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IJPP-277; No. of Pages 13 ARTICLE IN PRESS


International Journal of Paleopathology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Paleopathology


journal homepage: www.elsevier.com/locate/ijpp

Histology of ancient soft tissue tumors: A review


Gino Fornaciari
Division of Paleopathology, Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via
Roma, 57, 56126 Pisa, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Ancient neoplasms diagnosed in the soft tissues of mummies are limited to 18 cases so far, with only 5
Received 23 February 2017 malignant tumors. The apparent paucity of neoplasms in ancient populations is sometimes attributed to
Received in revised form 25 February 2017 shorter life spans and fewer oncogenic substances in the environment. However, this paucity may also be a
Accepted 28 February 2017
result of the scarcity of autopsies of mummies, together with technical difficulties in detecting neoplastic
Available online xxx
lesions in mummified tissues. An exception, and example of the benefits of thorough systematic analysis,
is the small sample of 10 Renaissance mummies from Naples (15th–16th centuries), in which 3 cases of
Keywords:
cancer were found. In order to increase detection of soft tissue tumors, it is imperative that mummies
Ancient neoplasm
Cancer
undergo systematic autopsies and histological examinations performed by skilled paleopathologists. This
Histopathology review of the known ancient soft tissue neoplasms demonstrates the state of histology of malignant
Ancient DNA and benign soft tissue neoplasms in mummies, and the potential for further study. The limitations of
Paleopathology paleopathological diagnosis will be discussed and an argument will be made for the use of autopsies and
histological analysis on mummified human remains.
© 2017 Published by Elsevier Inc.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Malignant tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.1. Rectal adenocarcinoma in a Roman Period Egyptian mummy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.2. Colorectal adenocarcinoma from Naples (15th century) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.3. Colon adenocarcinoma from Naples (16th century) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2.1. Basal cell carcinoma from Naples (16th century) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Skeletal muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.1. Rhabdomyosarcoma in a pre-Columbian mummy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Benign Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.1. Solar keratosis with squamous papilloma from Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.2. 3.1.2. Verruca vulgaris from Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.3. Verruca vulgaris in an Inca mummy from Chile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.4. Cutaneous angiokeratoma in an Inca mummy from Chile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.5. Condyloma acuminatum from Naples (16th century) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.6. Histiocytoma from Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.1. Mammary fibroadenoma from Late Period Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Mammary fibroadenoma from Naples (16th century) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.4. Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.4.1. Ovarian cystadenoma from Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

E-mail address: gino.fornaciari@med.unipi.it

http://dx.doi.org/10.1016/j.ijpp.2017.02.007
1879-9817/© 2017 Published by Elsevier Inc.

Please cite this article in press as: Fornaciari, G., Histology of ancient soft tissue tumors: A review. Int. J. Paleopathol. (2017),
http://dx.doi.org/10.1016/j.ijpp.2017.02.007
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IJPP-277; No. of Pages 13 ARTICLE IN PRESS
2 G. Fornaciari / International Journal of Paleopathology xxx (2017) xxx–xxx

3.5. Ovarian cystadenoma from central Italy (19th century) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00


3.6. Urinary bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.6.1. Vesical papilloma from Roman Period Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.7. Nerve sheath . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.7.1. Neurilemmoma from Late Period Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.8. Adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.8.1. Lipoma from pre-Columbian Chile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction 2.1.2. Colorectal adenocarcinoma from Naples (15th century)


The anthropogenic mummy of Ferrante I of Aragon
Although cancer currentlyrepresents the second leading cause (1424–1494), King of Naples, revealed a hollow fibrous struc-
of death in advanced countries (Torre et al., 2015), it has been said ture in the pelvis, identified as the rectum at autopsy. After
that the prevalence of cancer may have been lower in the past rehydration, the specimen reached a size of 14 × 6 × 1 cm (Fig. 2a)
(David and Zimmerman, 2010). The number of neoplastic lesions and on cross-section it appeared dark brown, with many small
documented so far in the paleopathological literature, distributed roundish grey-white areas 0.5–3.0 mm in diameter (Fig. 2b). His-
over a long time span and in different countries, includes about two tology revealed epithelial tumor cells, disposed in cords, solid nests
hundred cases in the skeletal apparatus (Strouhal, 1994; Capasso, and glands (Fig. 3a, b), disseminated in a fibrous stroma containing
2005; Hunt et al., in this issue). However, there are only eigh- striated muscular fibers (Fig. 4c). The cells were crowded and
teen cases of soft tissue tumors in the literature, all discovered tall, with abundant cytoplasm and pseudo-stratified pleomorphic
by paleopathologists (Fornaciari and Giuffra, 2012) using different hyperchromatic nuclei (Fig. 4a). Bizarre nuclei, with indentations
methods of rehydration (Ruffer, 1910; Sandison, 1955) and stain- and irregular clumps of chromatin appeared in electron microscopy
ing for light microscopy (Allison and Gerszten, 1982; Reyman and (Fig. 4b). The mucus was scarce and limited to pseudo-glandular
Dowd, 1980) or electron microscopy (Riddle, 1980). formations, as shown by the specific staining with Alcian-blue and
The main reasons for the rarity of soft tissue tumors in pale- PAS (Fig. 4d). These results pointed out a moderately differentiated
opathology, especially malignancies, are apparently the short life mucinous adenocarcinoma infiltrating the muscular-fibrous layers
span of past populations, the scarcity of mummified remains avail- of the small pelvis. A strong intracytoplasmic immunoreactivity
able in comparison with skeletal remains, and technical difficulties of the neoplastic cells for pancytokeratin was shown (Fig. 4e)
in the detection of neoplastic lesions in mummified tissues. This and a positive staining, showing actively proliferating cells, was
review of the known ancient soft tissue neoplasms demonstrates observed for Proliferating Cell Nuclear Antigen (PCNA) (Fig. 4f),
the state of histology of malignant and benign soft tissue neoplasms whereas Prostate-specific Antigen (PSA) and Carcinoembryonic
in mummies, and the potential for further study. The limitations Antigen (CEA) gave negative results. The histological, histochemi-
of paleopathological diagnosis will be discussed and an argument cal and immunohistochemical results clearly indicate a mucinous
will be made for the use of autopsies and histological analysis on adenocarcinoma of the digestive tract, most probably of the
mummified human remains. colorectum (Fornaciari, 1993).
DNA hybridization probe and sequencing analysis of K-RAS
exons 1–2 demonstrated the presence of the codon 12 GGT > GAT
2. Malignant tumors
transition (Marchetti et al., 1996; Ottini et al., 2011). This muta-
tion represents the most frequent mutation of the K-RAS gene in
2.1. Colon
sporadic colorectal cancer and is associated with exposure to chem-
ical carcinogens, probably present in the diet (Saffhill et al., 1985;
2.1.1. Rectal adenocarcinoma in a Roman Period Egyptian
Kuhnle and Bingham, 2007).
mummy
An increased intake of red meat is known to induce a signifi-
An abnormal tissue mass found in the rectum of an adult male
cant (3-fold) increase in fecal N-nitroso compound (NOC) levels,
mummy (West Cemetery #5, Body C) from the Dakhleh Oasis,
with a range of exposure evident in the feces similar to that from
Egypt, and dating back to the Roman Period, was examined his-
tobacco-specific NOC in cigarette smokers (Fornaciari et al., 1999).
tologically. The rectal wall was well-preserved, with a polypoid
A paleonutritional study with Carbon (13 C) and Nitrogen (15 N) sta-
mass protruding into the lumen and showing a relatively well-
ble isotopes revealed a massive intake of animal proteins caused
preserved hyperplastic colonic mucosa in a tubular pattern (Fig. 1a).
by a large consumption of meat by King Ferrante (Fornaciari, 2008),
The nuclei were not preserved, but the central portion of the lesion
and histology revealed severe atherosclerosis of the carotids (Gaeta
showed a deep invasion of the epithelium into the underlying
et al., 2013). In conclusion, the alimentary “environment” of the
muscularis (Fig. 1b, arrow). Although the cellular detail was not
Neapolitan court of the 15th century, with its abundance of natu-
well-preserved, the cells were shown to be periodic acid Schiff
ral endogenous alkylating agents, well explains the K-RAS mutation
(PAS)-positive and the reticulin stain showed an epithelial pattern,
that caused the tumor that killed the Aragonese king over five cen-
with clusters of cells surrounded by reticular fibers. Small clusters
turies ago.
of similar PAS-positive material were observed deep within the
muscularis, revealing a deep invasion through the wall (Zimmerman
and Aufderheide, 2010). The histological picture clearly demon- 2.1.3. Colon adenocarcinoma from Naples (16th century)
strated degenerated epithelial cells with prevalent non-invasive, Autopsy of the natural mummy of Luigi Carafa, Prince of
adenomatous structure, but some sections showed clear invasion Stigliano (1511–1576) (Fornaciari, 2006), showed “a hollow organ
and infiltration into the submucosa of an atypical glandular compo- with material” of about 8 × 3 cm, identifiable as a portion of a bowel
nent. This lesion is consistent with an infiltrating adenocarcinoma loop with feces. Histology revealed a tract of colon wall with very
occurring in a benign villous adenoma. well-preserved mucosa, submucosa, muscularis propria and vis-

Please cite this article in press as: Fornaciari, G., Histology of ancient soft tissue tumors: A review. Int. J. Paleopathol. (2017),
http://dx.doi.org/10.1016/j.ijpp.2017.02.007
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IJPP-277; No. of Pages 13 ARTICLE IN PRESS
G. Fornaciari / International Journal of Paleopathology xxx (2017) xxx–xxx 3

Fig. 1. a: Transition of rectal mucosa into villous adenoma (Hematoxylin Eosin, 40X); b: central portion of the adenoma shows malignant transformation, with deep invasion
of the epithelium into the underlying muscularis (arrow) (PAS, 40 X) (courtesy of M. Zimmerman).

Fig. 2. a, b: Section of the hollow structure of small pelvis at stereomicroscope after


rehydration: tumor massively infiltrating the internal, dark brown tissues of the
pelvis with many roundish yellow-white areas 0.5–3.0 mm in diameter (8X and
16X).

Fig. 3. a, b: Pseudo-glandular lumina and solid cords of tumor infiltrating fibrous


ceral peritoneum (Fig. 5a). The mucosa showed many pedunculated stroma (Hematoxylin Eosin, 40X and 100X).
villous projections, with narrow or wide base, long fronds of pap-
illary epithelium, and strong positivity of immunohistochemistry
®
for keratins (Anti-Pan Keratin Ventana ) springing directly from
the mucosal surface (Figs. 5a, b; 6a ). Upon further magnification, invasion of the stalk of a polyp (Fig. 6b, arrow) or of submucosa
dysplastic epithelial cells with an increased nuclear-to-cytoplasmic (Fig. 6a, arrow) was evident. The histological picture is that of a
ratio, hyperchromatic nuclei and nuclear pseudo-stratification, and well differentiated adenocarcinoma of the large bowel at stage T1,
atypical mucinous cells were apparent (Fig. 6b). This also revealed developed on a colonic villous adenoma (Rosai, 1996).
a strong positivity of immunohistochemistry against the altered It is quite probable that, in the last months of life, the prince
®
protein p53 (anti-p53 [BP53-11] Ventana ), present in many ade- suffered from intestinal colic, cured by the court doctors. The excel-
nocarcinomas (Bruner et al., 1993). In general, cribriform glands lent histological preservation of the cancer cells could be partly
interfaced directly with the lamina propria of the basement mem- explained by the use of alchemic, toxic drugs with antimicrobial
brane with no evident invasion. However, in some points, clear activity used in the Baroque medicine of the 16th century; particu-

Please cite this article in press as: Fornaciari, G., Histology of ancient soft tissue tumors: A review. Int. J. Paleopathol. (2017),
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Fig. 4. a: Pseudo-glandular lumen with tall cells and abundant cytoplasm (Hematoxylin Eosin, 800X); b: Irregular neoplastic nuclei with indentations and irregular clumps of
chromatin (EM, 6,000X); c: Neoplastic cells infiltrating muscular fibers (Van Gieson, 400X); d: Positivity for mucus stain of neoplastic glands (Alcian blue, 400X); e: Intense
®
positivity of neoplastic glands for Anti-Pan Keratin Sorin (immunofluorescence, 100X); f: Nuclear PCNA positivity of neoplastic cells (400X).

larly by the Paracelsus followers, to cure the colic pains (Paracelsus, epithelial-like aspects (Fig. 8a, b), well visible especially inside one
1573). of the largest lacunae (Fig. 8c). The border between the bone and the
A paleonutritional study with stable isotopes revealed a large underlying tissue in the lacunae is clear and sharp and the brownish
consumption of meat and minor consumption of marine fish by epithelial-like mass reveals a darker margin (similar to a palisade),
the prince (Fornaciari, 2008). The study of other immunohisto- and it is separated from the bone by clefting artifacts (Fig. 9a, b,
chemical markers as well as of the molecular (aDNA) picture of this arrows). The epithelial origin of the cells of the osteolytic lesion
extraordinarily well-preserved malignant tumor, that is unique in was confirmed by strong positivity for pancytokeratin.
the paleopathological literature, is in progress. The lesion of the facial skull of Ferdinando Orsini is macroscop-
ically and microscopically suggestive of a diagnosis of destructive
2.2. Skin basal cell carcinoma in an advanced stage of evolution (Fornaciari
et al., 1989; Gaeta et al., 2015). This tumor, which presents strong
2.2.1. Basal cell carcinoma from Naples (16th century) local aggressiveness and causes skin ulceration and bone destruc-
The natural mummy of Ferdinando Orsini, Duke of Gravina in tion (hence the Latin name of ‘ulcus rodens’ or erosive ulcer), is
Apulia (southern Italy), who died in 1549 at 50–55 years of age, currently one of the most common malignant skin neoplasms
showed a face completely covered by a veil and two small patches caused by exposure to sunlight (Crowson, 2006).
of cloth at the root of the nose and on the right orbit (Fig. 7a). After
removal of the veil and the patches, surely a medical dressing, an 2.3. Skeletal muscle
extensive and destructive lesion of the right orbit and the root of
the nose was apparent (Fig. 7b). At macroscopic examination, the 2.3.1. Rhabdomyosarcoma in a pre-Columbian mummy
lesion revealed complete destruction of the right nasal bone and A male child mummy, 12–18 months old, found in northern
root of the left nasal bone, and destruction of the medial wall of the Chile and belonging to the Cabaza culture, dating from 300 to
right orbit with extensive erosion of the glabellar region and the 600 CE., presented a large cheek tumor of 5.5 × 5.5 × 2 cm. The
upper third of the vomer (Fig. 7c). lesion, in the form of a hard swelling localized on the mummy’s
The histology of eroded fragments of the vomer and left nasal right cheek below the eye, forced that eye to close, but did not
bone showed large lacunae with clear borders, surrounded by involve the bones of the right orbit. Histology showed pleomor-
other smaller round lacunae, destroying the normal lamellar bone, phic, disintegrated cells surrounded by a delicate, fibrous stroma
sometimes containing clusters of partially necrotic cells with solid (Fig. 10

Please cite this article in press as: Fornaciari, G., Histology of ancient soft tissue tumors: A review. Int. J. Paleopathol. (2017),
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IJPP-277; No. of Pages 13 ARTICLE IN PRESS
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Table 1
Malignant soft tissue tumors in mummies.

No. Tumor Provenance Dating Age in years/Sex References

1 Rectum adenocarcinoma Egypt Roman Period adult/M Zimmerman and Aufderheide (2010)
2 Colorectal adenocarcinoma Naples 1494 70/M Fornaciari (1993), Marchetti et al.
(1996), Fornaciari et al. (1999), Ottini
et al. (2011)
3 Colon adenocarcinoma Naples 1576 65/M in this issue
4 Basal cell carcinoma Italy 1549 50–55/M Fornaciari et al. (1989), Gaeta et al.
(2015)
5 Rhabdomyosarcoma Chile 300–600 CE 1–2/M Gerszten and Allison (1991)

Fig. 5. a: Trait of colon wall with very well-preserved mucosa with villous pro-
jections, submucosa, muscularis propria and visceral peritoneum (Anti-Pan Keratin
®
Ventana , 20X); b: Pedunculated villous projections, with long fronds of papillary
epithelium and strong positivity at immunohistochemistry for keratins (Anti-Pan
®
Keratin Ventana , 50X).

a). Most of the cells revealed a shrunken cytoplasm; and in some


®
instances, nuclear material with a marked nuclear pleomorphism Fig. 6. a: Evident invasion of submucosa (arrows) (Anti-Pan Keratin Ventana ,
could be observed (Fig. 10b) (Gerszten and Allison, 1991; Gerszten 40X); b: Dysplastic epithelial cells with hypercromatic nuclei, nuclear pseudostrat-
ification, atypical mucinous cells and clear invasion of the stalk of a polyp (arrow)
et al., 2012). This histological picture is consistent with an alve- ®
(Anti-Pan Keratin Ventana , 160X).
olar rhabdomyosarcoma; a tumor occurring chiefly in sub-adults
under the age of 20 and also in very young children, as in this case
(Gerszten and Allison, 1991). More than 55% of rhabdomyosarcoma cells revealed slight positivity to anti-keratin antibodies. The his-
cases have a primary location in the head and neck (Weichert et al., tological picture is suggestive of verruca vulgaris (Fulcheri, 1987).
1976; Radzikowska et al., 2015) (Table 1).
3.1.3. Verruca vulgaris in an Inca mummy from Chile
3. Benign Tumors A frozen Inca mummy was found at a high altitude in the Andes,
on Cerro El Plomo, Chile. This 8–9 year old child, also known as
3.1. Skin ‘Prince of El Plomo’, was the victim of a human sacrifice (Horne,
1996). Two small lesions were observed at the base of the thumb
3.1.1. Solar keratosis with squamous papilloma from Egypt and index fingers of the left hand. These two rounded 2 mm neofor-
Histology of the hand skin of an adult female Egyptian mummy, mations, examined with transmission electron microscopy (TEM),
probably from the Late Period, showed a small ‘filiform’ squa- revealed the presence of viral-like, round structures, identified as
mous papilloma, marked hyperkeratosis, and a rather thinned-out human papilloma virus (HPV) (Fig. 13), allowing a diagnosis of ver-
epidermis (Fig. 11a). These changes suggest that the skin of this ruca vulgaris (Horne and Kawasaki, 1984; Horne, 1996).
individual was abnormal, with changes resembling those associ-
ated with solar keratosis (Fig. 11b) (Sandison, 1967). 3.1.4. Cutaneous angiokeratoma in an Inca mummy from Chile
Eight ulcerated lesions affected the legs of the aforementioned
3.1.2. 3.1.2. Verruca vulgaris from Egypt frozen Inca mummy. The lesions ranged from 0.5 to 1 cm in diam-
A protruding lesion 0.7 cm in diameter was observed on the eter, had well defined borders, and were covered by fibrinous
neck of an Egyptian mummy from the Marro Collection in Turin, exudate. Histology revealed numerous dilated vascular channels in
Italy (Cat. No. 61). The lesion was a raised, brown, roundish mass. the superficial dermis, filled with homogeneous eosinophilic mate-
Histology showed thickened epidermis with hyperkeratosis, parak- rial which may have been hemolyzed blood. These vessels appeared
eratosis, mild acanthosis, and some vascular spaces (Fig. 12). The to be capillaries and many were located immediately adjacent to

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Fig. 7. a: The face of Ferdinando Orsini covered by a veil and with two patches of cloth at the nose root and on the right orbit; b: Large, destructive lesion of the right orbit
and root of the nose; c: Complete destruction of the right nasal bone and the root of the left (nasal bone) and destruction of the medial wall of the right orbit with extensive
erosion of the glabella and the upper third of vomer.

the overlying epidermis, which sometimes appeared to encircle thickened epidermis and less dense internal tissue with dilated ves-
the vessels. Larger dilated capillaries were also present in the sub- sels (Fig. 14c, d). The histological picture suggested the diagnosis of
cutaneous fat. The epidermis was thickened and hyperkeratotic, condyloma acuminatum, a squamous lesion of the external genitalia
with a papillary configuration where the capillaries are most abun- induced by Human Papilloma Virus (HPV).
dant (Fig. 16). In this area the lesion was ulcerated, with an acute Amplification of DNA allowed for the detection of HPV 18, a
inflammatory exudate characterized by fibrin and an infiltrate of strain with high oncogenic potential for some epithelial cancers
polymorphonuclear leukocytes and other types of white blood of the female genital tract. Cloning and sequencing of amplified
cells. The histologic features are consistent with an angiokeratoma, fragments confirmed the infection with HPV 18 and also revealed
probably angiokeratoma circumscriptum, secondarily inflamed and the presence of JC9813 DNA, another HPV strain with low oncogenic
ulcerated (Horne and Kawasaki, 1984; Horne 1986; Horne, 1996). potential (Fornaciari et al., 2003).

3.1.5. Condyloma acuminatum from Naples (16th century) 3.1.6. Histiocytoma from Egypt
The anthropogenic mummy of Maria of Aragon (1503–1568), A dermal neoplasm was histologically observed on the skin of a
Marquise of Vasto, in the Basilica of S. Domenico in Naples, revealed mummified left heel from a tomb generically attributed to Upper
a small, pedunculated, branching skin neoformation of about Egypt (1290 BCE to 200 CE). One section of the skin showed a well-
3 × 12 mm in the right paravulvar region (Fig. 14a). After rehydra- circumscribed dermal mass composed of whorled, dark-staining
tion, hematoxylin-eosin and Masson’s trichrome staining allowed material. Masson’s trichrome staining revealed a small amount of
the observation of an exophytic papillary skin lesion (fig. 14b) with fine fibrous tissue within the lesion (Fig. 15) with positivity for

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Fig. 8. a, b: Large lacunae, surrounded by smaller round lacunae, destructing the


normal lamellar bone (Van Gieson, 50X; Hematoxylin Eosin, 30X); c: two lacu-
nae containing clusters of partially necrotic cells with solid epithelial-like aspects
(Hematoxylin Eosin, 60X).

Fig. 10. a: Pleomorphic, disintegrated cells surrounded by a delicate, fibrous stroma


(Hematoxylin Eosin, 200X); b: The cells reveal a shrunken cytoplasm and a marked
nuclear pleomorphism (HE, 600X) (courtesy of E. Gerszten).

iron stain and iron deposition confined to the lesion. The overly-
ing epidermis was necrotic. The dermal location, the features of
the lesion with its whorled appearance and the presence of iron
stain suggested a diagnosis of histiocytoma (Zimmerman, 1981).

3.2. Breast

3.2.1. Mammary fibroadenoma from Late Period Egypt


The Egyptian mummy known as PUM III (Pennsylvania Univer-
sity Museum III), belonging to a 35-year-old female and dating back
to approximately 835 BCE (Reyman and Peck, 1980), revealed a
small nodule of 1 cm in diameter in the lateral region of the left
breast. Through histology, it was revealed that the nodule was
not formed by connective tissue, but presented elements recogniz-
able as epithelial cells (Fig. 17a). The connective tissue contained
irregular cyst-like spaces, some of which presented large, partially
preserved cuboidal cells with recognizable nuclei (Fig. 17b). These
had the appearance of epithelial cells. The overall configuration and
residual microanatomy strongly suggested that this was a fibroade-
noma of the breast. The woman’s age, the size of the tumor, and its
lateral position in the breast supported this diagnosis (Reyman and
Peck, 1980).

Fig. 9. a: Brownish like-epithelial mass with a darker margin, looking like a pal- 3.3. Mammary fibroadenoma from Naples (16th century)
isade (arrows) (Van Gieson, 120X), separated from the bone by clefting artifacts
(Hematoxylin Eosin, 150X). Mammography, after breast rehydration, of the anthropogenic
mummy of Maria of Aragon (1503–1568), Marquise of Vasto, in

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Fig. 13. Papilloma virus from hand wart (EM, 300,000X; bar: 0.03 ␮m) (Horne,
1996).

the Basilica of S. Domenico in Naples, revealed a dense fibrous


tissue with cystic spaces and microcalcifications particularly evi-
dent in the right breast (Fig. 17a). Histology confirmed a dense
fibrous tissue with empty spaces and fibrous cyst walls, suggestive
of fibrocystic changes in advanced involution phase. Many single
and grouped microcalcifications, consisting of rounded basophilic
granules with a slightly eosinophil centre, were also evident. In
the upper outer quadrant of the right breast, two roundish forma-
Fig. 11. a: Marked hyperkeratosis with squamous papilloma (Phosphotungstic acid
tions of fibrous-hyaline connective tissue, with a diameter of about
Haematoxylin, 150X); b: solar keratosis (Heidenhein’s iron Hematoxylin, 300X).
1 and 0.8 cm respectively, suggested two hyaline fibroadenomas
(Fig. 18b) (Ventura et al., 2014).

3.4. Ovary

3.4.1. Ovarian cystadenoma from Egypt


A female mummy of the Ptolemaic Period was autopsied in 1825
by Granville, who concluded that “the disease which appears to have
destroyed her was ovarian dropsy attended with structural derange-
ment of the uterine system generally”. He also observed that the
uterus was larger than that of a 50–55-year-old woman, that there
was “a large sac connected with the left ovarium. . .”, that “the ovar-
ium and broad ligament of the right side are enveloped in a mass of
diseased structure. . .”, and that the right fallopian tube was nor-
mal (Granville, 1825). Fig. 1 of Plate XXII of Granville’s article is a
drawing that shows the right ovary and the parametrial tissues in
a confused mass of structures in continuity with the uterine body
(Fig. 19a). The upper part of what appears to be a “bulbous uterus”
emerges from behind these tangled structures. The left tube area is
shredded into three linear, strap-like structures terminating in two
rounded folds. A diagnosis of bilateral ovarian cystadenoma (or cys-
tadenocarcinoma) was consistent with this drawing (Aufderheide,
2003), but modern histology of this tumor showed no evidence
of malignancy, supporting the diagnosis of ovarian cystadenoma
(Fig. 19b) (Sandison and Tapp, 1998).

3.5. Ovarian cystadenoma from central Italy (19th century)

Among the natural mummies found in the Convent of S. George


of the Observants in Goriano Valli (L’Aquila, central Italy), the body
of a woman aged 43–50 years, dating back to the second half of
Fig. 12. Thickened epidermis with hyperkeratosis, parakeratosis, mild acantho- the 19th century, revealed the presence of a large neoformation
sis and vascular spaces, suggestive of verruca vulgaris (Hematoxylin Eosin, 200X) (approximately 10 cm in diameter) near the uterus in the abdom-
(courtesy of E. Fulcheri). inal cavity. CT examination showed a cribrous mass in the right
iliac fossa and pelvis. Histology showed a large cystic neoplasm,

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Fig. 14. a: Small pedunculated, branching skin tumor at stereomicroscope (7X); b: Section of papillary tumor, with peduncle and dilated vessels (Masson’s trichromic, 5X);
c, d: exophytic papillary branch with thickened epidermis and dilated vessels (Masson’s trichromic, 50X, 70X).

partially solid, with fibrous walls and small papillary formations growing in hour-glass shape, was observed outside the sacrum
partially covered by necrotic epithelium (Fig. 20). The macroscopic, (Fig. 22a) of an almost skeletonized female mummy of 35–45
radiological and histological pictures allowed a diagnosis of ovar- years, dating back to the late 26th Dynasty (prior to 625 BCE).
ian neoplasm, most probably a papillary cystadenoma, although it Histology revealed bundles of spindle-shaped cells disposed in
was impossible to establish the grade of malignancy (Ventura et al., collagenous stroma, showing nuclear palisading, sometimes in a
2006). whorl-like pattern (Fig. 22b) or arranged in networks, suspended
in a myxoid or microcystic matrix, accompanied by blood vessels
3.6. Urinary bladder with areas of hyalinization. Immunohistochemistry showed pos-
itivity for Glial Fibrillary Acidic Protein (GFAP) and for Epithelial
3.6.1. Vesical papilloma from Roman Period Egypt Membrane Antigen (EMA). At very high magnification by transmis-
Macroscopic examination of the bladder in an adult male sion electron microscopy (TEM), details of spindle-shaped tumor
mummy from the Dakhleh Oasis, Egypt, dating back to the Roman cells were obtained. The macroscopic, radiographic, and histologi-
Period, showed a small papillary excrescence. Histology revealed cal analysis allowed a diagnosis of neurilemmoma, a benign tumor
internal basophilic nuclear material and a reticulin stain. Small originating from a nerve sheath (Strouhal and Nemecková, 2004).
clusters of cells surrounded by reticulin were consistent with an
epithelial tumor (Fig. 21). The diagnosis was an epithelial tumor, 3.8. Adipose tissue
in particular papilloma (or low-grade carcinoma) of the bladder
(Zimmerman and Aufderheide, 2010). 3.8.1. Lipoma from pre-Columbian Chile
The poorly preserved body of an adolescent 14-year-old male
3.7. Nerve sheath from Northern Chile, dated to between 1100 and 1200 CE (Gerszten
et al., 2012), showed a subcutaneous mass of 4 × 4 × 2 cm, on
3.7.1. Neurilemmoma from Late Period Egypt the right side of the chest, approximately 6 cm below the axilla
A large, smooth-walled and rounded cavity, moulded by the (Fig. 23a). Histology revealed conglomeration of mature adipose
pressure of a relatively hard, globular and lobulated tissue mass tissue cells intermingling with fibrous septa (Fig. 23b). The micro-

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Table 2
Benign soft tissue tumors in mummies.

No. Tumor Provenance Dating Age in years/Sex References

1 Squamous skin papilloma Egypt Late Dynastic. adult/F Sandison (1967)


2 Verruca vulgaris Egypt ND adult/? Fulcheri (1987)
3 Verruca vulgaris Chile 15th century 8–9/M Horne and Kawasaki (1984), Horne (1996)
4 Condyloma acuminatum Naples 1568 65/F Fornaciari et al. (2003)
5 Histiocytoma Egypt 1290 BCE-200 CE adult/? Zimmerman (1981)
6 Angiokeratoma circumscriptum Chile 15th century 8–9/M Horne and Kawasaki (1986), Horne (1996)
7 Mammary fibroadenoma Egypt ca. 835 BCE 35/F Reyman and Peck (1980)
8 Mammary fibroadenoma Naples 1568 65/F Ventura et al. (2014)
9 Ovary cystadenoma Egypt Ptolemaic. 50–55/F Grenville (1825), Sandison and Tapp (1998)
10 Ovary cystadenoma Italy 19th century 45–50/F Ventura et al. (2006)
11 Vesical papilloma Egypt Roman. adult/M Zimmerman and Aufderheide (2010)
12 Neurilemmoma Egypt Late Dynastic. 35–45/F Strouhal and Nemecková (2004)
13 Lipoma Chile 110–1200 AD 14/M Gerszten and Allison (1991)

Fig. 16. Hyperkeratotic, acanthotic vascular lesion: The capillaries extend from the
epidermis, through the dermis, into subcutaneous adipose tissue. At right of plate,
the epidermis is ulcerated (Hematoxylin Eosin, 250X) (Horne and Kawasaki, 1992).

verrucae, one single case of condyloma, one squamous papilloma,


one histiocytoma, and one angiokeratoma), two breast fibroadeno-
Fig. 15. Well-circumscribed dermal mass composed of whorled, dark-staining
material with small amount of fine fibrous tissue within the lesion, suggesting mas, two ovary cystadenomas, and single cases of urinary bladder
histiocytoma (Hematoxylin Eosin, 40X) (courtesy of M. Zimmerman). papilloma, neurilemmoma and lipoma.
The rarity of soft tissue tumors in paleopathology, espe-
cially malignant ones, is a highly debated problem (David and
scopic features are those of a benign lipoma (Gerszten and Allison, Zimmerman, 2010). The most common types of bone tumors seen
1991; Gerszten et al., 2012) (Table 2). in modern patients have been detected in ancient skeletal remains
(Capasso, 2005). However, the apparent paucity of ancient can-
4. Conclusions cers of internal organs, such as lung, stomach, liver, prostate or
thyroid, that are so frequent in modern populations, needs some
Thus far, there have only been 18 soft tissue neoplasms recorded consideration.
and histologically examined in mummified human remains. Only With regard to Egyptian mummies, it has been suggested
five of these cases have been identified as malignant: three cases that the embalming practice of the Dynastic Period, which often
of colorectal carcinomas, one basal cell carcinoma and one rhab- required the removal of the internal organs, did not allow for pale-
domyosarcoma, with a prevalence of epithelial tumors. The other opathological diagnosis of visceral soft tissue neoplasms. However,
cases are benign tumors, including as many as six skin tumors (two in the natural mummies (e.g. Predynastic and Roman Period Egyp-

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Fig. 17. a: Breast sample with nodule of connective tissue and without adipose
tissue, with elements recognizable as epithelial cells (Fig. 15a) (Weigert, 5X); b:
Irregular cyst like spaces, with large, partially preserved, epithelial cells with recog-
nizable nuclei (Fig. 15b) (Weigert, 200X) (Reyman and Peck, 1980). Fig. 18. a: Mammography with dense fibrous tissue, cystic spaces and microcalcifi-
cations in the right breast; b: In dense fibrous tissue and fibrous walls of cysts with
rare microcalcifications, two roundish formations of fibrous-hyaline connective, of
tian mummies, and the majority of South American mummies), about 1 and 0.8 cm in diameter, suggest two hyaline fibroadenomas (Hematoxylin
which maintain the internal organs, the relative scarcity of neo- Eosin, 10X).
plastic diagnoses requires a different explanation.
Tumoral proliferation, itself, could lead to severe alteration of
the tissues, making them more susceptible to rapid deterioration.
However, experimental studies about the effects of mummification
on neoplastic tissues and cells clearly demonstrated that malig-
nant tumors are histologically much better preserved than normal
organs (Zimmerman, 1977). For these reasons, the lack of evidence
in mummies could indicate a different occurrence in past societies.
The longer life span of modern populations can explain the high
incidence of cancer, which is the second leading cause of death in
modern developing countries, as a result of population aging (Torre
et al., 2015). On the contrary, the average age at death in past soci-
eties was considerably lower and death often arrived before cancer
could manifest itself (Capasso, 2005). Additionally, several risk fac-
tors such as cigarette smoke, pollution, chemical substances, drugs
and anthropogenic radiation related to modern industrial society,
have increasingly contributed to the current prevalence of cancer,
as many of these factors were not present in the pre-Modern era.
It should be noted that mummified remains are much rarer find-
ings than skeletal remains, but many Egyptian and South-American
mummies found in the course of the 19th and 20th centuries were
submitted to unscientific dissection without documented results.
The few paleopathological tumor diagnoses were obtained only
when autopsies of mummies were performed by a specialist in soft
tissue paleopathology (Aufderheide, 2003).
The most recent studies on mummies have been conducted with
non-invasive methods. Unfortunately, the diagnosis of soft tissue
tumors is extraordinarily difficult on the basis of only radiologi-
cal and endoscopic examination; moreover, lesions suggestive of Fig. 19. a: Macroscopic aspect of bilateral cystadenoma of ovary (Granville, 1825);
malignant tumors still require confirmation by histology. For this b: Wall of the ovarian cystic tumor of Granville’s mummy, with rounded remains of
reason, the small series of Renaissance mummies from Naples, the papillary projections (Sandison and Tapp, 1998) (Hematoxylin Eosin, 160X).

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Fig. 20. Fibrous wall of partially solid, large cystic neoplasm, with small papillary
formations partially covered by necrotic epithelium (Hematoxylin Eosin, 100X).

composed of eleven adults (10 males and only 1 female) (Fornaciari,


2006) with three cases of cancer in individuals between 55 and 71
years of age, is particularly important. Despite the limited num-
ber of examined individuals, the cancer prevalence of 33.3% in this
small group is similar to that of 30.9% we find in more developed
Fig. 21. Wall of urinary bladder with small papillary transitional cell papilloma
modern countries (Torre et al., 2015). As a result, we can conclude (Hematoxylin Eosin, 40X) (courtesy of E. Gerszten).
that probably, at least in some particular environmental and age
conditions as in this series of Spanish nobles interred in Naples,
of damaged or partial mummies, under the supervision of a com-
cancer in the past must have been frequent.
petent paleopathologist, paying maximum attention to any small
In conclusion, even if mummy autopsies have been avoided in
sign of neoplastic disease. I am convinced that in this manner, the
the last decades for their destructive character, it may still be ben-
number of known ancient soft tissue tumors will increase greatly.
eficial and possible to perform them without problems in cases

Fig. 22. a: X-ray of sacrum showing oval cavities in right half of the second segment and a large and minor cavities cavity in left half of the second and third segment;
b: Bundles of spindle-shaped cells arranged in collagenous stroma showing nuclear palisading, in whorl-like pattern (white triangle) (Toluidine blue, 200X) (Strouhal and
Nemecková, 2004).

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Please cite this article in press as: Fornaciari, G., Histology of ancient soft tissue tumors: A review. Int. J. Paleopathol. (2017),
http://dx.doi.org/10.1016/j.ijpp.2017.02.007