which merge with abundant
less-differentiated conventional SCC structures that are particularly
seen in the deeper parts of the picture. Here, the tumour invades with
poorly defined infiltrating borders. H&E
Virchows Arch

Table 1 Comparison between

terms used to report, Kaiser's Kaiser's third biopsya Verrucous carcinomab
third biopsy and to describe
verrucous carcinoma Hard warty growth Wart-like tumour
Papillary surface of various sizes Club-shaped-to-filiform surface papillae
Club-shaped flattened base with outgrowths in juxtaposition Blunt down-growing bulbous invaginations
Connective tissue thin, soft, vascular Thin fibrovascular connective tissue cores
Large epithelial cells flattened towards outer part Large intermediate keratinocytes
a
No penetration inwards Expansive pushing margins
References [7–9]
b
No new formation Bland appearance belies malignancy
References [27–29, 37]

doctor, it still looks like a papilloma, but I must say it is the
BAD kind of papilloma”.
Does this enlightened conversation not remind us of the
pioneering difficulties faced by Virchow in 1887 in his
report on the third biopsy from the Kaiser's tumour, whose
passages fit like a jigsaw puzzle with Ackerman's descrip-
tion of “verrucous carcinoma” in 1948 [29]? In our view,
what in Virchow's time was sarcastically regarded as a
wrong diagnosis should nowadays be considered a master-
piece on how to report an unknown tumour that was first
recognized as a distinct clinicopathologic entity 61 years
later (Table 1). A similar view was previously held by Lin
[16]. However, this is only the first part of the riddle.
The solution to the second part of this conundrum lies
behind the differential diagnosis of VC and the report of the
Kaiser's autopsy. The differential diagnosis of VC includes
exophytic SCC, hybrid VC, papillary SCC, verruca
vulgaris, keratinizing squamous cell papilloma and verru-
cous hyperplasia [27]. VC lacks cytological atypia, and this
distinguishes it from exophytic SCC, hybrid VC and
papillary SCC; the latter tumour distinctly shows more
prominent branching of the papillae than the former two.
The pushing margins of VC are smooth in distinction to the
irregular-shaped invasive islands of SCC. Papillomas have
thin, well-formed papillary fronds with limited keratiniza-
tion, as compared to the markedly keratinized papillae of
VC. Verruca vulgaris of the larynx contains layers of
parakeratotic squamous cells with large keratohyaline
granules identical to their counterpart in the skin [42].
Invasion below the level of the basal cell layer of the
neighbouring normal squamous epithelium distinguishes VC
from verrucous hyperplasia [43]; this latter term is similar to
the “pachydermia verrucosa laryngis” of Virchow's termi-
nology. Whether this feature adequately discriminates
between VC and verrucous hyperplasia is debatable, as
verrucous hyperplasia could be an initial form of VC as well
[40, 44, 45].
The autopsy report that ultimately disclosed the whole
spectrum of the malignant new growth that the Kaiser
suffered from revealed not only carcinoma at the base of
the epiglottis, but also metastatic squamous carcinoma
that involved one cervical lymph node ipsilateral to the
primary tumour. This latter finding precludes VC as the
final diagnosis for the Kaiser’s cancer, because by
definition it never metastasizes to lymph nodes [36].
Nevertheless, this lymph node metastasis provides the
final additional piece of the jigsaw puzzle. It is what
makes the Kaiser's cancer fit the complex and subtle entity
we know nowadays as “hybrid verrucous carcinoma”,
which was initially reported in the larynx by Batsakis et al.
in 1982 [40], and thereafter in the oral cavity by Medina et
al. in 1984 [46] and by Luna and Tortoledo in 1988 [45].
In 1998 Orvidas et al. [28] expanded our knowledge of
this variant of VC of the larynx, documenting for the first
time three patients with metastases to regional lymph
nodes (Table 2).
HVC is an aggressive variant of VC, composed of
“pure” VC mixed with nests of conventional SCC, usually
sitting in the deeper parts of the tumour (Fig. 4b). These
less-differentiated nests enable HVC to recur more fre-

Table 2 Comparison of the course of Kaiser's cancer with that of verrucous carcinomas of larynx metastasizing to regional lymph nodes

Cases Initial diagnosis Recurrence Recurrence Diagnosis after Follow-up Dead months
in months recurrence

Kaiser's cancer [7] Pachydermia verrucosa 4 Local + regional Squamous cell Dead of disease 12
laryngis lymph nodes carcinoma
Orvidas et al., Mayo Verrucous carcinoma 14 Regional lymph Squamous cell Dead of other 128
Clinic [28] nodes carcinoma cause
Orvidas et al., Mayo Verrucous carcinoma 4 Local + regional Squamous cell Dead of disease 16
Clinic [28] lymph nodes carcinoma
Orvidas et al., Mayo Hybrid verrucous 3 Local + regional Squamous cell Dead of disease 4
Clinic [28] carcinoma lymph nodes carcinoma

quently than VC and to metastasize into the regional lymph
nodes. An adequate, full-thickness biopsy specimen must be
taken when a clinician suspects HVC. Moreover, multiple
biopsies and serial sectioning of the entire specimen may be
needed to rule out a conventional SCC component in any VC
[28]. Very recently, analysis of desmosomal proteins has
proven to be of assistance in problematic cases of VC, as the
expression of desmocollin 3 is retained in pure VC but lost
in the SCC nests of HVC [47]. If the diagnosis of HVC is
confirmed, the patients must be treated as if they had
conventional SCC [28, 46]. It appears that some of the
reported cases of transformation of VC to SCC after
radiotherapy were examples of HVC [28, 40, 46].
In its early stages, HVC goes unrecognized as just
another verruciform growth. Different from pure VC, which
evolves as a persistent and progressive lesion with a clinical
phase that last several years, HVC may arise suddenly, or a
period of slow growth may be followed by rapid enlarge-
ment [40]. HVC has a higher tendency to recur locally than
pure VC [28]. Recurrence of HVC can be either in the form
of a hybrid pattern or as conventional SCC [28]. The report
by Batsakis et al. consisted of three HVC out of seven
verrucous malignant tumours of the larynx [40]. The one by
Medina et al. documented 20% HVC out of a series of 104
VC of the oral cavity; none of these HVC was found to
metastasize [46]. In the series of 53 VC of the larynx
reported by Orvidas et al., there were six (10%) HVC
observed de novo [28]; four additional patients with an
initial diagnosis of pure VC recurred in the form of
conventional SCC, and were considered cases of HVC that
were not apparent at the initial diagnosis. Eventually, three
of these ten aggressive cases metastasized to the regional
lymph nodes as typical SCC. Their initial diagnosis was
pure VC in two patients and a hybrid VC in one [28].
To conclude this review on the fatal cancer afflicting
Friedrich III, we propose for the first time that it was HVC,
a very rare, metastasizing variant of VC composed of pure
VC mixed with nests of “conventional” SCC that is difficult
to diagnose even today which challenged the diagnostic
skills of the founder of pathology. Was Virchow totally
wrong? Not in our view which differs from what was
contended in Virchow's time. We rather believe, based on
our retrospective evaluation of pathology reports and
clinical records in comparison with our current knowledge
of larynx cancer, that in the case of the Kaiser's cancer,
Virchow's reports described in detail the microscopic
features and the loco-regional dissemination of a very
complex and extremely rare neoplastic entity. Assuming
that our hypothesis is correct, these thorough descriptions
anticipated the first paper on VC [29] by 61 years and
preceded the paper that contributed to the full understanding
of HVC of the larynx [28] and its subsequent worldwide
recognition [14, 27] by 110 years.
Virchows Arch
Acknowledgements The authors would like to thank Professor
Manfred Dietel and Professor Thomas Schnalke for the information
they provided concerning the fate of the histological slides and of
Virchow's original reports on the case. They are also grateful to Mrs.
Katherine Dege for language editing.
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