Case report
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Kan Ikegami

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Bilateral Adrenal Primary Malignant Lymphomawith Inappropriate Secretion of Antidiuretic Hormone p
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Review article
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Daisuke Mizokami

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Granulomatous Mastitis with Erythema Nodosum
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Fumitaka Yoshimura

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Contrast-enhanced ultrasonographic diagnosis
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Naoya Fujita

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Fibroma caused by years of carrying a portable Shinto shrine：
Mikoshi-kobu p
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JHGM 2022：4-4

174― Case report ―A case of cervical esophageal cancer
with a supraclavicular abscess
Kan Ikegami1)2)※
Daisuke Mizokami1)
Saki Takihata1)
2)
Kosuke Uno
Akihiro Shiotani2)
1) Nishisaitama-Chuo National Hospital, Otolaryngology, Head & Neck Surgery2) National Defense Medical College, Otolaryngology, Head & Neck Surgery

Key Words：esophageal cancer, supraclavicular abscess, lymph node metastasis

Advanced esophageal cancer is known to cause perforation leading to mediastinitis or
mediastinal abscess, however, it is very rare for the cervical abscess to be the initial presentation.
Here, we report a case of cervical esophageal cancer which was first diagnosed as a cervicalabscess. A 64-year-old female was referred to our hospital with a diagnosis of a cervical abscessin the left supraclavicular fossa. The laryngoscopic result showed no abnormal findings. The
abscess was incised and drained under local anesthesia, in addition to wound irrigation andsystemic antibiotics, which lead to a quick recovery of her condition. One month after thedischarge, a tumor mass increased in her incision, with contrast-enhanced CT showing thickeningof the esophagus, which indicated esophageal cancer. Upper gastrointestinal endoscopy revealed
advanced cervical and thoracic esophageal cancer (squamous cell carcinoma). Deep cervicalabscesses are often caused by dental infection or tonsillitis in the upper neck, but it is rare to form
a confined abscess in the supraclavicular fossa. Therefore, malignant tumors should be suspected
depending on the location of the cervical abscess.

Introduction

Case presentation

Perforation caused by advanced esopha-

A 64-year-old Asian female with a three-geal cancer is known to cause mediastinitis, but

week history of fever, progressive swelling, and1)

a cervical abscess is rarely the first sign .

pain in the left side of her neck was referred toFurthermore, abscesses of metastatic lymph

our hospital. She had had a lower left molar

nodes have often been reported, but it is very

tooth extracted three weeks ago and has beenrare to form a confined abscess in the supracla-complaining of pain and swelling in her left

2)

vicular fossa . Malignant tumors should beneck for two weeks. Her family doctor diag-suspected depending on the location and nature

nosed cervical lymphadenitis and administeredof the abscess. Here, we report a case of cervicaloral antibiotics, but her symptoms did notesophageal cancer which was difficult toimprove. The inflammatory response on blood

distinguish from a cervical abscess.

tests was very high, and contrast-enhanced CT
scans showed abscess formation in her left
supraclavicular fossa. There were no significant※ Correspondence to：2-1671, Wakasa, Tokorozawa City,
Saitama, Japan
Nishisaitama-Chuo National Hospital,
Otolaryngology, Head & Neck Surgery

findings in the esophagus (Fig. 1 ). Therefore,
the patient was referred to our head and neck

JHGM 2022：4-4

175

Figure 1

Figure 2

First contrast-enhanced CT showed a poor internal
enhanced effect, suggesting abscess formation in the left
supraclavicular fossa. There was no tumorous lesion in theesophagus.

Second contrast-enhanced CT at readmission showed asolid tumor with internal contrast effect, as big as fig.1.
The cervical esophageal wall was irregularly thickened
and was compressed extramurally by a subclavian tumor,
indicating supraclavicular metastasis from cervical esophageal cancer.

surgery department urgently for surgical drain-

return to her primary care physician, where sheage. She had a 10 years history of depression.

had her wounds cleaned and was given oral

She had no smoking and alcoholic history.

penicillin. One month after the discharge,

Physical examination showed no abnormal

contrast-enhanced CT was performed due to an

findings

pharynx.

increased mass in her wound and complaints ofLaryngoscopy of her throat and chest X-ray alsodysphagia. The patient was readmitted to ourshowed normal findings. Admission investiga-

hospital because of a tumorous lesion on thetions revealed a leukocytosis of neutrophilsright side of the upper esophagus and anwith white blood cell counts at 13900 /mcl

increasing trend of the left neck mass lesion(reference range 3500-8500 /mcl), high C-(Fig. 2 ). The biopsy at the supraclavicular

reactive protein level at 21.96 mg/dl (reference

mass showed squamous cell carcinoma. The

range 0. 00-0. 14 mg/dL), normocytic anemia

head and neck area were examined again,

with hemoglobin at 10.1 g/dL (reference range

including endoscopy, but no primary lesion was

11.7-14.7 g/dL), low albumin at 3.1 g/dl

found.

(reference range 3. 4-5. 0 g/dL), and normal

showed a progressing ulcerative tumor in the

total protein at 6.9 g/dL (reference range 6.4-

cervical and thoracic esophageal mucosa (Fig.

8.2 g/dL). T-SPOT.TB test was negative. Soluble

3 ). Videofluorography showed partial narrow-interleukin-2 receptor (sIL-2R) was high at 864

ing of the upper esophagus and has shifted to

U/mL (range 158-623 U/mL). Her abscess was

the right side, but there was no fistulaincised and drained under local anesthesia. The

formation. Since biopsy from the esophageal

culture of the pus from the abscess showed

ulcer showed squamous cell carcinoma, we. Surgical drainage

concluded that the cervical esophageal cancer

and intravenous antibiotics dramatically im-

resulted in a supraclavicular abscess. After

proved her symptoms and the inflammatory

diagnosis, the patient was transferred toresponse on blood tests. She was instructed toanother hospital due to difficulty in treatment.

in

the

oral

cavityorUppergastrointestinalendoscopy

Esophageal cancer with a neck abscess

176

Figure 3Upper gastrointestinal endoscopy, including narrow-band imaging, showed advanced neoplastic lesions in the cervicalesophagus.

The patient was treated with palliative irradia-

Deep cervical infection is a general term fortion, but her condition worsened, and she died

infections occurring in the cervical space,four months after the initial visit.

including lymphadenitis, cellulitis, and abscesses. The parapharyngeal space is the mostDiscussioncommon site of infection, followed by the

Dysphagia is the most common initialcarotid and posterior pharyngeal space, but

symptom of esophageal cancer, and pain incases of abscess formation confined to theswallowing is present in 17% of cases. Other

supraclavicular fossa have not been reported.

symptoms such as weight loss, dyspnea, cough,Contrast-enhanced CT showed a ring-shaped

hoarseness, and back pain may also becontrast pattern with an internal low-density

3)

observed . However, detection of a neck1)

region, which indicated not only an abscess but

infection as the first sign is extremely rare . In

also another benign or malignant lymph node.

this case, esophageal fluorography shows no

Benign diseases include histiocytic necrotizing

signs of fistula, suggesting that the metastatic

lymphadenitis, tuberculosis, syphilis, and cat-lymph nodes were infected by the hematoge-scratch disease, while malignant diseases in-nous or lymphatic route and formed an abscess.

clude metastases from head and neck cancer,

Although central necrosis is often the cause of

distant metastases from organs other than theabscess formation in metastatic lymph nodes,

head and neck, and malignant lymphoma. It isabscesses are less likely to occur in the headsaid that metastasis from the primary lesion

and neck region than in other parts of the body

below the clavicle occurs in the supraclavicular

2,4)

. The

fossa lymph nodes as Virchowʼs node metasta-

fact that the culture from her abscess was

sis, while first metastasis from head and neck, a common oral

cancers occur in others area of the neck5). In

organism, and the fact that the molar tooth had

Japan, supraclavicular lymph node metastasis isbeen extracted by the dentist 3 months before

classified to be a second or third group of

the diagnosis suggests that the disease may

affiliated lymph nodes by upper thoracic andhave been caused by a dental infection.

mid-thoracic esophageal cancer or a third group

because of the abundant blood flow

JHGM 2022：4-4

177

of metastatic lymph nodes by lower thoracic
6)

esophageal cancer . On the other hand,according

to

the

8th

UICC

(UnionofInternational Cancer Control) TNM classification, supraclavicular lymph nodes are notincluded in the regional lymph nodes and areclassified as distant metastases (M1). Wen
reported7) that 517 patients (8.7%) withsupraclavicular lymph nodes were found in
6,178 patients with thoracic esophageal cancer.
The left supraclavicular lymph node, commonly
known as the Virchowʼ s lymph node, collects
lymph from most of the body, primarily theabdomen. Therefore, lymph node metastasis in
the left supraclavicular fossa is consideredsuggestive of abdominal cancer. On the other
hand, the right supraclavicular lymph node
receives its supply mainly from the mediastinum, lungs, and esophagus8). When recallingthese as primary cancer, it is important to pay
attention to the bilateral supraclavicular lymph
nodes9). Metastasis in the supraclavicularlymph node may cause a poor prognosis5).
Supraclavicular abscesses should be examinedwith upper gastrointestinal endoscopy.

Conclusions
We report a rare case of thoracic esophageal carcinoma detected by a cervical abscess. A
malignant tumor should be suspected behind
the abscess when abscess formation is confinedto the supraclavicular fossa. Not only head andConflict of interest The authors declare that they have noconflicts of interest.

neck cancers but also metastases from the area
below the clavicle should be considered.

Ethical approval
The case report is exempt from ethicalapproval at our institution.

References
１) Rehders A, Baseras B, Telan L, et al. Esophageal cancer
complicated by esophagopulmonary fistula and lungabscess formation. A surgical approach. Thoracic
Cancer 2014；5：468-71.
２) Lee WC, Walsh RM, and Tse A. Squamous cell
carcinoma of the pharynx and larynx presenting as aneck abscess or cellulitis. J. Laryngol. Otol 1996；
110：893-5
３) Enzinger PC and Mayer RJ. Esophageal Cancer. N Engl
J Med 2003；349：2241-52.
４) Thompson HY, Fulmer RP, and Schnadig VJ.
Metastatic squamous cell carcinoma of the tonsil
presenting as multiple cystic neck masses. Report of acase with fine needle aspiration findings. Acta Cytol
1994；38：605-7
５) Tong C, Luk MY, Chow SM, et al. Cervical nodal
metastases from occult primary：UndifferentiatedCarcinoma versus squamous cell carcinoma. Head
Neck 2002；24：361-9
６) Japan Esophageal Society. Japanese Classification of
Esophageal cancer, 11th Edition：Part I. Esophagus.
2017；14：1-36
７) Wen J, Chen D, Zhao T, et al. Should the clinicalsignificance of supraclavicular and celiac lymph nodemetastasis in thoracic esophageal cancer be reevaluated?. Thoracic Cancer 2019；10：1725-35
８) Mizutani M, Nawata S, Hirai I, et al. Anatomy andhistology of Virchowʼs node. Anat Sci Int 2005；80：
193-8.
９) Tanaka T and Ohmichi M, Recurrent ovarian cancer
presenting in the right supraclavicular lymph nodewith isolated metastasis：a case report. Journal of
Medical Case Reports 2012；6：176

JHGM 2022：4-4

178― Case report ―Bilateral Adrenal Primary Malignant Lymphomawith Inappropriate Secretion of Antidiuretic Hormone
Mari Arikawa1)※
Jun Ando2)

Yuichi Takahashi1)
Tomonori Ochiai2)

Nagamasa Kano1)
Kohei Yamada2)
2)
Sakiko Harada
Toshio Naito1)

1) Department of General Medicine, Juntendo University Faculty of Medicine
2) Department of Hematology, Juntendo University Hospital

Key Words：adrenal gland primary malignant lymphoma, bilateral adrenal tumor,
syndrome of inappropriate secretion of antidiuretic hormone

Herein, we report a case of bilateral adrenal primary malignant lymphoma withinappropriate secretion of antidiuretic hormone. A 63-year-old man was admitted to Juntendo
University Hospital after experiencing weight loss for two months and fever for one month. The
blood tests showed normocytic normochromic anemia, liver dysfunction, hypoalbuminemia,
hyponatremia, high levels of blood sedimentation, and the presence of sIL-2R. Computed
tomography (CT) revealed bilaterally enlarged adrenal glands. We suspected an adrenal primarymalignant lymphoma with concomitant inappropriate secretion of antidiuretic hormone. CTguided bottom adrenal gland biopsy was performed. Beause the histopathology showed adiagnosis of diffuse large B-cell lymphoma (DLBCL), rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP) therapy was administered.

Introduction

thus we report it in this study, along with areview of literature.

Over the past ten years, there has been an

Case Presentation

increasing number of reports on the incidenceof adrenal primary malignant lymphoma；cur-A63-year-oldmanexperienced

cold

rently, there are approximately 200 reports ofsweats, dyspnea, and numbness in both feet forcases. The incidence of extra-nodal lymphoma

two months before being hospitalized at theof non-Hodgkinʼs lymphoma of adrenal origin is

Cranial Nerve Internal Medicine Department ofless than 1%, with the median survival time

the Juntendo University hospital. Magnetic

being usually within one year, and the progno-

resonance imaging (MRI) of the head did not

sis being very poor. Therefore, quick diagnosis

reveal any significant findings. Subsequently, heand early initiation of chemotherapy is crucial.

was diagnosed with a transient ischemic attack

To the best of our knowledge only one case of

by a physician, and was treated with clopidogrelbilateral adrenal primary malignant lymphoma

and rosuvastatin. However, this was stopped

complicated with inappropriate antidiuretic

approximately two weeks later because hehormone secretion (SIADH) has been found,reported neck pain after initiation of treatment.
The patient then consulted our department and※ Correspondence to：Japan Hongo 3-1-3, Bunkyo-ku,
Tokyo, 113-8421, Japan.
Department of General Medicine,
Juntendo University Faculty of Medicine

was hospitalized for further investigation because he had lost approximately 12 kg over the

JHGM 2022：4-4

179

Figure 1 Contrast-enhanced CT of the abdomen

Figure 2 Contrast-enhanced magnetic resonance imaging of the abdomen. (T2WI)

past two months, had a fever of 侒 38 ℃, andanorexia and night sweats for one month.
A physical examination did not indicate thepresence of lymphadenopathy or any otherabnormal findings, except for a low BMI. Bloodtests showed that he had normocytic normochromic anemia, liver dysfunction, inflammatory reaction hyponatremia, and increased sIL2R levels. Abdominal ultrasonography showedenlargement of both adrenal glands, with theleft adrenal gland measuring 58 × 17 mm andthe right adrenal gland measuring 62 × 14
mm. Computed tomography (CT) (Fig . 1 )revealedbilateraladrenalenlargement.

Figure 3 FDG-PET

Moreover, the abdominal cystography MRI (Fig.
2 ) showed similar bilateral adrenal enlarge-

tuberculous acid-fast bacilli were negative. LDH

ment with the inside exhibiting a relatively

level was within normal range；however,uniform low signal on T1WI and an equal signal

primary malignant adrenal lymphoma wason T2WI. The dynamic contrast showed ansuspected because enlarged bilateral adrenalaugmentation effect that was more heterogene-

lymphoma also presents with similar symptoms

ous than that observed in the early phase. There(fever, anemia, high ferritin levels, high IL-2R

was no lymphadenopathy or ascites.

levels) and radiological findings, as seen in thisBecause of the patientʼs symptoms(fever,case. Therefore, we performed a PET-CT scanweight loss, and bilateral adrenal enlargement),(Fig . 3 ), which showed bilateral adrenal en-

we considered differential diagnoses of infec-

largement in the same area as observed in thetions, such as tuberculosis, malignant lympho-

contrast CT；in addition, there was strong

ma, and adrenal tumor. The blood culture test

accumulation of FDG. The spleen showed

did not yield any significant bacteria, and the

diffuse enlargement and weak FDG accumula-

PCR

tion represented by DLBCL, while the lumbar

resultsfortuberculosis

and

non-

Adrenal primary malignant lymphoma

180

vertebrae, femur, and ribs showed light accumulation. We suspected the presence of an
intravascular malignant lymphoma and performed a random skin biopsy. We also performed a CT-guided adrenal gland biopsy todiagnose malignant lymphoma and an adrenal
tumor. Histopathological examination of theskin revealed mild perivascular lymphocyte
infiltration. The adrenal histopathology (Fig. 4 )Figure 4 Pathology of adrenal glandalso revealed the presence of a malignant

CD20 staining (150x)

lymphoma with CD3 (‑), CD5 (‑), CD10 (＋),
CD20(＋), CD79a (＋), Bcl-2 (＋), Bcl-6(＋),

Table 1 Laboratory Data on Admission to Our Department
Hematology

Blood osmolality

272 mOsm/L

WBC

8500 /μL

Ferritin

1602 ng/mL

RBC

347 × 104/μL

ADH

0.9 pg/mL

Hb

9.9 g/dL

IL-2R

6910 IU/mL

Ht

30.30%

ImmunityPlt

49.7 × 105/μL

IgG

2395 mg/dL

Blood Chemistry

IgG4

76.2 mg/dL

T-bil

0.8 mg/dL

IgA

503 mg/dL

ALP

696 IU/L

IgM

42 mg/dL

AST

90 IU/L

EndocrineALT

95 IU/L

TSH

1.31 μIU/mL

LDH

221 IU/L

FT3

1.3 pg/mL

γ GTP

70 IU/L

FT4

1.1 ng/dL

BUN

13 mg/dL

cortisol

19.4 μg/dL

Cre0.50 mg/dL

ACTH20.0 pg/mLUA

2.0 mg/dL

Plasma renin activity

0.8 ng/mL/h

CK＜ 5 IU/L

catecholamine

normalNa

129 mEq/L

infectionK

4.5 mEq/L

EBVAZIgG(＋)

Cl

93 mEq/L

EBVCAIgM(−)

Ca

7.8 mEq/L

EBNA

(＋)

CRP

13.78 mg/dL

EBDRIgG(−)

Fe

9 μg/dL

T-SPOT

negative

TIBC

99 μg/dL

Blood Culture

negative

UIBC

90Urinalysis

TP

6.6 g/dL

Urinary osmolality

366 mOsm/L

Alb

1.7 g/dL

Urine Na

48 mEq/L

Alb

28.9%

Urine K

22.2 mEq/L

α1-G

10.1%

Urine metanephrine

0.07 mg/L

α2-G

13.0%

Urine normetanephrine

0.33 mg/L

β1-G

5.3%

β2-G

9.4%

γ

33.3%

JHGM 2022：4-4

181

MUM-1(＋), and a Ki-67 index ＞ 80%. After

results of serum osmolality (272 mOsm/L),

the patient was transferred to the hematology

urine osmolarity (366 mOsm/L), urine Na (48department, we received the first report on themmol/L), urine K (22. 2 mmol/L), Cre (0. 50

pathology of the skin biopsy tissue. The READ

mg/dL), cortisol (19.4 μg/dL), and ADH (0.9system, a diagnostic system for malignant

pg/mL), the diagnosis of SIADH secondary tolymphoma in pathology, was used；however,lymphoma was made. After admission, fluid

we did not consider intravascular large B-cellintake was restricted from the first day, but thelymphoma (IVL). Meanwhile, the second andserum sodium level did not increase. Salt

final reports supported this diagnosis. Based on

supplementation was started 8 days after

the above-mentioned results, the patient wasadmission, and 3% saline was administereddiagnosed with diffuse large B-cell lymphoma

intravenously(DLBCL).

Nevertheless, the serum sodium concentration

Clinical course
Rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (RCHOP) therapy was subsequently administeredand the patient was discharged without any

10

days

after

admission.

did not increase, and the sodium level recovered
to normal 50 days after admission to thehospital after the treatment for primary adrenal
lymphoma (PAL) was started.

Discussion

observed side effects. The patientʼs sodium level

The number of cases of malignant primary

was normal for two months. However, it

adrenal lymphoma (PAL) has increased overreduced to 131 mmol/L one month before

the past 10 years. At present, 200 cases haveadmission. He was taking clopidogrel andbeen reported1), with 54% of the cases of PAL

rosuvastatin that was prescribed by a neurolo-

being reported in Asia. The average age ofgist on an outpatient basis, and he discontinued

diagnosis worldwide is approximately 68 years.

the treatment 33 days prior to admission.

The ratio of men to women was found to be

Subsequently, his sodium levels were 129

1.8：1 with approximately 70% having bilateral

mmol/L on admission；therefore, he was

PAL2,3,4). The index case was a male of average

examined closely. Blood samples and urinalysis

age, who had bilateral PAL.

revealed normal extracellular fluid. A hormone

PAL has been confirmed in less than 1% of

test was performed as he had hypotonic

non-Hodgkinʼs lymphoma cases5), and has been

hyponatremia, but renin and aldosterone levels

found to be a diffuse large B-cell lymphoma

were also normal, which ruled out mineralocor-(DLBCL) in 85-91% of cases3,6). Meanwhile,

ticoid responsive hyponatremia of the elderly

there are fewer cases of adrenal primary IVL(MRHE). Thyroid function was also normal.

reported. The index case was diagnosed as IVL.

There was no cortisol deficiency, normal ACTH,

Although the etiology of PAL has not yet been

and no pituitary or adrenal hypofunction.

identified, autoimmune-related infections andHyponatremia persisted even after discontinua-

immunodeficiencies that are due to polymeriction of oral medications prescribed by the

associations cause the appearance of hemato-neurologist, and drug-related factors were ruled

poietic tissue in the adrenal gland in a bid toout. There were no other episodes of polydipsia

stop mutations of EBV infection；in addition,that could have led to hyponatremia. Based thethe p53 and c-kit genes have been found to beAdrenal primary malignant lymphoma

182

etiological factors6,8,9). However, the index

the performance status (PS) of the patientscase showed only the presence of an existing

were found to influence prognosis10,11).

EBV infection. According to the results of the

The treatment of IVL is chemotherapy withplasma and urinary osmotic pressure, electro-

R-CHOP therapy (rituximab, cyclophospha-lyte, and plasma vasopressin level, this was amide, hydroxydaunorubicin, oncovin, and pre-case of hypo-osmotic hyponatremia merged

dnisone), with a better prognosis after thewith SIADH that was associated with a malig-

administration of this treatment. However, as

nant lymphoma. There has been one previous

with an adrenal primary malignant lymphoma,

report of a case of IVL and SIADH. It has been

the median survival time was approximately

proposed that the malignant lymphoma produ-

one year12). Two years have passed since theces IL-6 and IL-1 β, and cytokines which

patient was admitted to the hospital；he isstimulate

producecurrently experiencing a complete metabolic

vasopressin . The SIADH that developed in this

response (CMR) because of chemotherapy thatcase may have occurred through a similar

included six courses of R-CHOP. His PS is now 1

mechanism.

and he continues to make good progress. We

thehypothalamus

to7)

The clinical manifestation of PAL includes

will continue to monitor his progress. PAL is a

symptoms such as stomach ache, anemia,

disease with a poor prognosis；rapid diagnosis

weight loss, fever of unknown origin, hypercal-

and early initiation of chemotherapy is neces-cemia, thrombocytopenia, and adrenal insuffi-sary. Therefore, it is important to recognize PAL

ciency. The patient presented with fever, weightas early as possible；moreover, the discrimi-

loss, night sweats, anemia, and thrombocytope-

nant presentation of PAL is critical for earlynia. The differential diagnoses were bilateral

identification.

adrenal masses and metastatic diseases (lungcancer, lymphoma, melanoma, renal carcinoma,

Conclusions

and ovarian cancer), adrenocortical carcino-

Bilateral adrenal primary malignant lym-mas, pheochromocytomas, myelolipomas, nod-phoma has a poor prognosis；therefore, earlyular adrenal hyperplasias, congenital adrenal

diagnosis and treatment is necessary. It is

hyperplasias, functional adenomas, invasive

important to include this factor in the differen-causes (sarcoidosis), and infections (tuberculo-

tial diagnosis. PAL should be considered insis, cryptococcosis, and histoplasmosis).

cases of adrenal enlargement. Furthermore, if

The symptoms displayed in this case werehyponatremia is present, a thorough examina-

atypical：fever, weight loss, night sweats,tion along with a systemic search and acytopenia (anemia and thrombocytopenia), anddiagnosis of SIADH may provide clues to thehigh IL-2R levels；therefore, malignant lym-cause of the lymphoma.

phoma was highly suspected. Furthermore, we
performed an abdominal ultrasonography andsystemic CT, the results of which did not show aclear lymphadenopathy. The results indicatedonly adrenal enlargement, leading to thesuspicion of PAL. In addition, age, bilaterallesions, adrenal insufficiency, serum LDH, andReferences
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lymphoma with initial presentation concerning forbilateral adrenal pheochromocytomas. BMJ Case Rep
2017；2017：bcr2017220549.
２) Rashidi A, Fisher SI. Primary adrenal lymphoma：asystematic review. Ann Hematol 2013；92：1583-93.

183

JHGM 2022：4-4

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diffuse large B cell lymphoma without adrenal
insufficiency：a case report and review of theliterature. Mol Clin Oncol 2017；7：145-7.
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６) Grigg AP, Connors JM. Primary adrenal lymphoma.
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７) Morimoto K, Ogihara T, Shiomi T, et al. Intravascularlarge B-cell lymphoma with preceding syndrome of
inappropriate secretion of antidiuretic hormone.
Intern Med 2007；46：1569-72.

Conflict of interest The authors declare that they have noconflicts of interest.

８) Ohsawa M, Tomita Y, Hashimoto M, et al. Malignant
lymphoma of the adrenal gland：its possible correlation with the Epstein-Barr virus. Mod Pathol 1996；9：534-43.
９) Padhi S, Sahoo J. Primary adrenal non Hodgkin
lymphoma：changing trends. Turk J Gastroenterol
2015；26：85-6.
10) Meyyur Aravamudan V, Kee Fong P, Sam YS, et al. A
rare case of primary bilateral adrenal lymphoma. Case
Rep Med 2017；2017：1251950.
11) Khurana A, Kaur P, Chauhan AK, et al. Primary nonHodgkinʼ s lymphoma of left adrenal gland - a rare
presentation. J Clin Diagn Res 2015；9：XD01-XD03.
12) Horiguchi K, Hashimoto K, Hashizume M, et al.
Primary bilateral adrenal diffuse large B-cell lymphoma demonstrating adrenal failure. Intern Med 2010；49：2241-6.

JHGM 2022：4-4

184― Review article ―Cytokine storm mechanism and treatment in COVID-19
Ichiro Ohashi
Department of Anesthesiology and Intensive Care Medicine 3
Kawasaki Medical School

Key Words：COVID-19, SARS-CoV-2, cytokine storm

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its associatedcoronavirus disease 2019 (COVID-19) continues to be a serious public health threat. As of thiswriting in February 2022, more than 400,000,000 people worldwide have been infected by
SARS-CoV-2, and over 6,000,000 have died. SARS-CoV-2 is highly infectious and can lead tomultiple-organ failure, mainly triggered by respiratory failure. The most severe cases of COVID19 often involve a cytokine storm, which is an important factor in multiple-organ failure.
This report gives an overview of the characteristics of SARS-CoV-2, as well as thepathological characteristics and the pathophysiological mechanism of COVID-19 related cytokine
storms. The current understanding of COVID-19 treatment is also discussed. Understanding themechanism of a cytokine storm and the available treatment options is essential to reduce
mortality in critically ill COVID-19 patients.

Introduction
The term “cytokine storm” first appeared ina 1992

tions, obesity, and chronic disorders such as
diabetes and kidney or liver disease. It is also
known that cytokine storm-like symptoms

paper titled “Cytokine dysregula-similar to those in COVID-19 are detected astion and acute graft-versus-host disease” by JL

side effects from immunomodulatory drugs3,4).

Ferrara at Mount Sinai Hospital1,2). A cytokine

Coronaviruses are so named for the ring ofstorm is a state in which the immune systemcrown-like spikes on the envelope of the virus

hyperactivates and causes the body to releasethat can look reminiscent of the corona around

too many cytokines into the bloodstream, which

the sun. There are seven kinds of coronavirus

2)

becomes life-threatening . As the severity of athat are known to be contagious to humans.

case of COVID-19 increases, so does theFour of the seven can cause common cold

possibility of a cytokine storm, but it does not

symptoms in the upper airway (nose, throat

occur in all infected patients. In fact, mostand pharynx). The other three (SARS-CoV,

patients with COVID-19 have no symptoms or

MERS-CoV, SARS-CoV-2) are β-coronaviruses

recover after only mild symptoms. Risk factors

with positive-strand RNA virus genomes thatfor developing a severe case, and thus a higher

can infect the lower airway (trachea, bronchi,

chance of a cytokine storm, are age, pre-and lung) and can cause serious to severe

existing lung, heart or immune system condi-

symptoms.
In the β -coronaviruses, the corona-like※ Correspondence to：2-6-1 Nakasange, Kita-ku, Okayama-City,
Okayama 700-8505, Japan
Department of Anesthesiology and Intensive Care Medicine 3
Kawasaki Medical School

spikes bind to angiotensin-converting enzyme 2(ACE2), and the infection occurs when the

JHGM 2022：4-4

185

virus RNA genome is injected into the ACE2
host cell4,5). Infection from any of these three

Cytokine storm mechanism in COVID-19

viruses can cause serious inflammation in the

As SARS-CoV-2 infects the lungs, the innate

lungs. Fatal outcomes have occurred after

immune system becomes activated, and themultiple organ failure. This multiple organ

adaptive immune system later responds to thefailure is induced by the very cytokines thatspecific virus. If the immune system is working

immune cells produce in order to fight against

normally at this point, the virus is removed andthe virus. Cytokine production becomes uncon-

does not cause serious symptoms10). However,trollable, and the overproduced cytokines cause

in patients that develop a cytokine storm, T-a “cytokine storm,” which damages healthy

cells, especially T helper cells, become overacti-

6‑10)

cells

.

vated and produce too much cytokine. The

However, cytokine storms in Covid-19

cytokine affects interleukin-6 amplifier (IL-6

patients are rare. Around 80% of those withamplifier) in non-immune cells, such as aged

COVID-19 have only light symptoms, and there

fibroblasts, especially in alveolar epithelial cells

are a certain number of people who have noand vascular endothelial cells. Activated IL-6

discernable symptoms after being infected andamplifiers excessively stimulate the NF-κ B

develop antibodies without realizing that they

pathway. The body will then be in a full cytokine

have been infected. As of now, there is no

storm of IL-6, chemotactic cytokines (chemo-

scientifically, medically sound method to pre-kines), and other growth factors3,13). At thedict which patients will eventually have asame time, SARS-CoV-2 begins to replicate andcytokine storm or even why it is a β -assemble new viral particles through ACE2,

coronavirus that specifically leads to a cytokine

which eventually causes higher levels ofstorm. However, cytokine storms are said toinflammation. The large amount of humoral

occur more often in elderly people and thosefactor produced from the inflammation triggers

with the pre-existing conditions listed above.

T-cell anergy and the virus spreads throughThose risk factors indicate the possibility that avascular endothelial cells into organs other thanrobust immune system plays a role in avoiding a

the lungs13). Even more inflammation through-cytokine storm from being triggered9‑12).

out the body leads to additional humoral factor,

The details of the molecular mechanismthat cause the overactivation of the immune
system, as well as the process at the molecularlevel of how a cytokine storm can be fatal toinfected patients, are not yet well elucidated.

and this downward spiral leads to functional
failure in organs and can eventually be fatal.

Mechanisms of inflammation
amplification by IL-6

Also, details such as the molecular mechanism

Figure1, which shows schematic molecularthat determines the severity of the symptoms

cascade of the cytokine storm induced by SARS-

that can lead to organ failure are still unclear.

CoV-2 infection, is modified from Fig. 1 in

While not every mechanism has been discov-

reference 13. Locally, the activated CD4＋ T

ered, below is the currently available under-

helper cells produce inflammatory cytokines,

standing of the molecular mechanism of thechemokines, and amplifying factors that include

cytokine storm and treatment options.

IL-6. The cytokines produced by the activatedcells stimulate both the NF-κ B and STAT3

Cytokine storm in COVID-19

186

Figure 1 Schematic model of cytokine storm induced by COVID-19 infection through activated IL-6-AMP(modified from a figure in reference 13；Hojyo S.et al.).
SARS-CoV-2 infection starts from the binding of the virus to cell membrane-localized ACE2 depending on TMPRSS2
activities. The biding of the virus to ACE2 increases the free Ang II due to a reduction of ACE2-mediated degradation, which
activate ADAM17 protease activity via AT1R. ADAM17 and ADAM10 protease cause production of TNF-α, EGF, and sIL6R α, which activate the IL-6R-STAT3, TNFR- and EGFR-NF-κ B signaling pathways in non-immune cells .Both STAT3 andNF-κB activation ignite IL-6 AMP, causing cytokine storm, resulting in ARDS, multiorgan failure and fatal intravascular
coagulation.
SARS-CoV-2：severe acute respiratory syndrome coronavirus-2 , IL-6：interleukin-6, NF-κB：nuclear factor-κB, ACE2：
anti-oangiotensin-converting enzyme 2, Ang II：angiotensin II, ARDS：acute respiratory distress syndrome, TMPRSS2：
transmembrane protease serine subtype 2

pathways simultaneously in non-immune cells
such as fibroblasts or vascular endothelial cells.
The IL-6 produced in this process activates

Immune system activationfrom viral infection

STAT3, which in turn continues to activate IL-6

Viral infection induces both an innate andamplifiers. The inflammatory cytokines, ampli-

adaptive immune response. An excessive num-fying factors, and chemokines produced by theber of inflammatory cytokines that are pro-

IL-6 amplification mechanisms migrate and the

duced due to an infection in epithelial cells or

cytokines cause local cells in new areas of thethe innate immune system are called a cytokine

body to activate and proliferate. Moreover, thestorm, while B cells produce antibodies against

enhanced IL-6 amplification can contribute tomainly Hemagglutinin antigen (HA). Moreover,the inflammation becoming chronic, with thisCD8＋ T cells produce anti-viral cytokines,

continuous induction leading to a cytokine

which promote virus removal and the recovery

storm, which can occur in both viral andof the immune mechanism by killing infectedbacterial infections, including in COVID-19, andcells recognized by peptides.

can lead to the exhaustion and death of the T
11,13)

cells.

Angiotensin II (Ang II) supports homeostasis of the cardiovascular system by upregulating the renin-angiotensin-system and downre-

JHGM 2022：4-4

187

gulating ACE2. It is reported that angiotensin II

can be expected to effectively suppress viralsignaling through the AT1 receptor pathway

infection.

promotes inflammation and fibrosis, which canlead to serious acute lung injuries that accompany a cytokine storm, but angiotensin II

Immunotherapy targeting hostdefense immune mediators

signaling through the AT2 receptor pathway

The immune response is triggered by

reduces the effects of inflammation and fibrosis

SARS-CoV-2 and can be regulated by targeting13)

through the Mas receptor.

mediators that drive various effector mechanisms. These can be non-specific and broad,

Renin-angiotensin system and lunginjuries accompanying cytokine storm
caused ARDS and SIRS

such as corticosteroids, or specifically targeted
inhibitors, such as kinase inhibitors and anticytokine drugs16).

Activated AT1 receptor and inhibited AT2
receptor both exacerbate lung injuries that

Corticosteroids

accompany acute respiratory distress syndrome

Clinical trials with corticosteroids against(ARDS). Through the decreased expression of

COVID-19 have shown their usefulness in a

ACE2, the spike proteins in SARS-CoV-2 en-prospective meta-analysis led by the World

hance the Ang II-AT1 pathway, resulting in the

Health Organization (WHO). These trials pro-13)

. Patients meet-

vided important evidence for the efficacy of

ing the clinical systemic inflammatory response

corticosteroids in inpatients with COVID-19

syndrome (SIRS) criteria show inflammation on

who require assisted ventilation16). The obser-

vascular walls. Immune cells attach to andvation that the beneficial effects of corticoste-

invade vascular walls, destroying the structures

roids are important for critically ill patientsof the wall and causing blood vessel disruption

might be described by the multifaceted effects

andocclusionof steroids that target a variety of pathophysio-. Anti-inflammatory steroids can belogical signaling in critically ill patients withexacerbation of lung injuries

intravascular
10)13)

occur

stenosisor

8,9,11)

used to treat SIRS, within limits.

COVID-19. It would be important to discuss theACE2, which functions as a receptor of

appropriate timing of steroid administration in

SARS-CoV-2, is expressed in type II pneumocyte

a variety of conditions. Overdosage of cortico-

myocytes, renal proximal tubule epithelial cells,

steroids, especially in the early stages of theintestinal or esophageal epithelial cells, as welldisease, when such treatment can drive adverse

as in squamous epithelial cells such as nasal andeffects, remains an important issue16).

oral mucosa. In order for SARS-CoV-2 to enter acell, the spike protein needs to be cut off by the

Kinase inhibitor

transmembrane protease serine 2 (TMPRSS2),

Tyrosine kinases have pleotropic effects

which exists on the surface of the cells. In fact,

and are considered attractive targets in thethe inhibition of TMPRSS2 inhibited intracellu-

treatment of COVID-19. Tyrosine kinase inhibi-

lar uptake in experiments. ACE2 antibodies also

tors can inhibit cytokine signaling pathways

3,6,13).

and many immune effector pathways. A double-

Therefore, molecules that inhibit the bonding ofblind, randomized, placebo-controlled trial ofthe virus to ACE2 or the inhibition of TMPRSS2

adult patients with COVID-19 and randomly

inhibit the viral intracellular uptake

Cytokine storm in COVID-19

188

assigned to receive oral baricitinib (a janus

pneumonia, the use of anakinra was welltyrosine kinase (JAK) inhibitor) or placebo fortolerated and was effective in improving clinical17)

up to 14 days was performed. Patientsand biological markers. In another cohort study

receiving baricitinib took less time to recoverof patients with severe COVID-19, Anakinra

than those in the placebo group (median 7 vs. 8

reduced both the need for invasive ventilationdays). The effect was obvious in the subgroupand mortality in the intensive care unit17).

requiring high flow oxygen or non-invasive

Tocilizumab (Actemra®) is a recombinantventilation when compared to patients receiv-

humanized antibody that can specifically bind17)

. In a Phase Ⅲ,

to membrane-bound IL-6 receptor (mIL6R) anddouble-blind, randomized, placebo-controlled

soluble IL-6 receptor (sIL6R), thereby inhibit-

trial of 1,525 participants, 764 received barici-

ing signal transduction. It is a human IL-6

tinib and 76 received placebo. Mortality wasreceptor monoclonal antibody17). A small scale

reduced by 38.2%, and 28-day all-cause mortal-

trial showed its usefulness. The results of future

ity was 8% for baricitinib, and 13% for placebo,

clinical trials will be necessary to clarify its

with a hazard ratio of 0.57 (95% CI 0.41-

utility17).

ing placebo (10 vs. 18 days)

0.78)17). This was an additional effect onstandard of care, including corticosteroids, as

Conclusions

79.3% of participants with available data

Much useful evidence has been elucidated

received systemic corticosteroids at baseline.

about the pathophysiological characteristics of

The FDA recently approved balacitinib for

COVID-19, the detailed mechanism of cytokine

17)

emergency use to treat COVID-19.

Target Strategy：Anti-cytokine treatment

storms, and the construction of therapeuticstrategies compared to the early stages of thecoronavirus pandemic. Considering the current

Both IL-1 and IL-6 have localized effects

situation in which new mutant strains of thesuch as macrophage activation, endothelial

coronavirus appear repeatedly, there remain aleakage, and extravasation of fluids, as well as

number of issues to be clarified, including thesystemic effects such as fever, somnolence, andstrengthening of global systems for the preven-acute phase protein synthesis. Host defense

tion of pandemics. In this paper, we reviewed

requires the induction of moderate inflamma-

the mechanisms of cytokine storms involved intion, but excessive release of these mediators isthe aggravation of COVID-19 and the current

16,17)

detrimental.

treatment situation.

Interleukin (IL) -1 receptor antagonist
Anakinra is a recombinant human IL-1 receptor

List of abbreviations

antagonist indicated for rheumatoid arthritis

SARS-CoV-2：severe acute respiratory(RA) and cryopyrin-associated periodic syn-syndrome coronavirus-2

drome. It inhibits the pro-inflammatory cytokines IL-1α and IL-1β. Currently, there are no

MERS-CoV：Middle East respiratory syndrome
coronavirus

explicit published controlled clinical trials

ACE2：anti-oangiotensin-converting enzyme 2

supporting the efficacy or safety of anakinra in

IL-6：interleukin-6

17)

the treatment of COVID-19. In a small sizedclinical trial with moderate to severe COVID-19

NF-κB：nuclear factor-κB
CD4：cluster of differentiation 4

JHGM 2022：4-4

189

STAT3：signal transducer and activatorof transcription 3
HA：hemagglutinin antigen
CD8：cluster of differentiation 8
Ang II：angiotensin II
AT1：angiotensin Ⅱ type 1
AT2：angiotensin Ⅱ type 2
ARDS：acute respiratory distress syndrome
TMPRSS2：transmembrane protease serine
subtype 2
IL-6 AMP：interleukin-6 amplifire
ADAM17：disintegrin and metalloproteinasedomain-containing protein 7
ADAM10：disintegrin and metalloproteinasedomain-containing protein 10
TNF-α：tumor necrosis factor-alpha
EGF：epidermal growth factor
sIL-6Rα：soluble interleukin-6 receptor alphaFundingnone

References
１) Antin JH, Ferrara JL. Cytokine dysregulation andacute graft-versus-host disease. Blood 1992；80：2964-8.
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３) Fajgenbaum DC, June CH. Cytokine Storm. N Engl J
Med 2020；383：2255-73.
４) Papanikolaou V, Chrysovergis A, Ragos V, et al. Fromdelta to Omicron：S1-RBD/S2 mutation/deletion
equilibrium in SARS-CoV-2 defined variants. Gene
2022；814：146134.

Conflict of interest The authors declare that they have noconflicts of interest.

５) Kandeel M, Kitade Y, Fayez M, et al. The emerging
SARS-CoV-2 papain-like protease：Its relationshipwith recent coronavirus epidemics. J Med Virol
2021；93：1581‒8.
６) Guo W, Porter LM, Crozier TW, et al. Topical
TMPRSS2 inhibition prevents SARS-CoV-2 infection indifferentiated human airway cultures. Life Sci Alliance2022；5：e202101116.
７) Krasemann S, Haferkamp U, Pfefferle S, et al. The
blood-brain barrier is dysregulated in COVID-19 andserves as a CNS entry route for SARS-CoV-2. Stem Cell
Reports 2022；17：307-20.
８) Mehra MR, Desai SS, Kuy S, et al. Cardiovascular
Disease, Drug Therapy, and Mortality in Covid-19. N
Engl J Med 2020；382：e102.
９) Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid19 in Critically Ill Patients in the Seattle Region - Case
Series. N Engl J Med 2020；382：2012-22.
10) Ackermann M, Verleden SE, Kuehnel M, et al.
Pulmonary Vascular Endothelialitis, Thrombosis, andAngiogenesis in Covid-19. N Engl J Med 2020；383：
120-8.
11) Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N
Engl J Med 2020；383：2451-60.
12) Wiersinga WJ, Rhodes A, Cheng AC, et al.
Pathophysiology, Transmission, Diagnosis, andTreatment of Coronavirus Disease 2019 (COVID19)：A Review. JAMA 2020；324：782-93.
13) Hojyo S, Uchida M, Tanaka K, et al. How COVID-19
induces cytokine storm with high mortality. Inflamm
Regen 2020；40：37.
14) Atmar RL, Lyke KE, Deming ME, et al. Homologous
and Heterologous Covid-19 Booster Vaccinations. N
Engl J Med 2022；NEJMoa2116414.
15) Hammond J, Leister-Tebbe H, Gardner A, et al. Oral
Nirmatrelvir for High-Risk, Nonhospitalized Adults
with Covid-19. N Engl J Med 2022. doi：10.1056/
NEJMoa2118542.
16) van de Veerdonk FL, Giamarellos-Bourboulis E,
Pickkers P, et al. A guide to immunotherapy for
COVID-19. Nat Med 2022；28：39-50.
17) Rizk JG, Kalantar-Zadeh K, Mehra MR, et al.
Pharmaco-Immunomodulatory Therapy in COVID19. Drugs 2020；80：1267-92.

JHGM 2022：4-4

190― Review article ―Alcohol-related organ dysfunction
in general hospital medicine
Motoo Kikuchi
Department of General Medicine, Nagoya City University West Medical Center

Key Words：Potation, General Medicine

Various factors affect the overall condition of the body, and inappropriate lifestyle habits canlead to a series of abnormalities in various organs that can eventually lead to the development oflifestyle-related diseases. General practitioners need to intervene in inappropriate lifestyles toappropriately treat such diseases. One of the inappropriate lifestyle habits that should beconsidered is excessive drinking, which has been linked to various health conditions. Previous
basic and epidemiological studies have shown that inappropriate drinking habits increase theincidence of five major diseases, with musculoskeletal diseases especially affected：cancer (e.g.
colon, esophageal, laryngeal, and breast cancer), neurodegenerative diseases (dementia),
diabetes, atherosclerotic diseases (coronary artery disease and stroke), and osteoporosis, thelatter of which is the most common cause of a need for nursing care. Social losses due to alcohol
consumption are estimated to be four trillion yen per year, and confronting drinking-related
conditions has become an urgent issue. During the process of diagnosis, it is important for the
primary care physician to thoroughly interview the patient about alcohol use, consider the
possible relation of alcohol to the disease, and provide guidance on sobriety and abstinence asneeded. Diagnosis, treatment, and lifestyle guidance for alcohol-related disorders by the primarycare physician can reduce social losses.

Introduction

should be considered is inappropriate orexcessive drinking2‑3). The excessive use of

In general practice, it is important to focus

alcohol is known to play a major role in diseaseson the entire body of the patient. Various

such as acute alcohol intoxication, alcoholic

factors can affect the overall condition of thehepatitis

body, and inappropriate lifestyle habits can lead

Wilnickeʼ s encephalopathy. Recently, alcohol

to a series of abnormalities in various organs,consumption has been found to have a greater

which can eventually develop into lifestyle-impact on the background of various diseases

related diseases. General practitioners need tothan previously thought.

intervene in inappropriate lifestyles and treat1)

diseases appropriately .
One such inappropriate lifestyle habits thatandcirrhosis,

pancreatitis,

andPrevious basic and epidemiological studies
have shown that inappropriate drinking habits
increase the incidence of five major diseases,
with musculoskeletal diseases being the most

※ Correspondence to：1-1-1 Kita-ku, Nagoya City,
Aichi pref, Japan
Department of General Medicine,
Nagoya City University West Medical Center

common：cancer (e. g. colon, esophageal, laryngeal, and breast cancer)4)；increased resist-

JHGM 2022：4-4

191

ance to cancer treatment, such as metastasis5)；
6)

neurodegenerative diseases (e.g. dementia) ；7)

diabetes ；atherosclerotic diseases (e.g. coro8)

much higher risk of developing oral, pharyngeal, and esophageal cancers. Alcohol consumption has also been shown to cause cancers ofnary artery disease and stroke) ；and osteo-

the oral cavity, pharynx, larynx, esophagus,

porosis, which is the most common cause of aliver, colon, and breast in women4). Ethanol isneed for nursing care9).

associated with the metastasis of various

Social losses due to alcohol consumption

cancers5), and in regards to carcinogenesis

are estimated to be four trillion yen per year,

related to alcohol consumption, there is no safe

and confronting drinking-related conditions has

amount of alcohol to drink.

10)

thus become an urgent issue. In this section,

we discuss the relation between alcohol consumption and organ damage, which is impor-

Alcohol-related cardiovascular disease
Appropriate drinking is protective against

tant in general practice.

cardiovascular diseases, while excessive drink-

Here, we introduce the recent trends in thising is a risk factor. This is from a slightly older

field of general medicine.

study on the cause of coronary artery disease.

Alcohol consumption and dementia

Daily consumption of two drinks by men and
one drink by women can reduce the risk of

Heavy drinking increases the risk ofheart-related death by 20%. Regarding heart

dementia；brain atrophy is more common in

failure, drinking about one or two drinks is11), and more

protective, but drinking more than that in-people who drink heavily or have abusedcreases the incidence of heart failure12). Here,alcohol develop dementia6). Prior studies have“one drink” is equivalent to 12 grams of alcohol.

identified a positive correlation between the

Abstinence from alcohol is essential in cases ofamount of alcohol consumed and the degree ofalcoholic cardiomyopathy. Small amounts ofbrain atrophy, and brain atrophy caused byalcohol can temporarily lower blood pressure；alcohol consumption improved with abstinence

however, long-term habitual drinking canfrom alcohol consumption. Conversely, it has

increase blood pressure and cause hyperten-

been suggested that drinking small amounts ofsion.

alcoholics and heavy drinkers

6)alcohol may help prevent dementia . However,Regarding arrhythmias, drinking more than

it is important to note that there is no evidence

four drinks approximately doubles the risk ofthat drinking prevents dementia in people who

developing atrial fibrillation13). Previous epide-

do not have the habit of drinking.

miological studies have shown that appropriate

Alcohol consumption and cancer

drinking may have a preventive effect against
non-hemorrhagic and arrhythmic cardiovascu-

During the metabolism of alcohol, ethanol

lar diseases. The anticoagulant and antioxidant

is converted to acetaldehyde by alcohol dehy-

effects of ethanol have been identified as thedrogenase (ADH) and metabolized to acetic

causes of this phenomenon8). In cerebrovascu-

acid by aldehyde dehydrogenase (ALDH).

lar disease, drinking approximately two drinks

Alcohol and acetaldehyde are carcinogenic, andis protective against cerebral infarction, but theindividuals with weak functioning of these tworisk of cerebral hemorrhage increases linearly

enzymes who consume excessive alcohol are atwith increasing alcohol consumption. Recently,

Potation and General Medicine

several reports8) have been published that may
negate the J-curve effect of alcohol consumption on cardiovascular disease.

192

Drinking and dyslipidemia
Because correlations between plasma lipids

It should be noted that the estimatedand alcohol intake are related to sex, age,amounts considered appropriate are averages

bodymass index, and ApoE genotype17), an

for the entire study population, and that someadequate consumption volume of ethanol

individuals may have lower alcohol tolerance

cannot be unconditionally defined8). The risk ofdepending on their physical constitution andcardiovascular diseases in heavy drinkers

body size. Because some of antiarrhythmic

seems to be enhanced in patients with theantihypertensive drugs are metabolized by theapolipoprotein E4 allele, interleukin-6-174

liver, alcohol consumption should be avoided bypolymorphism, and cholesteryl ester transfer

patients taking them as it can adversely affectprotein TaqIB polymorphism. Single nucleotide

liver function.

polymorphisms may influence the relation
between alcohol consumption, high-density

Alcohol consumption and diabetes

lipoprotein (HDL) cholesterol level, and athero-

Although moderate alcohol consumption

sclerotic risk. Ethanol is unique among toxin, inthrough proper drinking may prevent thethat it perturbs almost all aspects of hepaticdevelopment of diabetes, excessive alcohol

lipid metabolism. Various mechanisms have

7‑8)been suggested to affect mitochondrial β -consumption can lead to hyperglycemia.

Alcohol consumption of approximately 20-25 g
per day was reported to reduce the incidence of
14)

diabetes in a 2009 report, and this effect was

confirmed in a 2013 meta-analysis that in15)

cluded 38 observational studies

oxidation,

fatty

acid,

and

triglyceride

18)synthesis. A meta-analysis of patients withnonalcoholic

fatty

liver

disease(NAFLD)

showed that triglyceride and HDL levels were

. High alco-

not significantly different between alcohol

hol consumption can increase blood sugar

drinkers and non-drinkers19). In contrast, otherlevels by affecting the fat stored in the liver andthan NAFLD patients, it is widely accepted thatsuppressing insulin secretion by the pancreas.

alcohol consumption increases the HDL choles-

High alcohol consumption is the largest andterol level in a dose-dependent manner. The

most important cause of elevated blood glucose

effects on LDL and triglycerides have been welllevels owing to excessive energy intake during

elucidated20).

drinking and meals. Long-term excessive alcohol intake leads to alcoholic cirrhosis andDiscussion

pancreatitis16). Alcoholic cirrhosis leads to

As aforementioned, habitual alcohol con-hyperglycemia, and alcoholic pancreatitis leads

sumption can cause a variety of damage toto both hyperglycemia and hypoglycemia due

systemic organs. Social losses due to alcohol

to the destruction of alpha and beta cells in the

consumption are estimated to be four trillion

pancreas.

yen per year, and confronting drinking-related
conditions has become an urgent issue10). The
economic cost of excessive alcohol consumption in the United State was 223.5 billion dollars(approximately 26 trillion yen) in 2006.

JHGM 2022：4-4

193

Problems associated with inappropriate alcohol
consumption are thus a pressing issue thatmust be resolved21). When diagnosing apatientʼ s condition, it is important for the
primary care physician to thoroughly interview
the patient about alcohol use, consider the
possible relation of alcohol to the disease, andprovide guidance on sobriety and abstinence asneeded. Patient awareness of alcohol-relateddiseases is extremely important. In this regard,
the website of the Ministry of Health, Labourand Welfare is also useful, although the data
used are somewhat outdated22)
With this in mind, general physicians
should pay serious attention to alcohol consumption and manage patientsʼ drinking habits
to achieve a healthy society and promotelongevity.

References
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Hospital general medicine, Daidougakkan, Fukuoka,
Japan 2017.
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1804-12.
８) Minzer A, Losno R, Casas R：The effect of alcohol on

Conflict of interest The authors declare that they have noconflicts of interest.

cardiovascular risk factors. Nutrients. 2020；12：912.
９) Pasco J, Anderson K, Hyde N, et al.：High alcohol
intake in older men and the probability of osteoporotic fracture according to the FRAX Algorithm.
Nutrients. 2021；13：2955.
10) Ozaki Y：Epidemiology of Alcohol (in Japanese).
Journal of Clinical and Experimental Medicine. 2015；
254：896-900.
11) Evangelou E, Suzuki H, Bai W, et al.：Alcohol
consumption in the general population is associatedwith structural changes in multiple organ systems.
Elife. 2021；10：e65325.
12) Thun M, Peto R, Lopez A, et al.：Alcohol consumption
and mortality among middle-aged and elderly U. S.
adults. N Engl J Med. 1997；337：1705-14.
13) Csengeri D, Sprünker N, Castelnuovo A, et al：Alcohol
consumption, cardiac biomarkers, and risk of atrial
fibrillation and adverse outcomes. Eur Heart J. 2021；
42：1170-7.
14) Baliunas D, Taylor B, Irving H, et al.：Alcohol as a risk
factor for type 2 diabetes：A systematic review andmeta-analysis. Diabetes Care. 2009；32：2123-32.
15) Knott C, Bell S, Britton A：Alcohol consumption andthe risk of type 2 diabetes：a systematic review anddose-response meta-analysis of more than 1.9 million
individuals from 38 observational studies. Diabetes
Care. 2015；38：1804-12.
16) Schwarzinger M, Thiébaut S, Baillot S, et al.：Alcohol
use disorders and associated chronic disease - anational retrospective cohort study from France. BMC
Public Health. 2017；18：43.
17) Ceci F, Ceccanti M, Petrella C, et al.：Alcohol drinking,apolipoprotein polymorphisms and the risk of cardiovascular diseases. Curr Neurovasc Res. 2021；18：
150-61.
18) You M, Arteel G：Effect of ethanol on lipid metabolism. J Hepatol. 2019；70：237-48.
19) Kwon I, Jun D, Moon J：Effects of moderate alcohol
drinking in patients with nonalcoholic fatty liverdisease. Gut Liver. 2019；13：308-14.
20) Chiva-Blanch G, Badimon L：Benefits and risks ofmoderate alcohol consumption on cardiovasculardisease ： Current findings and controversies.
Nutrients. 2019；12：108.
21) Bouchery E, Harwood H, Sacks J, et al.：Economic
costs of excessive alcohol consumption in the U. S.,
2006. Am J Prev Med. 2011；41：516-24.
22) Ministry of Health, Labour and Welfare Japan：ehealthnet -Alcohol-. https: //www. e-healthnet. mhlw.
go.jp/information/alcohol. 2022；Viewed on May 1.

JHGM 2022：4-4

194― Key Image of General Medicine ―Characteristic Findings of Omicron Throat
Daisuke Mizokami1)※
Saki Takihata1)
Shin Tadokoro1)2)
3)
Koji Araki
Akihiro Shiotani3)
1) Nishisaitama-Chuo National Hospital, Otolaryngology, Head & Neck Surgery
2) Chubu University Graduate School of Engineering3) National Defense Medical College, Otolaryngology, Head & Neck Surgery

Key Words：omicron, SARS-CoV-2, COVID-19

The coronavirus infection (COVID-19)
continues to be epidemic with repeated mutations. The mutant strain B. 1. 1. 529 (Omicronstrain), which was reported to have firstoccured in South Africa in November 2021, ismore infectious in the upper airway than the
mutant strains previously reported, indicatingthat Omicron may cause severe inflammation in
the upper respiratory tract1).
We present a case of COVID-19 withcharacteristic throat findings. A 26-years-old
Asian male presented to the emergency department with a 1-day history of high fever andFigure 1 Transoral fiber-endoscopic finding

severe sore throat. A nasopharyngeal polymer-

The soft palate is edematous and reddish with white
exudate on the edge of the posterior palatal arch.

ase chain reaction test was positive for SARSCoV-2. He complained of a very strong sorethroat, leading to difficulty in speaking andswallowing saliva. An otolaryngologist wascalled to evaluate the upper respiratory tract.
Disposable video rhinolaryngoscopy showed
white exudate concentrated on the posterior
palatal arch (Fig. 1 ) and laryngeal vestibule
mucosa (Fig. 2 ), which are indicated to be
characteristic of throat findings in omicron
pharyngitis/laryngitis2). Sotrovimab and intravenous dexamethasone were given to prevent
upper airway obstruction.

Figure 2 Transnasal fiber-endoscopic finding※ Correspondence to：2-1671 Wakasa, Tokorozawa,
Saitama, 359-1151 Japan
Nishisaitama-Chuo National Hospital, Otolaryngology,
Head & Neck Surgery

White exudate is localized to the vestibule of the larynx.

JHGM 2022：4-4

195

Before the Omicron pandemic, localized

Upper airway obstruction should be sus-

white exudate in the laryngeal vestibule waspected if there is inspiratory wheezing, muffledusually regarded as being from viral croup due

voice, severe pain, or dysphasia, even withouttoviruses.

oxygen desaturation. Upper airway stenosis

Currently, it is important to consider that thisdoes not reduce oxygen saturation until justfinding may indicate an omicron infection.

before the patient suffocates. Note that theRSvirusesorparainfluenza

The larynx is composed of the laryngeal
vestibule, the tongue side of the epiglottis, thevocal fold, and the arytenoids. Histologically,
the laryngeal vestibule is mainly covered withpseudostratified ciliated epithelium, in contrast
to the others that are covered with squamous
epithelium. Oropharynx mucosa is dominatedby the ciliated epithelium on the nasal side andthe squamous epithelium on the pharyngeal
side. The posterior palatal arch mucosa ispresumed to have a high proportion of ciliatedepithelium because it is located at the boundary
between the nasal and the oral cavities.
These characteristic endoscopic findings,
white exudate localized in the posterior palatinearch and laryngeal vestibule, may be observed
probably because Omicron is as prone toinflammation on the ciliated epithelium, as are
the reported characteristics of SARS-CoV-23).
Conflict of interest The authors declare that they have noconflicts of interest.

patient can be misclassified as mild.

Ethical approval
Case reports are exempt from ethicalapproval at our institution.

References
１) UK Heath Security Agency. SARS-CoV-2 variants ofconcern and variants under investigation in EnglandTechnical briefing 34 [UK Health Security Agency
website]. January 14, 2022. Available at https://assets . publishing . service . gov . uk / government /uploads / system / uploads / attachment ̲ data / file /1050236 / technical - briefing - 34 - 14 - january - 2022.
pdf. Accessed March 14, 2022
２) K Piersiala, L Kakabas, A Bruckova, et al. Acuteodynophagia-a new symptom of COVID-19 during the
SARS-CoV-2 Omicron variant wave in Sweden. J Intern
Med 2022 Feb 15.
３) J H Ahn, JM Kim, SP Hong, et al. Nasal ciliated cells areprimary targets for SARS-CoV-2 replication in theearly stage of COVID-19. J Clin Invest 2021；131：e148517.

JHGM 2022：4-4

196― Key Image of General Medicine ―Granulomatous Mastitis with Erythema Nodosum
and Polyarthritis
Kyohei Hoshino

Takashi Nakagawa※Hiroki Takahashi

Department of General Internal Medicine, National Hospital Organization Sendai Medical Center

Key Words：granulomatous mastitis, erythema nodosum, polyarthritis

A 32-year-old woman presented to ourabscess, but her condition did not improve.

hospital with fever, arthralgia, and leg pain.

Cultures of the drained fluid were negative.

Physical examination revealed arthritis in theComputed tomography showed masses in her

wrist and knee joints. Erythema with heat,right mammary gland, some of which wereedema, and tenderness was observed on her

contrasted in a ring shape, suggesting breast

lower leg, which was diagnosed as erythema

abscess (Figure 3 ). Vacuum-assisted breast

nodosum (EN) (Figure 1 ). A mass withbiopsy showed numerous inflammatory cell

redness and heat was palpated in the outer

infiltrates in the mammary tissue and nonca-

lower part of her right breast, and an incision

seating granulomas containing epithelioid his-scar was observed (Figure 2 ). The patient had

tiocytes and multinucleated giant cells (Figure

developed right mastitis a month earlier despite4 ). There were no pulmonary lesions orbreastfeeding over a year ago. She had received

lymphadenopathy, and the serum calcium andantibiotics and drainage at another hospital forangiotensin converting enzyme levels werea diagnosis of infectious mastitis and breast

normal. Ophthalmology examination revealed

Figure 1
Erythema nodosum on the extensor surfaces of both lower
legs※ Correspondence to：2-11-12 Miyagino, Miyagino-ku,
Sendai, Miyagi, 983-0821, Japan
Department of General Internal Medicine,National Hospital Organization Sendai Medical Center

Figure 2
Redness and an incisional scar are observed in the outerlower part of her right breast

JHGM 2022：4-4

197

Figure 3

Figure 4

Computed tomography shows masses in the rightmammary gland, some of which were contrasted in a ring
shape, suggesting breast abscessHistopathology shows numerous inflammatory cell infiltrates in the mammary tissue and noncaseating granulomas containing epithelioid histiocytes and multinucleatedgiant cellsnosarcoidosis.

cancer and granulomatous diseases, such as

Sarcoidosis, tuberculosis, breast cancer, autoim-

sarcoidosis and tuberculosis1,2). Furthermore,

mune disease, and streptococcal infection were

GM can be complicated by symptoms otherruled out based on clinical history and various

than mammary gland symptoms. For example,

examinations. Finally, granulomatous mastitis

18% of GM cases have EN and 14% have(GM) with EN and polyarthritis was diagnosed.

arthritis2). When mastitis develops during the

GM is a rare chronic inflammatory diseasenonlactating period with EN or arthritis, as infindings

suggestiveofof the mammary glands. It is most common
among young or middle-aged women with ahistory of breastfeeding. Infection, prolactin,
and autoimmune mechanisms are thought to be
involved,

but

its

exact

cause

remains1)

unknown . GM forms benign masses orabscesses in the breast and is histologicallycharacterized by inflammatory cell infiltrates
and noncaseating granulomas. Therefore, thediagnosis of GM is based on the exclusion ofConflict of interest The authors declare that they have noconflicts of interest.

this case, GM should be considered.

References
１) Altintoprak F, Kivilcim T, Ozkan OV. Aetiology of
idiopathic granulomatous mastitis. World J Clin Cases.
2014；2：852-8
２) Sarah Ringsted, Marcia Friedman. A rheumatologic
approach to granulomatous mastitis：a case series
and review of the literature. Int J Rheum Dis. 2021；
24：526-32

JHGM 2022：4-4

198― Key Image of General Medicine ―Milianʼs ear sign：A woman with a red ear
Fumitaka Yoshimura※

Kotaro Kunitomo

Takahiro Tsuji

Junko Kubosaki

Department of General Medicine, National Hospital Organization Kumamoto Medical Center

Key Words：Milianʼs ear sign, erysipelas

A 62-year-old woman visited our clinic due

The feature is called Milianʼ s ear sign1).

to redness of the right ear that began the

Cellulitis, in which the infection is mainly fromprevious day (Figure 1 ). Physical examination

the deep dermis to the subcutaneous adipose

revealed a slight fever (37. 6 ℃), chills, andtissue, does not occur because the auricle has aheat and tenderness on her right ear andthin dermis and lacks subcutaneous adipose

preauricular area. There were no blisters on, in,tissue. In this case, acute unilateral auricularor around the ear. Otoscopy showed noredness with tenderness and without blistering,abnormalities of the external auditory canal or

numbness of the tongue, or taste disorder was

tympanic membrane. Blood tests showed an

noted. Therefore, the diagnosis of erysipelas

elevated white blood cell count (11,600

was made.

cells/µL). Therefore, unilateral ear erysipelas

The pathogenesis of red ears can be

was diagnosed. After oral amoxicillin for 7 days,

inferred by careful anatomical observation.

the redness on the right ear and the preauricu-

Making the correct diagnosis is importantlar area disappeared.

because the treatment and prognosis vary

When redness of the auricle is present, theaccording to the cause.

main differential diagnoses are erysipelas,
Ramsay-Hunt syndrome, relapsing polychondritis, and chilblain lupus. In order to differentiate
between them, it is necessary to ascertain
whether the redness is unilateral or bilateraland whether blisters or tenderness are present.
In particular, Ramsay-Hunt syndrome can cause
sequelae such as facial paralysis if treatment isdelayed；therefore, it is also necessary to checkfor numbness of the tongue and taste disorders.
If a bacterial infection is suspected as thecause of the auricular redness, erysipelas, which
involves infection of the epidermis that extends
to the superficial dermis layer, can be diagnosed.
Figure 1※ Correspondence to：1-5, Ninomaru, Chuo-ku,
Kumamoto-shi, Kumamoto, 860-0008, Japan
Department of General Medicine,National Hospital Organization Kumamoto Medical Center

JHGM 2022：4-4

199

References
１) Madke B, Nayak C. Eponymous signs in dermatology.
Indian Dermatol Online J. 2012；3：159-65.

Conflict of interest The authors declare that they have noconflicts of interest.

JHGM 2022：4-4

200― Key Image of General Medicine ―Contrast-enhanced ultrasonographic diagnosis
of focal nodular hyperplasia in a 15-year-old boy
Naoya Fujita※

Yosuke Ono

Department of General Medicine, National Defense Medical College

Key Words：focal nodular hyperplasia, contrast-enhanced ultrasonography

A 15-year-old boy with severe intellectual

40 mAU/mL). We initially intended to perform

disability was referred for further investigation

gadolinium ethoxybenzyl diethylenetriamineof a mildly elevated serum gamma-glutamyl

pentaacetic acid (GD-DTPA) -enhanced mag-transferase level (113 U/L). He had no othernetic resonance imaging (MRI) to differentiate

medical history and was not on any medica-

between FNH and fibrolamellar hepatocellulartions. Contrast-enhanced computed tomogra-

carcinoma；however, we performed contrast-

phy showed an 11-cm liver tumor with a centralenhanced ultrasonography (CEUS) instead

stellate scar, which is typical of focal nodular

because the patient could not lie still for1)

hyperplasia (FNH) (Figure 1 ) . The liver

extended periods of time. CEUS did not detecttumor markers detected were alpha-fetoprotein

the spoke-wheel appearance typically observed(2. 0 ng/mL, reference range：＜ 10 ng/mL)

in FNH, although a small arterial signal in theand protein induced by vitamin K absence or

center of the tumor was detected. (Figure 2 ).

antagonist-II (30 mAU/mL, reference range：＜

The tumor was hyperechoic in the arterial

Figure 1 Contrast-enhanced computed tomography of
the abdomen
A large tumor is present in the right liver lobe. The tumor
displays hyperenhancement in the arterial phase and has acentral stellate scar.

※ Correspondence to：3-2 Namiki, Tokorozawa,
Saitama 359-8513, Japan.
Department of General Medicine,National Defense Medical College

Figure 2 Grayscale ultrasonography of the liver
The liver tumor is homogeneous and isoechoic with thenormal liver. The spoke-wheel appearance typicallyobserved in focal nodular hyperplasia is not detected,
although there is a small arterial signal in the center of thetumor.

JHGM 2022：4-4

201

Figure 3 Contrast-enhanced liver ultrasonography in thearterial phase：harmonic and grayscale imaging

Figure 4 Contrast-enhanced liver ultrasonography in the
Kupffer phase：harmonic and grayscale imaging

The tumor is hyperechoic.

The tumor is isoechoic.

phase (Figure 3 ) and isoechoic in the Kupffer

carcinoma is hypoenhancing3). FNH can bephase (Figure 4 ). Based on these findings, FNH

diagnosed with a high probability if the typical

was diagnosed, and follow-up imaging wasenhancement patterns seen on CEUS are

performed. The tumor size had not changed at

detected. CEUS is useful in the diagnosis of FNH

the 2-year follow-up.

when MRI is not available, as in this case.

FNH is the second most common benign
liver tumor after hemangioma1). FNH typicallydevelops in women in their 40s and 50s and is1)

rare in adolescent boys . Although the etiology
of FNH has not yet been established, it ispresumed to be caused by arterial malformations in the liver1). The CEUS findings of FNH
reflect central vascular blood flow. FNH is
hyperenhancing in the arterial phase in ＞ 90%
of cases2). In the Kupffer phase, the perfusion
pattern in FNH is typically hyperechoic or
isoechoic, while fibrolamellar hepatocellular
Conflict of interest The authors declare that they have noconflicts of interest.

References
１) Marrero JA, Ahn J, Rajender Reddy K. American
College of Gastroenterology. ACG clinical guideline：
the diagnosis and management of focal liver lesions.
Am J Gastroenterol 2014；109：1328-47.
２) Piscaglia F, Venturi A, Mancini M, et al. Diagnostic
features of real-time contrast-enhanced ultrasound in
focal nodular hyperplasia of the liver. Ultraschall Med
2010；31：276-82.
３) Dong Y, Wang WP, Mao F, et al. Imaging features offibrolamellar hepatocellular carcinoma with contrastenhanced ultrasound. Ultraschall Med 2021；42：306-13.

JHGM 2022：4-4

202― Key Image of General Medicine ―Fibroma caused by years of carrying
a portable Shinto shrine：Mikoshi-kobu
Yosuke Sasaki※

Tomoyuki Shigeta

Tadashi Maeda

Yoshihisa Urita

Department of General Medicine and Emergency Care, Toho University School of Medicine

Key Words：hump, lipoma, mass, nuchal-type fibroma, palanquin

Manuscript

mobile and painless without any rash or
pigmentations. The size of the mass was 20 cm

A previously healthy 56-year-old man

x 15 cm. His right shoulder was lower than his

visited our hospital with a complaint of dyspnea

left shoulder and the right clavicle was de-on effort. He was diagnosed with an asthma

formed. The patient stated that he had carried

attack because of bilateral expiratory wheeze on

Japanese wooden portable Shinto shrines called

auscultation of the lungs and normal cardiac“mikoshi” for many years in religious festivals,

examinations, electrocardiogram, and chest X-

and that he rested the wooden support beam ofray. He was successfully treated for asthma withthe portable shrine on his right shoulder. Hea bronchodilator, systemic glucocorticoid, andhad noticed that the mass had gradually grown

subsequent corticosteroid inhaler. On examina-

larger over his years of carrying portabletion, we found a soft mass at the nuchal area

shrines. He stated that many of his fellows whoand right shoulder (Figure 1 ). The mass was

carried portable shrines had similar shoulder
masses, and they regarded the masses as“badges of honor” for portable shrine carriers.
There have been some reports on similar
masses, which are known as “mikoshi-kobu” inJapan, from other Asian countries1‑2). Although
the physical findings of the mass resembled
those of a lipoma1), previous reports indicatedthat these masses were composed of thickened
dermal collagenous fibers and interspersed
adipose tissue1‑3), which is compatible with anuchal-type fibroma2‑3). Because “mikoshi”
usually weigh 500-1, 000 kg, repetitive andlong-term pressure and friction to the shoulder

Figure 1

are believed to cause “mikoshi-kobu”1‑2). As thepatient stated that many of his fellows had※ Correspondence to：6-11-1 Omori-Nishi, Ota-ku,
Tokyo 143-8541, Japan
Department of General Medicine and Emergency Care,
Toho University School of Medicine
Omori Hospital

similar masses, it appears that “mikoshi-kobu” isrelatively common in people who carry portableshrines. However, “mikoshi-kobu” is not well

203

JHGM 2022：4-4

known to health care providers, probably
because patients regard the masses as “badgesof honor” and do not seek medical service forthem. Given that “mikoshi-kobu” is usually abenign and asymptomatic mass, it is important
to ask a patient with such a mass if they are in
the habit of carrying heavy loads that cause
chronic pressure to the shoulder and nuchal
area. Such loads may be portable shrines1‑2) orweights lifted during weight training3). This
simple clinical query should be performed
before considering invasive evaluations such as
biopsies when presented with suspicious shoulder masses1‑3).
Conflict of interest The authors declare that they have noconflicts of interest.

References
１) Mitsuhashi K, Hyakusoku H, Fumiiri M. A case of socalled Mikoshi-Kobu. Ann Plas Surg 1990；25：4946.
２) Lee CC, Lai CS, Lin CH, Lin YN, Chu SC, Chai CY et al.
Extra nuchal-type fibroma associated with repetitive
blunt trauma during religious activities. Trauma Case
Rep 2016；4：16-20.
３) Jayaram PR, Walsh J, Lari H, Mohammad N, Mallinson
Pl, Ouellette HA. Repetitive trauma-induced extranuchal-type fibroma. Skeletal Radiol 2022；51：6815.

Journal of Hospital General Medicine
Editor-in-Chief
Jun Hayashi, Fukuoka

Deputy Editor-in-Chief
Yasuharu Tokuda, Okinawa
Shuichi Yamashita, Saga

Associate Editor
Tomohide Adachi, Tokyo

Masaki Tago, Saga

Masanori Ito, Hiroshima

Toshio Naito, Tokyo

Yoshihisa Urita, Tokyo

Shigeki Nabeshima, Fukuoka

Fumio Otsuka, Okayama

Takahiro Maeda, Nagasaki

Hitomi Kataoka, Okayama

Takahide Matsuda, Kanagawa

Keiko Kowase, Gunma

Eishi Miyazaki, Oita

Noboru Saito, Saitama

Hiroyuki Morita, Gifu

Masamichi Sato, Gunma

Masahiro Yasutake, Tokyo

Taro Simizu, Tochigi

Aoi Yoshiiwa, Oita

Mai Suzuki, TokyoJapanese Society Hospital General Medicine
President
Susumu Tazuma, Hiroshima
3-1-1 Maidashi Higashi-ku,
Fukuoka-city, Fukuoka-prefecture 812-8582
Japan
TEL：+ 81-80-7985-8054
e-mailinfo@hgm-japan.com

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