The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage

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The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage

       The Latest Strategy for Keloid and Hypertrophic Scar Prevention and
                     Treatment: The Nippon Medical School (NMS) Protocol

                                          Rei Ogawa, Teruyuki Dohi, Mamiko Tosa,
                                              Masayo Aoki and Satoshi Akaishi

                  Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School Hospital, Tokyo, Japan

         In 2006, we established a scar/keloid-specialized unit in the Department of Plastic, Reconstructive, and
         Aesthetic Surgery at Nippon Medical School (NMS) in Tokyo, Japan. In the ensuing 15 years, we treated
         approximately 2,000 new scar/keloid patients annually. This extensive experience has greatly improved
         the efficacy of the treatments we offer. Therefore, we discuss here the latest NMS protocol for prevent-
         ing and treating keloids and hypertrophic scars. While this protocol was optimized for Japanese pa-
         tients, our experience with a growing body of non-Japanese patients suggests that it is also effective in
         other ethnicities. The extensive evidence-based experience underlying the NMS protocol suggests that it
         may be suitable as the foundation of a standard international prevention/treatment algorithm for
         pathological scars. (J Nippon Med Sch 2021; 88: 2―9)

         Key words: keloid, hypertrophic scar, wound

                          Introduction                                    tation, including trauma, burn, surgery, vaccination, skin
In 2006, we established a scar/keloid-specialized unit in                 piercing, acne, and herpes zoster. In general, the scars
the Department of Plastic, Reconstructive, and Aesthetic                  that spontaneously lose this dermal inflammation over
Surgery at Nippon Medical School (NMS) in Tokyo, Ja-                      time are defined as HSs, whereas the scars with enduring
pan. In the following 15 years, we treated approximately                  inflammation are defined as keloids. This difference in
2,000 new scar/keloid patients annually. This vast experi-                inflammation durability explains the disparate growth
ence has greatly improved the efficacy of the treatments                  habits of HSs and keloids. Thus, the temporary, waning
we offer. Therefore, we discuss here the latest NMS algo-                 inflammation in HSs means that they do not grow over
rithm for preventing and treating keloids and hy-                         the borders of the original wound. By contrast, the con-
pertrophic scars (HSs). While this algorithm has been op-                 tinuous, escalating inflammation of keloids causes them
timized for Japanese patients, our experiences with a                     to grow into the adjacent normal skin.
growing body of international patients suggest that it is                   In terms of histopathology, the inflammation and the
also effective in other ethnicities and could therefore                   resulting accumulation of extracellular matrix causes der-
serve as the starting point in the development of an in-                  mal nodules and thick eosinophilic (hyalinizing) collagen
ternational prevention/treatment algorithm.                               bundles called “keloidal collagen” to form over time2. If
                                                                          the dermal nodule is the main histological finding, it is
           Pathomechanisms of Keloids/HSs                                 diagnosed as an HS. This suggests that keloids/HSs are
To effectively prevent and treat keloids/HSs, it is neces-                manifestations of the same inflammatory fibroprolifera-
sary to understand the pathomechanisms that drive their                   tive condition and simply differ in the intensity and du-
formation and progression. The abnormal growth of                         ration of inflammation.
these scars is powered by chronic inflammation in the re-                   Multiple lines of evidence suggest that the intensity/
ticular dermis that is triggered by dermal injury or irri-                duration of dermal inflammation in keloids/HSs is dic-

  Correspondence to Rei Ogawa, MD, PhD, FACS, Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical
  School, 1―1―5 Sendagi, Bunkyo-ku, Tokyo 113―8603, Japan
  Journal Website (

  2                                                                                                      J Nippon Med Sch 2021; 88 (1)
The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
Keloid & Hypertrophic Scar NMA Protocol

tated by genetic, systemic, local, and lifestyle risk fac-                   lized by placing bandages or garments over the dressing.
tors1. Genetic causes include single nucleotide polymor-                        In normal wound healing, once epithelialization is
phisms            and genetic diseases such as Rubinstein-Taybi              completed, the inflammation in the dermis/dermal-like
syndrome . There are probably many other, as yet un-                         granulation tissues under the epidermis starts to subside
identified, genetic factors. Systemic factors include preg-                  spontaneously and the dermal tissues begin maturing.
        7                       8
nancy , hypertension , high circulating concentrations of                    However, if strong/repetitive mechanical forces are ex-
inflammatory cytokines9, and possibly female sex10.                          erted on the immature scar, they can prolong the inflam-
  The key local risk factor is mechanical force on the                       mation, thereby fomenting pathological scarring. One of
wound/scar: considerable evidence shows that this                            the keys to preventing such scarring is to understand
strongly           influences       inflammation-driven       pathological   that the healing rates of the epidermis and dermis differ
             11―13                                             13
scarring           . Indeed, our finite-element analysis suggests            completely. In the case of sutured wounds, the epidermis
that keloid shape is largely determined by the direction                     can regenerate within 7-10 days, leading both the patient
of the tension on the skin around the wound/scar site.                       and the physician to believe that the wound has healed
We also showed that keloids are particularly prevalent                       completely. In fact, it can take 3 months before the der-
on body regions with strong skin-stretching force due to                     mis regains 90% of its normal strength14. This lengthy
body movements, such as the joints, anterior neck, chest                     vulnerability   to      inflammation-triggering   mechanical
wall, scapula/upper-arm, and suprapubic region. Re-                          forces means that it is essential to provide the immature
peated dermal injury and infection is also a local risk fac-                 scar with protracted external mechanical support (i.e. scar
tor.                                                                         stabilization) until maturity has been attained (i.e. the
  Lifestyle risk factors include strong/continuous body                      scar becomes soft, pliable, and flat).
movements (e.g. those of athletes/manual workers) that                          Therefore, all immature scars should be fixed continu-
stretch the wounds/scars. Other factors are excessive                        ously with tape. Silicone tape is the best choice. The tape
consumption of hot/spicy foods and alcohol and over-                         is retained until it detaches naturally. Alternatively,
long bathing in hot water, which may augment wound/                          silicone-gel sheets or cheaper paper tapes can be used on
scar inflammation. Obesity may also be a risk factor.                        a case-by-case basis.
                                                                                When an individual is at high risk of keloid formation
                        Prevention of Keloids/HSs                            and/or the scars are located on keloid-prone regions,
Because traumatic, surgical, and burn wounds and                             scar stabilization should be prolonged for at least 6-12
wounds caused by infectious agents, can turn into patho-                     months after maturation. It should also be combined
logical scars, it is important to assess the pathological                    with first steroid ointment and then tape/plaster admini-
scarring risk of patients with such wounds. If the patient                   stration. In Japan, two types of steroid tapes are avail-
or his/her family has a history of keloid and/or the                         able15: the strong deprodone-propionate plaster (EclarⓇ
wound is on a high-risk zone, the patient should be con-                     plaster; Hisamitsu Pharmaceutical Co., Inc., Tokyo, Ja-
sidered to be high risk and treated appropriately, as de-                    pan) should be used for adults while the weak fludroxy-
scribed below.                                                               cortide tape (DrenisonⓇ tape; Teikoku Seiyaku Co., Inc.,
  Trauma and Burn Wounds with a Raw Surface                                  Kagawa, Japan) is suitable for children. The steroid oint-
  In general, the longer wounds take to epithelialize, the                   ment should be applied for the first 2-3 weeks after epi-
greater the risk that keloids/HSs develop. Therefore,                        thelialization because the epidermis is still immature (full
trauma/burn wounds should undergo primary suturing                           epithelialization takes 4 weeks) and could be injured by
or skin grafting/flap transfer as soon as possible. How-                     daily steroid tape/plaster changes. Once steroid tape/
ever, if surgery cannot be planned, the raw surface must                     plaster replaces the ointment, it is continued until the
be encouraged to epithelialize rapidly by applying con-                      scar is soft and flat. Scar redness should be ignored: con-
servative therapies that limit infection and inflammation                    tinuing steroid tape/plaster just because of redness ele-
and accelerate granulation-tissue formation. These thera-                    vates the risk of telangiectasia because the steroid thins
pies, which should be applied on a case-by-case basis, in-                   the structures supporting the blood vessels. Once steroid
clude negative-pressure wound therapy, appropriate                           tape/plaster is discontinued, a non-steroidal ointment/
wound dressing materials, topical drugs (e.g. basic fibro-                   cream such as heparinoid ointment/lotion/spray (Hiru-
blast       growth       factor      spray),   antibiotics,    and   anti-   doidⓇ; Maruho Co., Inc., Osaka, Japan) or an NSAID
inflammatory agents. The wound should also be stabi-                         ointment/cream (Ibuprofen piconol: StadermⓇ; Torii

  J Nippon Med Sch 2021; 88 (1)                                                                                                       3
The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
R. Ogawa, et al

Pharmaceutical Co., Ltd., Tokyo, Japan) should be ap-                           Treatment of Hypertrophic Scars and Keloids
plied to keep scar surface moist and inhibit inflamma-                    Diagnosis of Keloid/HS Risk
tion.                                                                     The Japan Scar Workshop (JSW) scar scale (JSS)16 helps
  In the case of low-risk individuals and/or wounded                    to differentially diagnose HS/keloid-like lesions. It also
regions (e.g. the face, lower leg), wound stabilization is              has indicators that suggest the scar may be or become in-
sufficient to prevent pathological scarring.                            tractable:
  Primarily Closed Wounds                                                 1. The patient has multiple keloid/HS-like lesions on
  Sutured wounds should be cleaned daily with tap                       the body
water/saline or disinfectant and covered with non-                        2. The keloid/HS-like lesion is large, even if it is soli-
adhesive materials until the sutures can be removed. This               tary
prevents infections and wound stretching, thereby block-                  3. Age at pathological-scar onset is
The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
Keloid & Hypertrophic Scar NMA Protocol

                 a                                                b
                 Fig. 1   The left scapular keloid of a woman in her 30s was treated by deprodone-propionate
                          (a) Pretreatment.
                          (b) Twenty-four months after starting treatment.
                          The tape was placed on the keloid 24 hours a day and changed daily. After 24 months,
                          the inflammation had completely resolved and the subjective and objective symptoms

                 a                                                b
                 Fig. 2   The right shoulder keloid of a woman in her 50s was treated by triamcinolone acetonide
                          steroid injections.
                          (a) Pretreatment.
                          (b) Twenty-four months after starting treatment.
                          The keloid underwent steroid injection (5 mg triamcinolone diluted with 1.5 mL xylo-
                          caine 1% with epinephrine) every 2–3 months. After 24 months, the subjective and objec-
                          tive symptoms improved.

  Steroid Injection                                                   ciently throughout the tissue. The consequent local pres-
  Triamcinolone acetonide is a powerful tool because it               sure may also cause pain. Rather, the target should be
rapidly reduces inflammation (Fig. 2). Each injection                 the scar border where it meets the normal skin: the nee-
should comprise 5-10 mg mixed with a local anesthetic                 dle should penetrate either shallowly to target the heav-
such as xylocaine 1% with epinephrine . Women may ex-                 ily inflamed leading edge of the scar or deeply towards
perience fewer menstrual irregularities if the dose does              the center (the scar tissue along this deep plane is softer
not exceed 5 mg. We use thin needles such as 30 G and                 than the upper central core). Once one or more injections
27 G along with syringes with locks. The initial target of            have softened the scar, the needle can be injected straight
the injection should not be the center of the mass: its               into the core. Smaller keloids/HSs can improve markedly
hardness means the injection fluid will not disperse suffi-           after just 1-2 injections. If these improvements can be

  J Nippon Med Sch 2021; 88 (1)                                                                                              5
The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
R. Ogawa, et al

  a                         b                         c                         d                         e
           Fig. 3 The left upper-arm keloid of a woman in her 30s was treated by z-plasty and postoperative radiotherapy.
 (a) Before surgery.
 (b) After keloid excision.
 (c) Z-plasty design.
 (d) Immediately after surgery.
 (e) Two years after surgery.
 The keloid developed from BCG vaccination. It was excised, tension was released by fascial sutures, and z-plasties were performed.
 Postoperative radiotherapy (18 Gy/3 fr/3days) was then conducted. No recurrence was observed 2 years after surgery.

continued/maintained with steroid tape/plaster, further              skin grafts, which often form pathological scars around
injections are unnecessary. If patients are afraid of                the graft. Compared to island flaps, skin-pedicled flaps
injection-induced pain, we recommend steroid tape/plas-              are superior because they extend more postsurgically and
ter until the scar has softened. Injections can then be              therefore release contractures more effectively19. Flap sur-
added because the risk of pain is much reduced.                      gery is especially suitable for severe keloids; however,
  Surgery                                                            multimodal therapy should be applied to both the exci-
  Surgical monotherapy associates with an atrocious rate             sion and donor sites to prevent recurrent and new le-
of keloid/HS recurrence. Therefore, surgical techniques              sions from forming.
that abrogate dermal tension, namely, subcutaneous/fas-                 Radiation
cial tensile-reduction sutures, z-plasties, and local flap              Post-excision keloid/HS recurrence can be effectively
transfer17,18, should be used in combination with postop-            controlled by adjuvant radiation. Radiation protocols are
erative radiation (described below) and steroid tape/                constantly improving. In the past, orthovoltage or super-
plaster.                                                             ficial or soft X-rays were used. However, the safety and
  Placing sutures on the superficial/deep fascia below               efficacy of radiotherapy protocols have improved mark-
the dermis causes the wound edges to juxtapose natu-                 edly recently; therefore, we now routinely use postopera-
rally. This allows dermal sutures to be placed with very             tive electron-beam irradiation after keloid/HS resection.
little tension, after which superficial sutures can be               This, when combined with the surgical and steroid tape/
added. It is essential to realize that without the deep su-          plaster modalities described above, markedly reduces the
tures, dermal sutures not only fail to reduce the dermal             recurrence rate: the keloid-recurrence rate after surgery is
tension, they may in fact exacerbate it.                             now less than 10% in our hospital18. Moreover, 15 years
  Zig-zag sutures, including z-plasties, are good for re-            of close monitoring and long-term follow-up has shown
leasing linear scar contractures and tension (Fig. 3). An-           that this protocol has no major side effects (Fig. 3, 4)18.
other advantage is that segmented scars mature faster                   Another, increasingly popular, radiation modality for
than long linear scars. Zig-zag incision/suturing is par-            keloids is high-dose rate-superficial brachytherapy. De-
ticularly indicated if scars cross a joint.                          pending on the shape of the surgical scar, an applicator
  Local flaps are also useful for releasing scar contrac-            can be used to ensure the evenness and localization of
tures (Fig. 4): they expand naturally after surgery and are          the radiation to the wound surface. However, we prefer
therefore not prone to postsurgical contractures, unlike             electron beams because they reach the reticular dermis

  6                                                                                                J Nippon Med Sch 2021; 88 (1)
The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
Keloid & Hypertrophic Scar NMA Protocol

  a                                b                                c                                  d
 Fig. 4   The chest and abdominal keloids of a man in his 70s were treated by flap surgery, z-plasties, and postoperative radiothera-
          (a) Before surgery.
          (b) Intraoperative view of the first operation, during which the chest keloid was excised and reconstructed with a flap.
          (c) Intraoperative view of the second operation, during which the abdominal keloid was removed and closed with z-plas-
          (d) Two years after the second operation.
          The keloids were removed in two operations. The donor and recipient sites were irradiated. The post-treatment course was
          uneventful. After 2 years, recurrence was not observed and the remaining pathological scars had matured.

                   a                                                b
                       Fig. 5 The chest-wall keloid of a woman in her 70s was treated by radiation monotherapy.
                   (a) Before treatment.
                   (b) Eighteen months after treatment.
                   This mild chest-wall keloid was treated by high-dose rate-superficial brachytherapy (25 Gy/5
                   fr/5days). The inflammation resolved completely. Six months later, the subjective and objective
                   symptoms improved dramatically. Eighteen months later, the pathological scars matured.

more selectively; moreover, the beam attenuates after                   higher than the postoperative radiation doses, the radia-
passing through the skin and thus has little effect on the              tion should be delivered carefully to avoid secondary ra-
internal organs.                                                        diation carcinogenesis. It is also essential to secure in-
  To further improve the safety of our adjuvant radio-                  formed consent. However, the risks of primary radiother-
therapy protocol, we optimized them in 2013 such that                   apy should be measured against its immense benefits: it
fewer fractions are now used18. As a result, high-                      rapidly decreases subjective symptoms such as pain and
recurrence keloid-excision sites are now treated with 18                itch and, over the following year, progressively normal-
Gy/3 fr/3days while low-recurrence sites (e.g. earlobe)                 izes scar color and thickness.
and other body sites are now treated with 8 Gy/1 fr/1                     Laser Therapy
day and 15 Gy/2 fr/2days, respectively.                                   In our institution, a 1,064-nm long-pulsed Nd:YAG la-
  We also occasionally employ radiation monotherapy to                  ser is used for flattish keloids/HSs that have low levels
treat older patients or patients with huge keloids (Fig.                of inflammation20,21. It is mainly used to decrease the red-
5)1. However, since the total radiation dose needed is                  ness/telangiectacia   caused       by   steroid   therapy.   Flat

  J Nippon Med Sch 2021; 88 (1)                                                                                                      7
The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
R. Ogawa, et al

keloids/HSs are particularly suitable for laser therapy           Conflict of Interest: The authors declare no conflicts of inter-
because the laser beam can reach the blood vessels in the         est.
  Once scar inflammation has been completely quelled                                        References
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The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol - J-Stage
Keloid & Hypertrophic Scar NMA Protocol

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                                                                   this article. The Medical Association of Nippon Medical School re-
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                                                                   mains the copyright holder of all articles. Anyone may download,
21.Tsai CH, Kao HK, Akaishi S, An-Jou Lin J, Ogawa R.              reuse, copy, reprint, or distribute articles for non-profit purposes
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   treatment time of hypertrophic scars: An analysis of 40
   cases of cesarean-section scars. Dermatol Surg. 2019 Nov

  J Nippon Med Sch 2021; 88 (1)                                                                                                      9
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